Ranjana Advani

All Publications

• Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma BLOOD LaCasce, A. S., Bociek, R., Sawas, A., Caimi, P., Agura, E., Matous, J., Ansell, S. M., Crosswell, H. E., Islas-Ohlmayer, M., Behler, C., Cheung, E., Forero-Torres, A., Vose, J., O'Connor, O. A., Josephson, N., Wang, Y., Advani, R. 2018; 132 (1): 40–48

  Abstract

  Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m2) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.

  View details for DOI 10.1182/blood-2017-11-815183

  View details for Web of Science ID 000439126500010

  View details for PubMedID 29703778

• The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project HAEMATOLOGICA Bellei, M., Foss, F. M., Shustov, A. R., Horwitz, S. M., Marcheselli, L., Kim, W., Cabrera, M. E., Dlouhy, I., Nagler, A., Advani, R. H., Pesce, E. A., Ko, Y., Martinez, V., Montoto, S., Chiattone, C., Moskowitz, A., Spina, M., Biasoli, I., Manni, M., Federico, M., Int T-cell Project Network 2018; 103 (7): 1191–97

  Abstract

  This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (P<0.001). Patients receiving or not salvage bone marrow transplantation had a 3-year survival of 48% and 18%, respectively (P<0.001). In a univariate Cox regression analysis, refractory disease was associated with a higher risk of death (HR=1.43, P=0.001), whereas late relapse (>12 months, HR 0.57, P=0.001) and salvage therapy with transplantation (HR=0.36, P<0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation.

  View details for DOI 10.3324/haematol.2017.186577

  View details for Web of Science ID 000437806000028

  View details for PubMedID 29599200

  View details for PubMedCentralID PMC6029527

• Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network BRITISH JOURNAL OF HAEMATOLOGY Federico, M., Bellei, M., Marcheselli, L., Schwartz, M., Manni, M., Tarantino, V., Pileri, S., Ko, Y., Cabrera, M. E., Horwitz, S., Kim, W. S., Shustov, A., Foss, F. M., Nagler, A., Carson, K., Pinter-Brown, L. C., Montoto, S., Spina, M., Feldman, T. A., Lechowicz, M. J., Smith, S. M., Lansigan, F., Gabus, R., Vose, J. M., Advani, R. H., T Cell Project Network 2018; 181 (6): 760–69

  Abstract

  Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL-NOS were retained for study. At a median follow-up of 46 months, the median overall survival (OS) and progression-free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1-2), and high risk (HiR, 74 patients, 24%, score 3-4), having a 3-year OS of 76% [95% confidence interval 61-88], 43% [35-51], and 11% [4-21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.

  View details for DOI 10.1111/bjh.15258

  View details for Web of Science ID 000435268600007

  View details for PubMedID 29672827

• Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma BLOOD Herrera, A. F., Moskowitz, A. J., Bartlett, N. L., Vose, J. M., Ramchandren, R., Feldman, T. A., LaCasce, A. S., Ansell, S. M., Moskowitz, C. H., Fenton, K., Ogden, C., Taft, D., Zhang, Q., Kato, K., Campbell, M., Advani, R. H. 2018; 131 (11): 1183–94

  Abstract

  In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo) administered in combination were evaluated as initial salvage therapy in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Patients received up to 4 cycles of combination treatment, with BV administered on day 1 and Nivo on day 8 of the first cycle. For cycles 2 to 4, BV and Nivo were both administered on day 1. After study treatment, responses were evaluated by investigators per the 2014 Lugano classification, and patients could proceed to autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled; the complete response rate among all treated patients (n = 61) was 61%, with an objective response rate of 82%. Before ASCT, adverse events (AEs) occurred in 98% of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least 1 infusion of BV. Five patients (8%) were treated with systemic steroids for immune-related AEs. A reduction of peripheral T-cell subsets including regulatory T cells was observed after the first dose of BV, and reduced serum levels of thymus- and activation-regulated chemokine concurrent with an increase in proinflammatory cytokines and chemokines were seen after the first BV plus Nivo infusions. The combination of BV plus Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

  View details for DOI 10.1182/blood-2017-10-811224

  View details for Web of Science ID 000430687500007

  View details for PubMedID 29229594

  View details for PubMedCentralID PMC5855021

• Allogeneic transplantation using TLI-ATG conditioning for Hodgkin lymphoma after failure of autologous transplantation. Blood advances Spinner, M. A., Advani, R. H., Hoppe, R. T., Lowsky, R., Muffly, L. S. 2018; 2 (13): 1547–50

  View details for DOI 10.1182/bloodadvances.2018021071

  View details for PubMedID 29970391

• PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. Journal of clinical oncology Roemer, M. G., Advani, R. H., Ligon, A. H., Natkunam, Y., Redd, R. A., Homer, H., Connelly, C. F., Sun, H. H., Daadi, S. E., Freeman, G. J., Armand, P., Chapuy, B., De Jong, D., Hoppe, R. T., Neuberg, D. S., Rodig, S. J., Shipp, M. A. 2016; 34 (23): 2690-2697

  Abstract

  Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined.We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations-polysomy, copy gain, and amplification-were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage [AS] III/IV) and progression-free survival (PFS).Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL.PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.

  View details for DOI 10.1200/JCO.2016.66.4482

  View details for PubMedID 27069084

• A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis LANCET ONCOLOGY Kim, S. J., Yoon, D. H., Jaccard, A., Chng, W. J., Lim, S. T., Hong, H., Park, Y., Chang, K. M., Maeda, Y., Ishida, F., Shin, D., Kim, J. S., Jeong, S. H., Yang, D., Jo, J., Lee, G., Choi, C. W., Lee, W., Chen, T., Kim, K., Jung, S., Murayama, T., Oki, Y., Advani, R., d'Amore, F., Schmitz, N., Suh, C., Suzuki, R., Kwong, Y. L., Lin, T., Kim, W. S. 2016; 17 (3): 389-400

  Abstract

  The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted.We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort.We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group.PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy.Samsung Biomedical Research Institute.

  View details for DOI 10.1016/S1470-2045(15)00533-1

  View details for Web of Science ID 000371234900051

  View details for PubMedID 26873565

• A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. British journal of haematology Advani, R. H., Ansell, S. M., Lechowicz, M. J., Beaven, A. W., Loberiza, F., Carson, K. R., Evens, A. M., Foss, F., Horwitz, S., Pro, B., Pinter-Brown, L. C., Smith, S. M., Shustov, A. R., Savage, K. J., M Vose, J. 2016; 172 (4): 535-544

  Abstract

  Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survial, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.

  View details for DOI 10.1111/bjh.13855

  View details for PubMedID 26627450

• Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era BRITISH JOURNAL OF HAEMATOLOGY Diefenbach, C. S., Li, H., Hong, F., Gordon, L. I., Fisher, R. I., Bartlett, N. L., Crump, M., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Stewart, D. A., Kahl, B. S., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J. M., Hoppe, R. T., Horning, S. J., Advani, R. H. 2015; 171 (4): 530-538

  Abstract

  The International Prognostic Score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P < 0·0001)]. IPS-3 outperformed the IPS-7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS-7 low risk patients were re-classified as intermediate risk and 13% of IPS-7 intermediate risk patients as low risk. For patients with advanced HL, the IPS-3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.

  View details for DOI 10.1111/bjh.13634

  View details for Web of Science ID 000363947300012

  View details for PubMedID 26343802

  View details for PubMedCentralID PMC4881845

• Hodgkin Lymphoma: the Changing Role of Radiation Therapy in Early-Stage Disease—the Role of Functional Imaging. Current treatment options in oncology Iberri, D. J., Hoppe, R. T., Advani, R. H. 2015; 16 (9): 45-?

  Abstract

  Early-stage classical Hodgkin lymphoma (CHL) is a highly curable malignancy. Historically, extended-field radiotherapy (EFRT) alone showed excellent cure rates, but the risk of radiotherapy (RT)-associated toxicities led to combined modality therapy (CMT) replacing RT alone. RT has subsequently evolved further with significant reductions of dose and field size, and is currently restricted to involved sites only (ISRT). Contemporary CMT yields cure rates in excess of 85 %, and most studies do not have adequate follow-up required to evaluate the risk reduction in late effects. In an effort to avoid RT altogether, response-adapted treatment approaches utilizing results of interim [(18)F]fluorodeoxyglucose (FDG) positron emission tomography with fused computed tomography (PET/CT) imaging have been studied. Results from two studies in favorable-risk (UK RAPID and EORTC H10F) and one in unfavorable-risk patients (EORTC H10U) suggest that omission of RT in patients with a negative interim PET/CT response (Deauville score ≤2) yields slightly inferior progression-free survival (PFS) compared to conventional CMT, but with no difference in overall survival (OS) albeit with short-term follow-up. In order to extrapolate results to daily practice, it is critical to understand the selection of patients entered on trials since definitions of favorable and unfavorable disease vary between study groups. Currently, CMT continues to be the standard of care for the vast majority of patients with early-stage CHL and RT is an integral part of therapy in patients with bulky disease. However, for selected patients with favorable characteristics, emerging data suggest that a chemotherapy-alone approach is reasonable.

  View details for DOI 10.1007/s11864-015-0360-6

  View details for PubMedID 26187795

• Response-adapted therapy for aggressive non-Hodgkin's lymphomas based on early [18F] FDG-PET scanning: ECOG-ACRIN Cancer Research Group study (E3404) BRITISH JOURNAL OF HAEMATOLOGY Swinnen, L. J., Li, H., Quon, A., Gascoyne, R., Hong, F., Ranheim, E. A., Habermann, T. M., Kahl, B. S., Horning, S. J., Advani, R. H. 2015; 170 (1): 56-65

  Abstract

  A persistently positive positron emission tomography (PET) scan during therapy for diffuse large B-cell lymphoma (DLBCL) is predictive of treatment failure. A response-adapted strategy consisting of an early treatment change to four cycles of R-ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET-positive patients received four cycles of R-ICE, PET-negative patients received two more cycles of R-CHOP. A ≥45% 2-year progression-free survival (PFS) for mid-treatment PET-positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two-year PFS was 70%; 42% [90% confidence interval (CI), 19-63%] for PET-positives and 76% (90% CI 65-84%) for PET-negatives. Three-year overall survival (OS) was 69% (90% CI 43-85%) and 93% (90% CI 86-97%) for PET-positive and -negative cases, respectively. The 2-year PFS for mid-treatment PET-positive patients intensified to R-ICE was 42%, with a wide confidence interval due to the low proportion of positive mid-treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.

  View details for DOI 10.1111/bjh.13389

  View details for Web of Science ID 000356716500009

  View details for PubMedID 25823885

• Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial. Journal of clinical oncology Advani, R. H., Hong, F., Fisher, R. I., Bartlett, N. L., Robinson, K. S., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Stewart, D. A., Gordon, L. I., Kahl, B. S., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J. M., Hoppe, R. T., Horning, S. J. 2015; 33 (17): 1936-1942

  Abstract

  The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL).Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS).Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm.For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.

  View details for DOI 10.1200/JCO.2014.57.8138

  View details for PubMedID 25897153

• Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial JOURNAL OF CLINICAL ONCOLOGY Advani, R. H., Hong, F., Fisher, R. I., Bartlett, N. L., Robinson, K. S., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Stewart, D. A., Gordon, L. I., Kahl, B. S., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J. M., Hoppe, R. T., Horning, S. J. 2015; 33 (17): 1936-U111

  Abstract

  The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL).Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS).Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm.For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.

  View details for DOI 10.1200/JCO.2014.57.8138

  View details for Web of Science ID 000355999800014

  View details for PubMedID 25897153

  View details for PubMedCentralID PMC4451176

• Ibrutinib in Previously Treated Waldenstrom's Macroglobulinemia NEW ENGLAND JOURNAL OF MEDICINE Treon, S. P., Tripsas, C. K., Meid, K., Warren, D., Varma, G., Green, R., Argyropoulos, K. V., Yang, G., Cao, Y., Xu, L., Patterson, C. J., Rodig, S., Zehnder, J. L., Aster, J. C., Harris, N. L., Kanan, S., Ghobrial, I., Castillo, J. J., Laubach, J. P., Hunter, Z. R., Salman, Z., Li, J., Cheng, M., Clow, F., Graef, T., Palomba, M. L., Advani, R. H. 2015; 372 (15): 1430-1440

  Abstract

  MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib.We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects.After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%).Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).

  View details for DOI 10.1056/NEJMoa1501548

  View details for Web of Science ID 000352417900007

  View details for PubMedID 25853747

• Bevacizumab and cyclosphosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology Group study (E2404). Leukemia & lymphoma Ganjoo, K., Hong, F., Horning, S. J., Gascoyne, R. D., Natkunam, Y., Swinnen, L. J., Habermann, T. M., Kahl, B. S., Advani, R. H. 2014; 55 (4): 768-772

  Abstract

  Peripheral T-cell lymphoma (PTCL) and natural killer (NK) cell lymphoma have poor survival with conventional cytotoxic chemotherapy. Because angiogenesis plays an important role in the biology of PTCL, a fully humanized anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab (A), was studied in combination with standard cyclosphosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy (ACHOP) to evaluate its potential to improve outcome in these patients. Patients were treated with 6-8 cycles of ACHOP followed by eight doses of maintenance A (15 mg/kg every 21 days). Forty-six patients were enrolled on this phase 2 study from July 2006 through March 2009. Forty-four patients were evaluable for toxicity and 39 were evaluable for response, progression and survival. A total of 324 cycles (range: 2-16, median 7) were administered to 39 evaluable patients and only nine completed all planned treatment. The overall response rate was 90% with 19 (49%) complete response/complete response unconfirmed (CR/CRu) and 16 (41%) a partial response (PR). The 1-year progression-free survival (PFS) rate was 44% at a median follow-up of 3 years. The median PFS and overall survival (OS) rates were 7.7 and 22 months, respectively. Twenty-three patients died (21 from lymphoma, two while in remission). Grade 3 or 4 toxicities included febrile neutropenia (n = 8), anemia (n = 3), thrombocytopenia (n = 5), congestive heart failure (n = 4), venous thrombosis (n = 3), gastrointestinal hemorrhage/perforation (n = 2), infection (n = 8) and fatigue (n = 6). Despite a high overall response rate, the ACHOP regimen failed to result in durable remissions and was associated with significant toxicities. Studies of novel therapeutics are needed for this patient population, whose clinical outcome remains poor.

  View details for DOI 10.3109/10428194.2013.816700

  View details for PubMedID 23786456

• Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. Journal of clinical oncology Advani, R. H., Horning, S. J., Hoppe, R. T., Daadi, S., Allen, J., Natkunam, Y., Bartlett, N. L. 2014; 32 (9): 912-918

  Abstract

  Universal expression of CD20 by malignant cells in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) led us to evaluate rituximab (R) as a therapeutic option.Patients with previously treated or newly diagnosed NLPHL were treated with R (375 mg/m(2) once per week for 4 weeks) or, after a protocol amendment, with R plus R maintenance (MR; administered once every 6 months for 2 years). Primary and secondary outcome measures were progression-free survival (PFS) and overall response rate (ORR), respectively.A total of 39 patients were enrolled (R, n = 23; R + MR, n = 16). After four once-per-week treatments, ORR was 100% (complete response, 67%; partial response, 33%). At median follow-ups of 9.8 years for R and 5 years for R + MR, median PFS were 3 and 5.6 years (P = .26), respectively; median overall survival (OS) was not reached. Estimated 5-year PFS and OS for patients treated with R versus R + MR were 39.1% (95% CI, 23.5 to 65.1) and 95.7% (95% CI, 87.7 to 100) versus 58.9% (95% CI, 38.0 to 91.2) and 85.7% (95% CI, 69.2 to 100), respectively. Nine of 23 patients experiencing relapse had evidence of transformation to aggressive B-cell lymphoma; six of these patients had infradiaphragmatic involvement at study entry.R is an active agent in NLPHL. Although responses are not durable in most patients, a significant minority experience remissions lasting > 5 years. R + MR results in a nonsignificant increase in PFS compared with R. R may be considered in the relapsed setting for NLPHL. The potential for transformation of NLPHL to aggressive B-cell lymphoma underscores the importance of rebiopsy and long-term follow-up.

  View details for DOI 10.1200/JCO.2013.53.2069

  View details for PubMedID 24516013

• Mature Results of a Phase II Study of Rituximab Therapy for Nodular Lymphocyte-Predominant Hodgkin Lymphoma. Journal of clinical oncology Advani, R. H., Horning, S. J., Hoppe, R. T., Daadi, S., Allen, J., Natkunam, Y., Bartlett, N. L. 2014; 32 (9): 912-918

  View details for DOI 10.1200/JCO.2013.53.2069

  View details for PubMedID 24516013

• Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood Chang, J. E., Li, H., Smith, M. R., Gascoyne, R. D., Paietta, E. M., Yang, D. T., Advani, R. H., Horning, S. J., Kahl, B. S. 2014; 123 (11): 1665-1673

  Abstract

  Rituximab, bortezomib, modified hyper-cyclophosphamide, doxorubicin, vincristine, dexamethasone (VcR-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) were evaluated for efficacy and safety in Eastern Cooperative Oncology Group protocol E1405. Patients with previously untreated mantle cell lymphoma received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant-eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary end points were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n = 44) vs ASCT (n = 22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in mantle cell lymphoma. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials comparing MR against ASCT should be considered and randomized clinical trials evaluating bortezomib's contribution to conventional therapy are under way. This study was registered at www.clinicaltrials.gov as #NCT00433537.

  View details for DOI 10.1182/blood-2013-08-523845

  View details for PubMedID 24458437

  View details for PubMedCentralID PMC3954048

• How I treat nodular lymphocyte predominant Hodgkin lymphoma BLOOD Advani, R. H., Hoppe, R. T. 2013; 122 (26): 4182-4188

  Abstract

  Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon entity that, in contrast to classical Hodgkin lymphoma (cHL), universally expresses CD20, a hallmark of the disease. The majority of the patients present with early-stage disease, and treatment with local radiation provides excellent disease control and overall survival (OS). For locally extensive or advanced stages, paradigms used for cHL have been employed, with similar outcomes. Unlike cHL, late relapses may occur, as well as a propensity to transform to an aggressive B-cell non-Hodgkin lymphoma that underscores the importance of long-term follow-up and rebiopsy at the time of relapse. Deaths caused by NLPHL are uncommon, and in older series, secondary malignancies and other treatment-related toxicities contributed appreciably to overall mortality. Expression of CD20 in NLPHL has led to the evaluation of rituximab as a therapeutic option. Although results with single-agent rituximab in the front-line setting are inferior to conventional therapy, rituximab is a reasonable choice for relapsed disease because of the high overall response rate and excellent tolerability. Most patients have a long OS; therefore, overall goals of therapy should be to minimize the risk for relapse and long-term toxicity.

  View details for DOI 10.1182/blood-2013-07-453241

  View details for Web of Science ID 000329741000012

  View details for PubMedID 24215035

• Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood Tan, D., Horning, S. J., Hoppe, R. T., Levy, R., Rosenberg, S. A., Sigal, B. M., Warnke, R. A., Natkunam, Y., Han, S. S., Yuen, A., Plevritis, S. K., Advani, R. H. 2013; 122 (6): 981-987

  Abstract

  Recent studies report an improvement in overall survival (OS) of patients with follicular lymphoma (FL). Previously untreated patients with grade 1-2 FL referred from 1960-2003 and treated at Stanford were identified. Four eras were considered: era 1, pre-anthracycline (1960-1975, n=180); era 2, anthracycline (1976-1986, n=426), era 3, aggressive chemotherapy/purine analogs (1987-1996, n=471) and era 4, rituximab (1997-2003, n=257). Clinical characteristics, patterns of care and survival outcomes were assessed. Observed OS was compared with the expected OS calculated from Berkeley Mortality Database life tables derived from population matched by gender and age at time of diagnosis. The median OS was 13.6 years. Age, gender and stage did not differ across the eras. Although primary treatment varied, event free survival after the first treatment did not differ between eras (p=0.17). Median OS improved from approximately 11 years in eras 1 and 2 to 18.4 years in era 3 and has not yet been reached for era 4 (p<0.001) with no suggestion of a plateau in any era. These improvements in OS exceeded improvements in survival in the general population during the same time period. Several factors, including better supportive care and effective therapies for relapsed disease, are likely responsible for this improvement.

  View details for DOI 10.1182/blood-2013-03-491514

  View details for PubMedID 23777769

• Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma NEW ENGLAND JOURNAL OF MEDICINE Wang, M. L., Rule, S., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., Williams, M. E., Barrientos, J. C., Chmielowska, E., Radford, J., Stilgenbauer, S., Dreyling, M., Jedrzejczak, W. W., Johnson, P., Spurgeon, S. E., Li, L., Zhang, L., Newberry, K., Ou, Z., Cheng, N., Fang, B., McGreivy, J., Clow, F., Buggy, J. J., Chang, B. Y., Beaupre, D. M., Kunkel, L. A., Blum, K. A. 2013; 369 (6): 507-516

  Abstract

  Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

  View details for DOI 10.1056/NEJMoa1306220

  View details for Web of Science ID 000322842000007

  View details for PubMedID 23782157

• Targeted Therapy in Relapsed Classical Hodgkin Lymphoma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Dinner, S., Advani, R. 2013; 11 (8): 968-976

  Abstract

  Although frontline treatment of advanced Hodgkin lymphoma (HL) produces high cure rates, disease either will not respond to or will relapse after initial therapy in approximately a quarter of patients. Many patients with disease relapse can be successfully salvaged with second-line chemotherapy followed by autologous stem cell transplantation (ASCT). Patients whose disease relapses after ASCT are rarely cured. A unique pathophysiologic feature of HL is that the malignant Reed-Sternberg (HRS) cell is rare and resides within a microenvironment of inflammatory and immune-related cells. The recent FDA approval of the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) for patients with either primary refractory HL or those whose disease relapses after ASCT represents a major advance in therapy. This article focuses on BV and other novel agents that target the HRS cell surface, intracellular signaling pathways, and tumor microenvironment.

  View details for Web of Science ID 000323156900007

  View details for PubMedID 23946175

• Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood Kanakry, J. A., Li, H., Gellert, L. L., Lemas, M. V., Hsieh, W., Hong, F., Tan, K. L., Gascoyne, R. D., Gordon, L. I., Fisher, R. I., Bartlett, N. L., Stiff, P., Cheson, B. D., Advani, R., Miller, T. P., Kahl, B. S., Horning, S. J., Ambinder, R. F. 2013; 121 (18): 3547-3553

  Abstract

  Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. We sought to determine whether plasma EBV-DNA could serve as a surrogate for EBER-ISH and to explore its prognostic utility in HL. Specimens from the Cancer Cooperative Intergroup Trial E2496 were used to compare pretreatment plasma EBV-DNA quantification with EBV tumor status by EBER-ISH. A cutoff of >60 viral copies/100 µL plasma yielded 96% concordance with EBER-ISH. Pretreatment and month 6 plasma specimens were designated EBV(-) or EBV(+) by this cutoff. Patients with pretreatment EBV(+) plasma (n = 54) had inferior failure-free survival (FFS) compared with those with pretreatment EBV(-) plasma (n = 274), log-rank P = .009. By contrast, no difference in FFS was observed when patients were stratified by EBER-ISH. Pretreatment plasma EBV positivity was an independent predictor of treatment failure on multivariate analyses. At month 6, plasma EBV(+) patients (n = 7) had inferior FFS compared with plasma EBV(-) patients (n = 125), log-rank P = .007. These results confirm that plasma EBV-DNA is highly concordant with EBER-ISH in HL and suggest that it may have prognostic utility both at baseline and after therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003389.

  View details for DOI 10.1182/blood-2012-09-454694

  View details for PubMedID 23386127

• Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell Lymphoma NEW ENGLAND JOURNAL OF MEDICINE Dunleavy, K., Pittaluga, S., Maeda, L. S., Advani, R., Chen, C. C., Hessler, J., Steinberg, S. M., Grant, C., Wright, G., Varma, G., Staudt, L. M., Jaffe, E. S., Wilson, W. H. 2013; 368 (15): 1408-1416

  Abstract

  Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).

  View details for DOI 10.1056/NEJMoa1214561

  View details for Web of Science ID 000317333600008

  View details for PubMedID 23574119

• Efficacy of abbreviated Stanford V chemotherapy and involved-field radiotherapy in early-stage Hodgkin lymphoma: mature results of the G4 trial ANNALS OF ONCOLOGY Advani, R. H., Hoppe, R. T., Baer, D., Mason, J., Warnke, R., Allen, J., Daadi, S., Rosenberg, S. A., Horning, S. J. 2013; 24 (4): 1044-1048

  Abstract

  To assess the efficacy of an abbreviated Stanford V regimen in patients with early-stage Hodgkin lymphoma (HL). PATIENTS AND METHODS PATIENTS: with untreated nonbulky stage I-IIA supradiaphragmatic HL were eligible for the G4 study. Stanford V chemotherapy was administered for 8 weeks followed by radiation therapy (RT) 30 Gy to involved fields (IF). Freedom from progression (FFP), disease-specific survival (DSS) and overall survival (OS) were estimated.All 87 enrolled patients completed the abbreviated regimen. At a median follow-up of 10 years, FFP, DSS and OS are 94%, 99% and 94%, respectively. Therapy was well tolerated with no treatment-related deaths.Mature results of the abbreviated Stanford V regimen in nonbulky early-stage HL are excellent and comparable to the results from other contemporary therapies.

  View details for DOI 10.1093/annonc/mds542

  View details for Web of Science ID 000316701300027

  View details for PubMedID 23136225

• The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496 BRITISH JOURNAL OF HAEMATOLOGY Evens, A. M., Hong, F., Gordon, L. I., Fisher, R. I., Bartlett, N. L., Connors, J. M., Gascoyne, R. D., Wagner, H., Gospodarowicz, M., Cheson, B. D., Stiff, P. J., Advani, R., Miller, T. P., Hoppe, R. T., Kahl, B. S., Horning, S. J. 2013; 161 (1): 76-86

  Abstract

  There is a lack of contemporary prospective data examining the adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) and Stanford V (SV; doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone) regimens in older Hodgkin lymphoma (HL) patients. Forty-four advanced-stage, older HL patients (aged ≥60 years) were treated on the randomized study, E2496. Toxicities were mostly similar between chemotherapy regimens, although 24% of older patients developed bleomycin lung toxicity (BLT), which occurred mainly with ABVD (91%). Further, the BLT-related mortality rate was 18%. The overall treatment-related mortality for older HL patients was 9% vs. 0·3% for patients aged <60 years (P < 0·001). Among older patients, there were no survival differences between ABVD and SV. According to age, outcomes were significantly inferior for older versus younger patients (5-year failure-free survival: 48% vs. 74%, respectively, P = 0·002; 5-year overall survival: 58% and 90%, respectively, P < 0·0001), although time-to-progression (TTP) was not significantly different (5-year TTP: 68% vs. 78%, respectively, P = 0·37). Furthermore, considering progression and death without progression as competing risks, the risk of progression was not different between older and younger HL patients (5 years: 30% and 23%, respectively, P = 0·30); however, the incidence of death without progression was significantly increased for older HL patients (22% vs. 9%, respectively, P < 0·0001). Altogether, the marked HL age-dependent survival differences appeared attributable primarily to non-HL events.

  View details for DOI 10.1111/bjh.12222

  View details for Web of Science ID 000316333300009

  View details for PubMedID 23356491

• Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and Advanced-Stage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496) JOURNAL OF CLINICAL ONCOLOGY Gordon, L. I., Hong, F., Fisher, R. I., Bartlett, N. L., Connors, J. M., Gascoyne, R. D., Wagner, H., Stiff, P. J., Cheson, B. D., Gospodarowicz, M., Advani, R., Kahl, B. S., Friedberg, J. W., Blum, K. A., Habermann, T. M., Tuscano, J. M., Hoppe, R. T., Horning, S. J. 2013; 31 (6): 684-691

  Abstract

  Although ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been established as the standard of care in patients with advanced Hodgkin lymphoma, newer regimens have been investigated, which have appeared superior in early phase II studies. Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD.The Eastern Cooperative Oncology Group, along with the Cancer and Leukemia Group B, the Southwest Oncology Group, and the Canadian NCIC Clinical Trials Group, conducted this randomized phase III trial in patients with advanced Hodgkin lymphoma. Stratification factors included extent of disease (localized v extensive) and International Prognostic Factors Project Score (0 to 2 v 3 to 7). The primary end point was failure-free survival (FFS), defined as the time from random assignment to progression, relapse, or death, whichever occurred first. Overall survival, a secondary end point, was measured from random assignment to death as a result of any cause. This design provided 87% power to detect a 33% reduction in FFS hazard rate, or a difference in 5-year FFS of 64% versus 74% at two-sided .05 significance level.There was no significant difference in the overall response rate between the two arms, with complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V. At a median follow-up of 6.4 years, there was no difference in FFS: 74% for ABVD and 71% for Stanford V at 5 years (P = .32).ABVD remains the standard of care for patients with advanced Hodgkin lymphoma.

  View details for DOI 10.1200/JCO.2012.43.4803

  View details for Web of Science ID 000315086400016

  View details for PubMedID 23182987

  View details for PubMedCentralID PMC3574266

• Risk of Therapy-Related Secondary Leukemia in Hodgkin Lymphoma: The Stanford University Experience Over Three Generations of Clinical Trials JOURNAL OF CLINICAL ONCOLOGY Koontz, M. Z., Horning, S. J., Balise, R., Greenberg, P. L., Rosenberg, S. A., Hoppe, R. T., Advani, R. H. 2013; 31 (5): 592-598

  Abstract

  To assess therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) risk in patients treated for Hodgkin lymphoma (HL) on successive generations of Stanford clinical trials.Patients with HL treated at Stanford with at least 5 years of follow-up after completing therapy were identified from our database. Records were reviewed for outcome and development of t-AML/MDS.Seven hundred fifty-four patients treated from 1974 to 2003 were identified. Therapy varied across studies. Radiotherapy evolved from extended fields (S and C studies) to involved fields (G studies). Primary chemotherapy was mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or procarbazine, mechlorethamine, and vinblastine (PAVe) in S studies; MOPP, PAVe, vinblastine, bleomycin, and methotrexate (VBM), or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in C studies; and VbM (reduced dose of bleomycin compared with VBM) or mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) in G studies. Cumulative exposure to alkylating agent (AA) was notably lower in the G studies compared with the S and C studies, with a 75% to 83% lower dose of nitrogen mustard in addition to omission of procarbazine and melphalan. Twenty-four (3.2%) of 754 patients developed t-AML/MDS, 15 after primary chemotherapy and nine after salvage chemotherapy for relapsed HL. The incidence of t-AML/MDS was significantly lower in the G studies (0.3%) compared with the S (5.7%) or C (5.2%) studies (P < .001). Additionally, in the G studies, no t-AML/MDS was noted after primary therapy, and the only patient who developed t-AML/MDS did so after second-line therapy.Our data demonstrate the relationship between the cumulative AA dose and t-AML/MDS. Limiting the dose of AA and decreased need for secondary treatments have significantly reduced the incidence of t-AML/MDS, which was extremely rare in the G studies (Stanford V era).

  View details for DOI 10.1200/JCO.2012.44.5791

  View details for Web of Science ID 000314820400017

  View details for PubMedID 23295809

  View details for PubMedCentralID PMC3565182

• Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma BLOOD Rubenstein, J. L., Li, J., Chen, L., Advani, R., Drappatz, J., Gerstner, E., Batchelor, T., Krouwer, H., Hwang, J., Auerback, G., Kadoch, C., Lowell, C., Munster, P., Cha, S., Shuman, M. A., Damon, L. E. 2013; 121 (5): 745-751

  Abstract

  Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although IV rituximab mediates superior disease control of systemic non-Hodgkin lymphoma (NHL), it fails to completely eliminate the risk of meningeal recurrence, likely due to minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy, we conducted the first phase 1 study of intraventricular immunochemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg or 25 mg intraventricular rituximab twice weekly for 4 weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. More than 150 doses were administered without serious toxicity. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall complete response in CSF and/or brain parenchyma. Two patients achieved a first complete response of CNS NHL with intraventricular rituximab/MTX, including 1 with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab. We conclude that intraventricular rituximab in combination with MTX is feasible and highly active in the treatment of drug-resistant CNS NHL that is refractory or unresponsive to IV rituximab.Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.

  View details for DOI 10.1182/blood-2012-07-440974

  View details for Web of Science ID 000314867200007

  View details for PubMedID 23197589

  View details for PubMedCentralID PMC3563362

• Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies JOURNAL OF CLINICAL ONCOLOGY Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Rodriguez, S., Chang, B. Y., Sukbuntherng, J., Izumi, R., Hamdy, A., Hedrick, E., Fowler, N. H. 2013; 31 (1): 88-94

  Abstract

  Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies.Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles.Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months.Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.

  View details for DOI 10.1200/JCO.2012.42.7906

  View details for Web of Science ID 000312911900021

  View details for PubMedID 23045577

• Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial BLOOD Tan, K. L., Scott, D. W., Hong, F., Kahl, B. S., Fisher, R. I., Bartlett, N. L., Advani, R. H., Buckstein, R., Rimsza, L. M., Connors, J. M., Steidl, C., Gordon, L. I., Horning, S. J., Gascoyne, R. D. 2012; 120 (16): 3280-3287

  Abstract

  Increased tumor-associated macrophages (TAMs) are reported to be associated with poor prognosis in classic Hodgkin lymphoma (CHL). We investigated the prognostic significance of TAMs in the E2496 Intergroup trial, a multicenter phase 3 randomized controlled trial comparing ABVD and Stanford V chemotherapy in locally extensive and advanced stage CHL. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tumor tissue and included 287 patients. Patients were randomly assigned into training (n = 143) and validation (n = 144) cohorts. Immunohistochemistry for CD68 and CD163, and in situ hybridization for EBV-encoded RNA were performed. CD68 and CD163 IHC were analyzed by computer image analysis; optimum thresholds for overall survival (OS) were determined in the training cohort and tested in the independent validation cohort. Increased CD68 and CD163 expression was significantly associated with inferior failure-free survival and OS in the validation cohort. Increased CD68 and CD163 expression was associated with increased age, EBV-encoded RNA positivity, and mixed cellularity subtype of CHL. Multivariate analysis in the validation cohort showed increased CD68 or CD163 expression to be significant independent predictors of inferior failure-free survival and OS. We demonstrate the prognostic significance of TAMs in locally extensive and advanced-stage CHL in a multicenter phase 3 randomized controlled clinical trial.

  View details for DOI 10.1182/blood-2012-04-421057

  View details for Web of Science ID 000311619200019

  View details for PubMedID 22948049

• Phase II Study of Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Immunochemotherapy Followed by Yttrium-90-Ibritumomab Tiuxetan in Untreated Mantle-Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499 JOURNAL OF CLINICAL ONCOLOGY Smith, M. R., Li, H., Gordon, L., Gascoyne, R. D., Paietta, E., Forero-Torres, A., Kahl, B. S., Advani, R., Hong, F., Horning, S. J. 2012; 30 (25): 3119-3126

  Abstract

  To test the hypothesis that consolidation therapy with yttrium-90 ((90)Y) -ibritumomab tiuxetan after brief initial therapy with four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated mantle-cell lymphoma would be a well-tolerated regimen that would improve outcomes compared with historical R-CHOP data.Patients ≥ 18 years old with histologically confirmed mantle-cell lymphoma expressing CD20 and cyclin D1 who had not received any previous therapy and had an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were eligible. The study enrolled and treated 57 patients, of whom 56 patients were eligible. Fifty-two patients (50 eligible patients) received (90)Y-ibritumomab tiuxetan. The study design required 52 eligible patients to detect a 50% improvement in the median time to treatment failure (TTF) compared with that reported for six cycles of R-CHOP.With 56 analyzed patients (median age, 60 years; men, 73%), the overall response rate was 82% (55% complete response/complete response-unconfirmed). With a median follow-up of 72 months, the median TTF was 34.2 months. The median overall survival (OS) has not been reached, with an estimated 5-year OS of 73% (79% for patients ≤ age 65 years v 62% for patients > age 65 years; P = .08 [log-rank test]). There were no unexpected toxicities.R-CHOP given for four cycles followed by (90)Y-ibritumomab tiuxetan compared favorably with historical results with six cycles of R-CHOP in patients with previously untreated mantle-cell lymphoma. This regimen was well tolerated and should be applicable to most patients with this disease.

  View details for DOI 10.1200/JCO.2012.42.2444

  View details for Web of Science ID 000308558800018

  View details for PubMedID 22851557

• Brentuximab Vedotin in Transplant-Naive Patients with Relapsed or Refractory Hodgkin Lymphoma: Analysis of Two Phase I Studies ONCOLOGIST Forero-Torres, A., Fanale, M., Advani, R., Bartlett, N. L., Rosenblatt, J. D., Kennedy, D. A., Younes, A. 2012; 17 (8): 1073-1080

  Abstract

  Brentuximab vedotin is an antibody-drug conjugate designed to selectively deliver monomethyl auristatin E, a microtubule-disrupting agent, to CD30-expressing cells. Brentuximab vedotin induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). The objective of this post-hoc analysis was to characterize the safety and efficacy of brentuximab vedotin for patients with relapsed or refractory HL who refused or were ineligible for ASCT.This case series included 20 transplant-naïve patients who were enrolled in two phase I multicenter studies. Patients received brentuximab vedotin intravenously every 3 weeks or every week for 3 out of 4 weeks.The majority of patients were transplant-naïve because of chemorefractory disease. Median age was 31.5 years (range, 12-87 years). Treatment-emergent adverse events in >20% of patients were peripheral neuropathy, fatigue, nausea, pyrexia, diarrhea, weight decreased, anemia, back pain, decreased appetite, night sweats, and vomiting; most events were grade 1 or 2. Six patients obtained objective responses: two complete remissions and four partial remissions. Median duration of response was not met; censored durations ranged from >6.8 to >13.8 months. Three of six responders subsequently received ASCT.Brentuximab vedotin was associated with manageable adverse events in transplant-naïve patients with relapsed or refractory HL. The objective responses observed demonstrate that antitumor activity is not limited to patients who received brentuximab vedotin after ASCT. The promising activity observed in this population warrants further study.

  View details for DOI 10.1634/theoncologist.2012-0133

  View details for Web of Science ID 000308126100010

  View details for PubMedID 22855426

• Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study JOURNAL OF CLINICAL ONCOLOGY Pro, B., Advani, R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandren, R., Fanale, M., Connors, J. M., Yang, Y., Sievers, E. L., Kennedy, D. A., Shustov, A. 2012; 30 (18): 2190-2196

  Abstract

  Systemic anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of T-cell lymphoma characterized by the uniform expression of CD30. The antibody-drug conjugate brentuximab vedotin delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells. A phase II multicenter trial was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory systemic ALCL.Patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion. The primary end point of the study was overall objective response rate as assessed by independent central review.Of 58 patients treated in the study, 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (CR), and 17 patients (29%) achieved a partial remission. The median durations of overall response and CR were 12.6 and 13.2 months, respectively. Grade 3 or 4 adverse events in ≥ 10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (12%).Brentuximab vedotin induced objective responses in the majority of patients and CRs in more than half of patients with recurrent systemic ALCL. Targeted therapy with this CD30-directed antibody-drug conjugate may be an effective treatment for relapsed or refractory systemic ALCL and warrants further studies in front-line therapy.

  View details for DOI 10.1200/JCO.2011.38.0402

  View details for Web of Science ID 000305413200010

  View details for PubMedID 22614995

• Cardiac toxicity associated with bevacizumab (Avastin) in combination with CHOP chemotherapy for peripheral T cell lymphoma in ECOG 2404 trial LEUKEMIA & LYMPHOMA Advani, R. H., Hong, F., Horning, S. J., Kahl, B. S., Manola, J., Swinnen, L. J., Habermann, T. M., Ganjoo, K. 2012; 53 (4): 718-720

  View details for DOI 10.3109/10428194.2011.623256

  View details for Web of Science ID 000302067100030

  View details for PubMedID 21916830

• STAGE I-IIIA NON-BULKY HODGKIN'S LYMPHOMA. IS FURTHER DISTINCTION BASED ON PROGNOSTIC FACTORS USEFUL? THE STANFORD EXPERIENCE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Advani, R. H., Hoppe, R. T., Maeda, L. S., Baer, D. M., Mason, J., Rosenberg, S. A., Horning, S. J. 2011; 81 (5): 1374-1379

  Abstract

  In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center.This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy (n=84 patients) or 20-Gy (n=17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors.At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n=55%; European Organization for Research and Treatment of Cancer, n=33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n=61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria (p=0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged.The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

  View details for DOI 10.1016/j.ijrobp.2010.07.041

  View details for Web of Science ID 000297602400024

  View details for PubMedID 20934280

  View details for PubMedCentralID PMC3020265

• MicroRNAs Are Independent Predictors of Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP CLINICAL CANCER RESEARCH Alencar, A. J., Malumbres, R., Kozloski, G. A., Advani, R., Talreja, N., Chinichian, S., Briones, J., Natkunam, Y., Sehn, L. H., Gascoyne, R. D., Tibshirani, R., Lossos, I. S. 2011; 17 (12): 4125-4135

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) heterogeneity has prompted investigations for new biomarkers that can accurately predict survival. A previously reported 6-gene model combined with the International Prognostic Index (IPI) could predict patients' outcome. However, even these predictors are not capable of unambiguously identifying outcome, suggesting that additional biomarkers might improve their predictive power.We studied expression of 11 microRNAs (miRNA) that had previously been reported to have variable expression in DLBCL tumors. We measured the expression of each miRNA by quantitative real-time PCR analyses in 176 samples from uniformly treated DLBCL patients and correlated the results to survival.In a univariate analysis, the expression of miR-18a correlated with overall survival (OS), whereas the expression of miR-181a and miR-222 correlated with progression-free survival (PFS). A multivariate Cox regression analysis including the IPI, the 6-gene model-derived mortality predictor score and expression of the miR-18a, miR-181a, and miR-222, revealed that all variables were independent predictors of survival except the expression of miR-222 for OS and the expression of miR-18a for PFS.The expression of specific miRNAs may be useful for DLBCL survival prediction and their role in the pathogenesis of this disease should be examined further.

  View details for DOI 10.1158/1078-0432.CCR-11-0224

  View details for Web of Science ID 000291644700029

  View details for PubMedID 21525173

  View details for PubMedCentralID PMC3117929

• Current concepts and controversies in the management of early stage Hodgkin lymphoma LEUKEMIA & LYMPHOMA Maeda, L. S., Lee, M., Advani, R. H. 2011; 52 (6): 962-971

  Abstract

  Over the past three decades, due to the recognition of late effects related to high-dose extended field radiotherapy and heavy alkylator chemotherapy, combined modality therapy with abbreviated chemotherapy and limited field radiotherapy has emerged as the standard of care for early stage Hodgkin lymphoma, with cure rates in excess of 80%. Currently, however, controversy remains over identifying the most appropriate criteria to risk-stratify patients with early stage disease, so that those with a favorable prognosis receive limited treatment without compromising cure rates and those with unfavorable risk receive more intensified therapy. The optimal risk stratification system remains unclear, with variable definitions of favorable and unfavorable disease used by research groups in North America and Europe. Thus, comparison of clinical trial results has been challenging, and additional controversies persist regarding optimal chemotherapy regimens, duration of therapy, and the role of radiotherapy. Investigations are ongoing to assess the potential of functional imaging and biomarkers as tools for risk stratification. The collective goal is to further refine current stratification strategies to allow for an individualized, risk-adapted treatment approach that minimizes long-term late effects without compromising high cure rates.

  View details for DOI 10.3109/10428194.2011.557455

  View details for Web of Science ID 000290869100010

  View details for PubMedID 21463118

  View details for PubMedCentralID PMC4570567

• Optimal therapy of advanced Hodgkin lymphoma. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program Advani, R. 2011; 2011: 310-316

  Abstract

  Advanced-stage Hodgkin lymphoma (HL) has become a curable disease in the majority of patients. Research during the last decade has challenged chemotherapy with Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) as the standard of care and debates continue regarding the role of radiation therapy (RT) in this patient population. The incorporation of interim positron emission tomography (PET) imaging and, recently, further characterization of HL on cellular and molecular levels are emerging as tools for treatment stratification and predictors of disease status. Newer targeted therapies have emerged that are very effective in the relapsed setting and are actively being explored as frontline therapy. Lastly, the expanding population of survivors cured of HL outnumbers patients with the disease and needs to be monitored for therapy-related late effects.

  View details for DOI 10.1182/asheducation-2011.1.310

  View details for PubMedID 22160051

• Comparison of conventional prognostic indices in patients older than 60 years with diffuse large B-cell lymphoma treated with R-CHOP in the US Intergroup Study (ECOG 4494, CALGB 9793): consideration of age greater than 70 years in an elderly prognostic index (E-IPI) 48th Annual Meeting of the American-Society-of-Hematology Advani, R. H., Chen, H., Habermann, T. M., Morrison, V. A., Weller, E. A., Fisher, R. I., Peterson, B. A., Gascoyne, R. D., Horning, S. J. WILEY-BLACKWELL PUBLISHING, INC. 2010: 143–51

  Abstract

  To assess if immunochemotherapy influenced the prognostic value of IPI in elderly diffuse large B-cell lymphoma (DLBCL) patients, we evaluated the performance of the standard International Prognostic Index (IPI) and following modifications: age adjusted (AA)-IPI, revised (R)-IPI, and an elderly IPI with age cut-off 70 years (E-IPI) in patients > 60 years treated with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). In 267 patients, by IPI/AA-IPI 60% were high-intermediate, 53% high and 12% low risk. With R-IPI, 60% were poor risk and none very good risk. Using E-IPI, 45% were high-intermediate/high risk and 27% low risk. No differences in outcome were seen in the low/low-intermediate groups with IPI/AA-IPI. For E-IPI, failure-free survival (FFS) and overall survival (OS) were significantly different for low/low-intermediate groups. No differences were detected in the four indices with model fit/discrimination measures; however, E-IPI ranked highest. For elderly R-CHOP treated patients, distribution of IPI/AA-IPI skewed toward high/high-intermediate risk with no differences in FFS/OS between low/low-intermediate risk. In contrast, with E-IPI, more are classified as low risk with significant differences in FFS/OS for low-intermediate compared to low risk. The R-IPI does not identify a very good risk group, thus minimizing its utility in this population. The prognostic discrimination provided by the E-IPI for low and low-intermediate elderly DLBCL patients needs validation by other datasets.

  View details for DOI 10.1111/j.1365-2141.2010.08331.x

  View details for Web of Science ID 000282374500003

  View details for PubMedID 20735398

• Risk stratification in extranodal natural killer/T-cell lymphoma EXPERT REVIEW OF ANTICANCER THERAPY Kohrt, H., Lee, M., Advani, R. 2010; 10 (9): 1395-1405

  Abstract

  Extranodal natural killer/T-cell lymphoma (ENKL), a subtype of natural killer/T-cell malignancies, is a rare subset of lymphomas with significant biological and clinical heterogeneity. The prognosis of ENKL is variable and therapeutic approaches are not well established. The optimal dose, combination, and sequence of radiotherapy and chemotherapy are evolving, as is the role of stem cell transplantation. Radiotherapy is an essential component of therapy for early-stage disease. The clinical course of advanced disease is highly aggressive, with frequent chemotherapy resistance and a poor prognosis. For relapsed disease, asparaginase-based regimens have provided encouraging results and are currently under investigation in the frontline setting. Our article discusses the key aspects of biology, pathogenesis and clinical presentation that contribute to the heterogeneity, and proposes a stratified approach to the treatment of ENKL based on clinical, pathologic and biologic risk factors. Although considerable advances have been made in our understanding of the biology and prognosis of this lymphoma, it remains critical that all patients with a diagnosis of ENKL are enrolled and treated in clinical trials so that optimal therapies can be identified.

  View details for DOI 10.1586/ERA.10.130

  View details for Web of Science ID 000282259800012

  View details for PubMedID 20836675

• Prediction of Survival in Diffuse Large B-Cell Lymphoma Based On the Expression of Two Genes: Integration of Tumor and Microenvironment Contributions 51st Annual Meeting and Exposition of the American-Society-of-Hematology Alizadeh, A. A., Gentles, A. J., Alencar, A. J., Kohrt, H. E., Houot, R., Talreja, N., Shyam, R., Natkunam, Y., Gascoyne, R. D., Briones, J., Advani, R., Lossos, I. S., Levy, R. AMER SOC HEMATOLOGY. 2009: 258–58

  View details for Web of Science ID 000272725800623

• Efficacy of Abbreviated Stanford V Chemotherapy and Involved Field Radiotherapy in Early Stage Hodgkin's Disease: Mature Results of the G4 Trial. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Advani, R. H., Hoppe, R. T., Baer, D. M., Mason, J., Rosenberg, S. A., Horning, S. J. AMER SOC HEMATOLOGY. 2009: 666–67

  View details for Web of Science ID 000272725802038

• Management of T-cell and natural-killer-cell neoplasms in Asia: consensus statement from the Asian Oncology Summit 2009 LANCET ONCOLOGY Kwong, Y., Anderson, B. O., Advani, R., Kim, W., Levine, A. M., Lim, S. 2009; 10 (11): 1093-1101

  Abstract

  T-cell and natural-killer (NK)-cell lymphomas are neoplasms with geographical variations in frequencies. T-cell lymphomas are more prevalent in Asia than in Europe and North America, and NK-cell lymphomas occur almost exclusively in Asia and South America. These low frequencies mean that the diagnosis and optimum treatment of patients with T-cell and NK-cell lymphomas have not been studied prospectively in randomised controlled trials. Because T-cell and NK-cell lymphomas are more prevalent in Asia, the establishment of management recommendations by Asian oncologists in collaboration with international experts is pertinent. This review outlines guidelines commensurate with different levels of health-care resources and expertise. Consensus statements were formulated for diagnosis, staging, follow-up, and treatment approaches in patients with T-cell and NK-cell lymphomas--aimed at unifying the design of studies and interpretation of results. For patients not in clinical trials, consensus opinions offer useful guidelines on optimum management.

  View details for Web of Science ID 000271852800019

  View details for PubMedID 19880063

• Phase I Study of the Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-Hodgkin's Lymphoma 10th International Conference on Malignant Lymphoma Advani, R., Forero-Torres, A., Furman, R. R., Rosenblatt, J. D., Younes, A., Ren, H., Harrop, K., Whiting, N., Drachman, J. G. AMER SOC CLINICAL ONCOLOGY. 2009: 4371–77

  Abstract

  To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL).In this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle.In the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in >or= 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade >or= 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients.Dacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.

  View details for DOI 10.1200/JCO.2008.21.3017

  View details for Web of Science ID 000269652200024

  View details for PubMedID 19636010

• Impact of positive positron emission tomography on prediction of freedom from progression after Stanford V chemotherapy in Hodgkin's disease 9th International Conference on Malignant Lymphoma Advani, R., Maeda, L., Lavori, P., Quon, A., Hoppe, R., Breslin, S., Rosenberg, S. A., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2007: 3902–7

  Abstract

  To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.

  View details for DOI 10.1200/JCO.2007.11.9867

  View details for Web of Science ID 000249416000019

  View details for PubMedID 17664458

• Angioimmunoblastic T cell lymphoma: Treatment experience with cyclosporine LEUKEMIA & LYMPHOMA Advani, R., Horwitz, S., Zelenetz, A., Horning, S. J. 2007; 48 (3): 521-525

  Abstract

  Angioimmunoblastic T cell lymphoma is a distinct entity for which there is no standard therapy. On the basis of the rationale that CsA may represent a novel drug for AITL, a disease with considerable immune dysregulation, and encouraging case reports, the authors have treated 12 patients with this agent. Ten had failed prior steroids and/or chemotherapy and two had no prior therapy. CsA was administered at a dose of 3 - 5 mg/kg PO bid for 6 - 8 weeks and gradually tapered by 50 mg every 1 - 3 weeks. Responding patients received a maintenance dose of 50 - 100 mg, with a gradual taper after a maximal response was achieved as tolerated. Doses were titrated for renal dysfunction or hypertension. CsA levels were not monitored. Eight of 12 patients responded (three complete and five partial remissions). Dose reductions were required in six patients; renal insufficiency (n = 3), fatigue (n = 2), and hypertension (n = 1). Two patients developed acute infections and one patient died shortly after active treatment. These results suggest that CsA deserves further testing as a novel therapy for AITL. By interrupting T-cell activation, CsA may alter the immune dysregulation that characterizes AILT. The efficacy of CsA is being explored in patients with recurrent AILT in a prospective trial (ECOG 2402).

  View details for DOI 10.1080/10428190601137658

  View details for Web of Science ID 000245108100015

  View details for PubMedID 17454592

• Stage I and II follicular non-Hodgkin's lymphoma: Long-term follow-up of no initial therapy 8th International Conference on Malignant Lymphoma Advani, R., Rosenberg, S. A., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2004: 1454–59

  Abstract

  To analyze the outcome of no initial therapy in stage I and II follicular small-cleaved (FSC) and follicular mixed (FM) non-Hodgkin's lymphoma (NHL) on overall survival, time to treatment, incidence and course of transformation, and cause of death.This was a retrospective analysis. Criteria for selection were patients with stage I and IIA FSC and FM (grades 1 and 2) NHL with therapy deferred for at least 3 months after diagnosis and a minimum follow-up of 1 year.Forty-three patients were identified (11 stage I, 32 stage II), with a median age of 58 years. Reasons for no initial therapy included: physician choice (n = 20), large abdominal radiation field required (n = 10), advanced age (n = 7), concern for xerostomia (n = 4), or patient refusal (n = 2). At a median follow-up of 86 months, 27 patients (63%) had not been treated. The median time to treatment in the remaining 16 patients was 22 months. Four of 16 patients transformed to a higher-grade lymphoma. Nine patients died-six due to progressive lymphoma. Estimated survivals at 5, 10, and 20 years were 97%, 85%, and 22%, respectively.In selected stage I and II follicular NHL patients, deferred therapy is an acceptable approach, as more than half of our patients remained untreated at a median of 6 or more years, and survival was comparable to that seen in reports with immediate treatment.

  View details for DOI 10.1200/JCO.2004.10.086

  View details for Web of Science ID 000220912200016

  View details for PubMedID 15024027

• Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas BLOOD Fanale, M. A., Horwitz, S. M., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Illidge, T., Uttarwar, M., Lee, S., Ren, H., Kennedy, D. A., Shustov, A. R. 2018; 131 (19): 2120–24

  Abstract

  This phase 1 study evaluated frontline brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab vedotin monotherapy) in 26 patients with CD30+ peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789.

  View details for DOI 10.1182/blood-2017-12-821009

  View details for Web of Science ID 000431897600006

  View details for PubMedID 29507077

• The Role of Radiation Therapy in Patients With Relapsed or Refractory Hodgkin Lymphoma: Guidelines From the International Lymphoma Radiation Oncology Group INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Constine, L. S., Yahalom, J., Ng, A. K., Hodgson, D. C., Wirth, A., Milgrom, S. A., Mikhaeel, N., Eich, H., Illidge, T., Ricardi, U., Dieckmann, K., Moskowitz, C. H., Advani, R., Mauch, P. M., Specht, L., Hoppe, R. T. 2018; 100 (5): 1100–1118

  Abstract

  Relapsed and refractory Hodgkin lymphoma (HL) challenges clinicians to devise treatment strategies that are effective and safe. This problem is particularly prominent in an era when de-escalation trials are designed to minimize therapeutic toxicities in both early- and advanced-stage disease. Radiation therapy is the single most effective treatment modality for HL, and its integration into salvage regimens, or its independent use in select patients, must be understood to maximize our success in treating these patients. The complexity of treating relapsed or refractory HL derives from the spectrum of primary treatment approaches currently in use that creates heterogeneity in both treatment exposure and the potential toxicities of salvage therapy. Patients can have relapsed or refractory disease after limited or aggressive primary therapy (with or without radiation therapy), at early or delayed time points, with limited or extensive disease volumes, and with varying degrees of residual morbidity from primary therapy. Their response to salvage systemic therapy can be partial or complete, and the use of consolidative stem cell transplantation is variably applied. New biologics and immunotherapeutic approaches have broadened but also complicated salvage treatment approaches. Through all of this, radiation therapy remains an integral component of treatment for many patients, but it must be used effectively and judiciously. The purpose of this review is to describe the different treatment scenarios and provide guidance for radiation dose, volume, and timing in patients with relapsed or refractory HL.

  View details for DOI 10.1016/j.ijrobp.2018.01.011

  View details for Web of Science ID 000428145600005

  View details for PubMedID 29722655

• NCCN Guidelines (R) Insights Hodgkin Lymphoma, Version 1.2018 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Armand, P., Bello, C. M., Benitez, C. M., Bierman, P. J., Chen, R., Dabaja, B., Dean, R., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Huang, J., Johnston, P. B., Kaminski, M. S., Kenkre, V. P., Khan, N., Maddocks, K., Maloney, D. G., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Mulroney, C., Rabinovitch, R., Seropian, S., Tao, R., Winter, J. N., Yahalom, J., Burns, J. L., Ogba, N. 2018; 16 (3): 245–54

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

  View details for DOI 10.6004/jnccn.2018.0013

  View details for Web of Science ID 000427032100007

  View details for PubMedID 29523663

• Phase II study of rituximab given in conjunction with standard chemotherapy in primary central nervous system lymphoma (PCNSL): a trial of the ECOG-ACRIN cancer research group (E1F05) ONCOTARGET Swinnen, L. J., O'Neill, A., Imus, P. H., Gujar, S., Schiff, D., Kleinberg, L. R., Advani, R. H., Dunbar, E. M., Moore, D., Grossman, S. A. 2018; 9 (1): 766–73

  Abstract

  Therapy of primary CNS lymphoma (PCNSL) has focused on multi-agent chemotherapy designed to cross the blood brain barrier. Rituximab has demonstrated activity in PCNSL. E1F05 is an ECOG-ACRIN multicenter phase 2 prospective trial of rituximab with high-dose methotrexate (HD-MTX)-based chemotherapy similar to the RTOG 93-10 regimen, omitting radiotherapy.Immunocompetent patients with newly diagnosed PCNSL received HD-MTX 3.5g/m2 with vincristine every two weeks for 5 doses; procarbazine for 7 days in weeks 1, 5, and 9; cytarabine 3g/m2/day IV for 2 days in weeks 11 and 14; a dexamethasone taper over 6 weeks; and rituximab 375mg/m2 IV infusion 3 times per week for weeks 1-4. Subjects with CSF involvement received intrathecal methotrexate 12mg every two weeks.Twenty-six patients were enrolled; median age was 57. Sixteen subjects (65%) completed treatment per protocol; the most common reason for discontinuation was adverse events, and 2 subjects discontinued due to progressive disease (PD). Complete response (CR) + unconfirmed CR (CRu) was 16/25 (64%), overall response rate was 20/25 (80%), and 4/25(16%) had PD as best response. Median progression free survival (PFS) was 34 months, and median overall survival has not been reached at 40 months' median follow up. Two year PFS was 63%. The most common grade 3-4 toxicities were hematologic.The addition of rituximab to multi-agent chemotherapy is well tolerated. Outcomes are comparable to or better than those seen in RTOG 93-10, which included RT. These and other results suggest rituximab has activity in the CNS. [ECOG-ACRIN E1F05].NCT00335140, clinicaltrials.gov.

  View details for DOI 10.18632/oncotarget.22332

  View details for Web of Science ID 000419615500062

  View details for PubMedID 29416652

  View details for PubMedCentralID PMC5787508

• Advances in the Management of Primary Mediastinal Large B-Cell Lymphoma CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY Advani, R. H. 2018; 16 (1): 33–34

  View details for Web of Science ID 000425929300005

  View details for PubMedID 29741502

• Outcomes in adolescents and young adults with Hodgkin lymphoma treated on US cooperative group protocols: An adult intergroup (E2496) and Children's Oncology Group (COG AHOD0031) comparative analysis CANCER Henderson, T. O., Parsons, S. K., Wroblewski, K. E., Chen, L., Hong, F., Smith, S. M., McNeer, J. L., Advani, R. H., Gascoyne, R. D., Constine, L. S., Horning, S., Bartlett, N. L., Shah, B., Connors, J. M., Leonard, J. I., Kahl, B. S., Kelly, K. M., Schwartz, C. L., Li, H., Friedberg, J. W., Friedman, D. L., Gordon, L. I., Evens, A. M. 2018; 124 (1): 136–44

  Abstract

  There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL).Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study.Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P < .001) and B symptoms (63% vs 27%; P < .001), and fewer had bulk disease (33% vs 77%; P < .001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study.Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2018;124:136-44. © 2017 American Cancer Society.

  View details for DOI 10.1002/cncr.30979

  View details for Web of Science ID 000418251600017

  View details for PubMedID 28902390

  View details for PubMedCentralID PMC5735034

• Magnetic Resonance Imaging of Tumor Associated Macrophages: Clinical Translation. Clinical cancer research : an official journal of the American Association for Cancer Research Aghighi, M., Theruvath, A. J., Pareek, A., Pisani, L., Alford, R., Muehe, A. M., Sethi, T. K., Holdsworth, S. J., Hazard, F. K., Gratzinger, D., Luna-Fineman, S., Advani, R. H., Spunt, S. L., Daldrup-Link, H. E. 2018

  Abstract

  Tumor associated macrophages (TAM) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with non-invasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.In a first-in-patient, IRB-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (2 lymphoma, 3 bone sarcoma) underwent pre- and post-contrast MRI. Subsequently, 20 patients (10 lymphoma, 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24-48 hours after intravenous injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.Significant ferumoxytol tumor enhancement was noted on post-contrast scans compared to pre-contrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies.

  View details for DOI 10.1158/1078-0432.CCR-18-0673

  View details for PubMedID 29764855

• Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma BLOOD Pro, B., Advani, R., Brice, P., Bartlett, N. L., Rosenblatt, J. D., Illidge, T., Matous, J., Ramchandren, R., Fanale, M., Connors, J. M., Fenton, K., Huebner, D., Pinelli, J. M., Kennedy, D. A., Shustov, A. 2017; 130 (25): 2709–17

  Abstract

  This pivotal phase 2 study evaluated the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.

  View details for DOI 10.1182/blood-2017-05-780049

  View details for Web of Science ID 000418895900006

  View details for PubMedID 28974506

  View details for PubMedCentralID PMC5746164

• KLHL6 Is Preferentially Expressed in Germinal Center-Derived B-Cell Lymphomas AMERICAN JOURNAL OF CLINICAL PATHOLOGY Kunder, C. A., Roncador, G., Advani, R. H., Gualco, G., Bacchi, C. E., Sabile, J. M., Lossos, I. S., Nie, K., Tibshirani, R., Green, M. R., Alizadeh, A. A., Natkunam, Y. 2017; 148 (6): 465–76

  Abstract

  KLHL6 is a recently described BTB-Kelch protein with selective expression in lymphoid tissues and is most strongly expressed in germinal center B cells.Using gene expression profiling as well as immunohistochemistry with an anti-KLHL6 monoclonal antibody, we have characterized the expression of this molecule in normal and neoplastic tissues. Protein expression was evaluated in 1,058 hematopoietic neoplasms.Consistent with its discovery as a germinal center marker, KLHL6 was positive mainly in B-cell neoplasms of germinal center derivation, including 95% of follicular lymphomas (106/112). B-cell lymphomas of non-germinal center derivation were generally negative (0/33 chronic lymphocytic leukemias/small lymphocytic lymphomas, 3/49 marginal zone lymphomas, and 2/66 mantle cell lymphomas).In addition to other germinal center markers, including BCL6, CD10, HGAL, and LMO2, KLHL6 immunohistochemistry may prove a useful adjunct in the diagnosis and future classification of B-cell lymphomas.

  View details for DOI 10.1093/AJCP/AQX099

  View details for Web of Science ID 000419179900001

  View details for PubMedID 29140403

• The landscape of new drugs in lymphoma NATURE REVIEWS CLINICAL ONCOLOGY Younes, A., Ansell, S., Fowler, N., Wilson, W., de Vos, S., Seymour, J., Advani, R., Forero, A., Morschhauser, F., Kersten, M. J., Tobinai, K., Zinzani, P. L., Zucca, E., Abramson, J., Vose, J. 2017; 14 (6): 335-346

  View details for DOI 10.1038/nrclinonc.2016.205

  View details for Web of Science ID 000401612500004

• Subsequent primary malignancies after diffuse large B-cell lymphoma in the modern treatment era. British journal of haematology Tao, L., Clarke, C. A., Rosenberg, A. S., Advani, R. H., Jonas, B. A., Flowers, C. R., Keegan, T. H. 2017

  Abstract

  With the addition of rituximab and other treatment advances, survival after diffuse large B-cell lymphoma (DLBCL) has improved, but subsequent primary malignancies (SPMs) have emerged as an important challenge for DLBCL survivorship. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPMs among 23 879 patients who survived at least 1 year after a first primary DLBCL diagnosed during 1989-2012, compared to the general population in California. Cumulative incidence (CMI) of SPMs, accounting for the competing risk of death, also was calculated. We found that the incidence of acute myeloid leukaemia (AML) nearly doubled in the post-rituximab era [SIR (95% CI) 4·39 (2·51-7·13) pre- (1989-2000) and 8·70 (6·62-11·22) post-rituximab (2001-2012)]. Subsequent thyroid cancer was rare pre-rituximab, but increased substantially after 2001 [0·66 (0·08-2·37) vs. 2·27(1·44-3·41)]. The 5-year CMI for all SPMs (4·77% pre- vs. 5·41% post-rituximab, P = 0·047), AML (0·15% vs. 0·41%, P = 0·003), thyroid cancer (0·03% vs. 0·15%, P = 0·003) and melanoma (0·25% vs. 0·42%, P = 0·020) were greater in DLBCL patients diagnosed in the post- versus pre-rituximab period. This study provides insight into the changing pattern of SPM occurrence after the introduction of rituximab, which may elucidate the aetiology of SPMs and should guide future cancer surveillance efforts among DLBCL patients.

  View details for DOI 10.1111/bjh.14638

  View details for PubMedID 28542862

• Hodgkin Lymphoma Version 1.2017 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Benitez, C. M., Bernat, K., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Huang, J., Johnston, P. B., Kaminski, M. S., Kenkre, V. P., Khan, N., Maloney, D. G., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Mulroney, C., Poppe, M., Rabinovitch, R., Seropian, S., Smith, M., Winter, J. N., Yahalom, J., Burns, J., Ogba, N., Sundar, H. 2017; 15 (5): 608-638

  Abstract

  This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

  View details for Web of Science ID 000401120200011

• Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Benitez, C. M., Bernat, K., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Huang, J., Johnston, P. B., Kaminski, M. S., Kenkre, V. P., Khan, N., Maloney, D. G., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Mulroney, C., Poppe, M., Rabinovitch, R., Seropian, S., Smith, M., Winter, J. N., Yahalom, J., Burns, J., Ogba, N., Sundar, H. 2017; 15 (5): 608-638

  Abstract

  This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

  View details for PubMedID 28476741

• International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Annals of oncology Younes, A., HILDEN, P., Coiffier, B., Hagenbeek, A., Salles, G., Wilson, W., Seymour, J. F., Kelly, K., Gribben, J., Pfreunschuh, M., Morschhauser, F., Schoder, H., Zelenetz, A. D., Rademaker, J., Advani, R., Valente, N., Fortpied, C., Witzig, T. E., Sehn, L. H., Engert, A., Fisher, R. I., Zinzani, P., Federico, M., Hutchings, M., Bollard, C., Trneny, M., Elsayed, Y. A., Tobinai, K., Abramson, J. S., Fowler, N., Goy, A., Smith, M., Ansell, S., Kuruvilla, J., Dreyling, M., Thieblemont, C., Little, R. F., Aurer, I., Van Oers, M. H., Takeshita, K., Gopal, A., Rule, S., de Vos, S., Kloos, I., Kaminski, M. S., Meignan, M., Schwartz, L. H., Leonard, J. P., Schuster, S. J., Seshan, V. E. 2017

  Abstract

  In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) or bidimensional tumor measurements on computerized tomography (CT) scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47,828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials, and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

  View details for DOI 10.1093/annonc/mdx097

  View details for PubMedID 28379322

• A Prospective Cohort Study of Patients With Peripheral T-Cell Lymphoma in the United States CANCER Carson, K. R., Horwitz, S. M., Pinter-Brown, L. C., Rosen, S. T., Pro, B., Hsi, E. D., Federico, M., Gisselbrecht, C., Schwartz, M., Bellm, L. A., Acosta, M. A., Shustov, A. R., Advani, R. H., Feldman, T. A., Lechowicz, M. J., Smith, S. M., Lansigan, F., Tulpule, A., Craig, M. D., Greer, J. P., Kahl, B. S., Leach, J. W., Morganstein, N., Casulo, C., Park, S. I., Foss, F. M. 2017; 123 (7): 1174-1183

  View details for DOI 10.1002/cncr.30416

  View details for Web of Science ID 000397760100015

• Phase I Study of the Anti-CD22 Antibody-Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research Advani, R. H., Lebovic, D., Chen, A., Brunvand, M., Goy, A., Chang, J. E., Hochberg, E., Yalamanchili, S., Kahn, R., Lu, D., Agarwal, P., Dere, R. C., Hsieh, H., Jones, S., Chu, Y., Cheson, B. D. 2017; 23 (5): 1167-1176

  Abstract

  Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses.Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167-76. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-0772

  View details for PubMedID 27601593

• NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia, Version 1.2017. Journal of the National Comprehensive Cancer Network Wierda, W. G., Zelenetz, A. D., Gordon, L. I., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Caimi, P., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Martin, M. G., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Snyder, E. D., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Dwyer, M. A., Sundar, H. 2017; 15 (3): 293-311

  Abstract

  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

  View details for PubMedID 28275031

• NCCN Guidelines (R) Insights Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia, Version 1.2017 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Wierda, W. G., Zelenetz, A. D., Gordon, L. I., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Caimi, P., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Martin, M. G., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Snyder, E. D., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Dwyer, M. A., Sundar, H. 2017; 15 (3): 293-311

  Abstract

  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

  View details for Web of Science ID 000395889300004

• Acquired mutations associated with ibrutinib resistance in Waldenstrom Macroglobulinemia. Blood Xu, L., Tsakmaklis, N., Yang, G., Chen, J. G., Liu, X., Demos, M., Kofides, A., Patterson, C. J., Meid, K., Gustine, J., Dubeau, T., Palomba, M. L., Advani, R., Castillo, J. J., Furman, R. R., Hunter, Z. R., Treon, S. P. 2017

  Abstract

  Ibrutinib produces high response rates and durable remissions in Waldenström macroglobulinemia (WM) that are impacted by MYD88 and CXCR4(WHIM) mutations. Disease progression can develop on ibrutinib, although the molecular basis remains to be clarified. We sequenced sorted CD19(+) lymphoplasmacytic cells from 6 WM patients who progressed after achieving major responses on ibrutinib using Sanger, TA cloning and sequencing, and highly sensitive and allele-specific polymerase chain reaction (AS-PCR) assays that we developed for Bruton tyrosine kinase (BTK) mutations. AS-PCR assays were used to screen patients with and without progressive disease on ibrutinib, and ibrutinib-naïve disease. Targeted next-generation sequencing was used to validate AS-PCR findings, assess for other BTK mutations, and other targets in B-cell receptor and MYD88 signaling. Among the 6 progressing patients, 3 had BTK(Cys481) variants that included BTK(Cys481Ser(c.1635G>C and c.1634T>A)) and BTK(Cys481Arg(c.1634T>C)) Two of these patients had multiple BTK mutations. Screening of 38 additional patients on ibrutinib without clinical progression identified BTK(Cys481) mutations in 2 (5.1%) individuals, both of whom subsequently progressed. BTK(Cys481) mutations were not detected in baseline samples or in 100 ibrutinib-naive WM patients. Using mutated MYD88 as a tumor marker, BTK(Cys481) mutations were subclonal, with a highly variable clonal distribution. Targeted deep-sequencing confirmed AS-PCR findings, and identified an additional BTK(Cys481Tyr(c.1634G>A)) mutation in the 2 patients with multiple other BTK(Cys481) mutations, as well as CARD11(Leu878Phe(c.2632C>T)) and PLCγ2(Tyr495His(c.1483T>C)) mutations. Four of the 5 patients with BTK(C481) variants were CXCR4 mutated. BTK(Cys481) mutations are common in WM patients with clinical progression on ibrutinib, and are associated with mutated CXCR4.

  View details for DOI 10.1182/blood-2017-01-761726

  View details for PubMedID 28235842

• T-Cell Lymphoma: Recent Advances in Characterization and New Opportunities for Treatment. Journal of the National Cancer Institute Casulo, C., O'Connor, O., Shustov, A., Fanale, M., Friedberg, J. W., Leonard, J. P., Kahl, B. S., Little, R. F., Pinter-Brown, L., Advani, R., Horwitz, S. 2017; 109 (2)

  Abstract

  Peripheral T-cell lymphomas (PTCLs) are uncommon, heterogeneous, and aggressive non-Hodgkin's lymphomas. Despite progress in the last several years resulting in a deeper understanding of PTCL biology and pathogenesis, there is currently no accepted single standard of care for newly diagnosed patients, and for those with relapsed or refractory disease, prognosis is dismal. The National Cancer Institute convened a Clinical Trials Planning Meeting to advance the national clinical trial agenda in lymphoma. The objective was to identify unmet needs specific to five major lymphoma subtypes and develop strategies to address them. This consensus statement reviews recent advances in the molecular and genetic characterization of PTCL that may inform novel treatments, proposes strategies to test novel therapies in the relapsed setting with the hopes of rapid advancement into frontline trials, and underscores the need for the identification and development of active and biologically rational therapies to cure PTCL at higher rates, with iterative biomarker evaluation.

  View details for DOI 10.1093/jnci/djw248

  View details for PubMedID 28040682

• Analysis of Peripheral T-cell Lymphoma Diagnostic Workup in the United States. Clinical lymphoma, myeloma & leukemia Hsi, E. D., Horwitz, S. M., Carson, K. R., Pinter-Brown, L. C., Rosen, S. T., Pro, B., Federico, M., Gisselbrecht, C., Schwartz, M., Bellm, L. A., Acosta, M., Collie, A. M., Gruver, A. M., Grzywacz, B. J., Turakhia, S., Shustov, A. R., Advani, R. H., Feldman, T., Lechowicz, M. J., Smith, S. M., Lansigan, F., Tulpule, A., Craig, M. D., Greer, J. P., Kahl, B. S., Leach, J. W., Morganstein, N., Casulo, C., Park, S. I., Foss, F. M. 2017

  Abstract

  With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. PATIENTS AND METHODS: We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States.A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01).The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.

  View details for DOI 10.1016/j.clml.2016.10.001

  View details for PubMedID 28209473

• How to Provide Gadolinium-Free PET/MR Cancer Staging of Children and Young Adults in Less than 1 h: the Stanford Approach. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Muehe, A. M., Theruvath, A. J., Lai, L., Aghighi, M., Quon, A., Holdsworth, S. J., Wang, J., Luna-Fineman, S., Marina, N., Advani, R., Rosenberg, J., Daldrup-Link, H. E. 2017

  Abstract

  To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography/magnetic resonance (PET/MR) imaging in less than 1 h.In this prospective clinical trial, 20 children and young adults (11-30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5 mg Fe/kg) and [(18)F]FDG (2-3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition, and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests.Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol "off label" as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. Compared to PET/CT, PET/MR had comparable detection rates for pulmonary nodules with diameters of equal or greater than 5 mm (94 vs. 100 %), yet detected significantly fewer nodules with diameters of less than 5 mm (20 vs 100 %) (p = 0.03). [(18)F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59 vs 49 %).Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved.

  View details for DOI 10.1007/s11307-017-1105-7

  View details for PubMedID 28721605

• Dramatic Response with Single-Agent Ibrutinib in Multiply Relapsed Marginal Zone Lymphoma with MYD88(L265P) Mutation CASE REPORTS IN ONCOLOGY Lynch, R. C., Advani, R. H. 2017; 10 (3): 813–18

  Abstract

  The B-cell receptor signaling pathway is important in the lymphomagenesis of many lymphomas, including marginal zone lymphoma (MZL). Herein we describe a case of extranodal MZL refractory to multiple lines of therapy. The presence of an IgM paraprotein prompted further evaluation, and the patient was found to have an MYD88L265P mutation. Treatment with ibrutinib led to a dramatic response with prompt resolution of symptoms and significant improvement in measurable sites of disease. The excellent response to ibrutinib in our patient with MYD88L265P-mutated refractory MZL supports a biological rationale for its use.

  View details for DOI 10.1159/000480292

  View details for Web of Science ID 000418467200004

  View details for PubMedID 29070995

  View details for PubMedCentralID PMC5649220

• Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry LEUKEMIA & LYMPHOMA Bartlett, N. L., Smith, M. R., Siddiqi, T., Advani, R. H., O'Connor, O. A., Sharman, J. P., Feldman, T., Savage, K. J., Shustov, A. R., Diefenbach, C. S., Oki, Y., Palanca-Wessels, M. C., Uttarwar, M., Li, M., Yang, J., Jacobsen, E. D. 2017; 58 (7): 1607-1616

  Abstract

  This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had ≥1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that ≥1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).

  View details for DOI 10.1080/10428194.2016.1256481

  View details for Web of Science ID 000399474000013

• Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study. The Lancet. Haematology Furman, R. R., Eradat, H. A., DiRienzo, C. G., Hofmeister, C. C., Hayman, S. R., Leonard, J. P., Coleman, M., Advani, R., Chanan-Khan, A., Switzky, J., Liao, Q. M., Shah, D., Jewell, R. C., Lisby, S., Lin, T. S. 2017; 4 (1): e24-e34

  Abstract

  The development of more effective and safer treatments, especially non-chemotherapeutics, is needed for patients with Waldenström's macroglobulinaemia. The aim of the study was to assess the safety and clinical activity of intravenous ofatumumab monotherapy for untreated and relapsed Waldenström's macroglobulinaemia.We did a phase 2, open-label, single-arm study at six centres (hospitals and cancer clinics) in the USA. Patients aged at least 18 years who were diagnosed with untreated or relapsed Waldenström's macroglobulinaemia and required treatment, received up to three cycles of weekly ofatumumab for 5 weeks. For cycle 1, patients received one of two treatment regimens. Group A received ofatumumab 300 mg during week 1 followed by 1000 mg during weeks 2-4. Because of the acceptable safety of the 1000 mg dose in treatment group A and clinical activity of the 2000 mg dose established in chronic lymphocytic leukaemia, the study was amended on Dec 9, 2009, to change cycle 1 for group B who received ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 5-16 for treatment group A and during weeks 6-16 for treatment group B (no treatment was given during this follow-up). Patients in both groups with stable disease or a minor response after 16 weeks were eligible to then receive a redosing cycle of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 6-16 after the redosing cycle (no treatment was given during this follow-up). Patients responding to cycle 1 or the redosing cycle who developed disease progression within 36 months could receive cycle 2 of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. The primary endpoint for this study was the proportion of patients who achieved an overall response (complete responses plus partial responses plus minor responses) after each treatment cycle in the intent-to-treat population every 4 weeks starting at week 8. This trial is registered at www.ClinicalTrials.gov, NCT00811733, and is now complete.Between March 17, 2009, and Feb 24, 2011, we enrolled and assigned 37 patients to treatment (15 in treatment group A and 22 in treatment group B). All 37 were included in the efficacy and safety analyses. 19 (51%, 95% CI 34·4-68·1) of 37 patients achieved an overall response after cycle 1 and 22 (59%, 42·1-75·2) of 37 achieved an overall response after the redosing cycle; 15 (41%) with partial responses, seven (19%) with minor responses. 13 patients received treatment cycle 2; ten (77%) of the 13 achieved a response. All 37 patients had at least one adverse event; 16 (43%) patients had events of grade 3 or more (30 grade 3, one grade 4). The most common grade 3 or 4 adverse events were infusion reactions (four [11%] of 37), chest pain (two [5%] of 37), haemolysis (two [5%] of 37), and neutropenia (two [5%] of 37). Two (9%) of 22 patients (both in treatment group B) had an IgM flare. 12 patients reported serious adverse events; haemolysis and pyrexia were the most common (each occurring in two [5%] of 37 patients).A high proportion of patients achieved an overall response with ofatumumab monotherapy and this treatment was well tolerated, with a low incidence of IgM flare. This therapy might be a non-chemotherapeutic treatment option for patients with Waldenström's macroglobulinaemia, especially those with high IgM concentrations.GlaxoSmithKline and Genmab.

  View details for DOI 10.1016/S2352-3026(16)30166-1

  View details for PubMedID 27914971

• The landscape of new drugs in lymphoma. Nature reviews. Clinical oncology Younes, A., Ansell, S., Fowler, N., Wilson, W., de Vos, S., Seymour, J., Advani, R., Forero, A., Morschhauser, F., Kersten, M. J., Tobinai, K., Zinzani, P. L., Zucca, E., Abramson, J., Vose, J. 2016

  Abstract

  The landscape of drugs for the treatment of lymphoma has become crowded in light of the plethora of new agents, necessitating the efficient prioritization of drugs for expedited development. The number of drugs available, and the fact that many can be given for an extended period of time, has resulted in the emergence of new challenges; these include determining the optimal duration of therapy, and the need to balance costs, benefits, and the risk of late-onset toxicities. Moreover, with the increase in the number of available investigational drugs, the number of possible combinations is becoming overwhelming, which necessitates prioritization plans for the selective development of novel combination regimens. In this Review, we describe the most-promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies that might enable more streamlined drug development. We also address new approaches for patient selection and for incorporating new end points into clinical trials.

  View details for DOI 10.1038/nrclinonc.2016.205

  View details for PubMedID 28031560

• ACR Appropriateness Criteria (R) Hodgkin Lymphoma-Favorable Prognosis Stage I and II AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Dhakal, S., Advani, R., Ballas, L. K., Dabaja, B. S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S. M., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2016; 39 (6): 535-544

  Abstract

  This topic addresses the treatment of newly diagnosed patients with favorable prognosis stage I and II Hodgkin lymphoma. In most cases, combined modality therapy (chemotherapy followed by involved site radiation therapy) constitutes the current standard of care. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the appropriate use of combined modality therapy for favorable prognosis stage I and II Hodgkin lymphoma. Increasing information about the late effects of treatment has led to attempts to decrease toxicity by using less chemotherapy (decreased duration and/or intensity or different agents) and less radiation therapy (reduced volume and/or dose) while maintaining excellent efficacy.

  View details for DOI 10.1097/COC.0000000000000331

  View details for Web of Science ID 000389157500001

  View details for PubMedID 27643717

• ACR Appropriateness Criteria (R) Recurrent Hodgkin Lymphoma ONCOLOGY-NEW YORK Winkfield, K. M., Advani, R. H., Ballas, L. K., Dabaja, B. S., Dhakal, S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mansur, D. B., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S. M., Terezakis, S. A., Younes, A., Constine, L. S. 2016; 30 (12): 1099-1108

  Abstract

  This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decision-making associated with the management of recurrent Hodgkin lymphoma.

  View details for Web of Science ID 000392195200011

  View details for PubMedID 27987203

• Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy BLOOD Cheson, B. D., Ansell, S., Schwartz, L., Gordon, L. I., Advani, R., Jacene, H. A., Hoos, A., Barrington, S. F., Armand, P. 2016; 128 (21): 2489-2496

  Abstract

  Uniformly adopted response criteria are essential for assessment of therapies incorporating conventional chemotherapy and chemoimmunotherapy regimens. Recently, immunomodulatory agents, such as immune checkpoint inhibitors, have demonstrated impressive activity in a broad range of lymphoma histologies. However, these agents may be associated with clinical and imaging findings during treatment suggestive of progressive disease (PD) despite evidence of clinical benefit (eg, tumor flare or pseudo-progression). Considering this finding as PD could lead to patients being prematurely removed from a treatment from which they actually stand to benefit. This phenomenon has been well described with checkpoint blockade therapy in solid tumors and anecdotally seen in lymphoma as well. To address this issue in the context of lymphoma immunomodulatory therapy, a workshop was convened to provide provisional recommendations to modify current response criteria in patients receiving these and future agents in clinical trials. The term "indeterminate response" was introduced to identify such lesions until confirmed as flare/pseudo-progression or true PD by either biopsy or subsequent imaging.

  View details for DOI 10.1182/blood-2016-05-718528

  View details for Web of Science ID 000392649400007

  View details for PubMedID 27574190

• Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry. Leukemia & lymphoma Bartlett, N. L., Smith, M. R., Siddiqi, T., Advani, R. H., O'Connor, O. A., Sharman, J. P., Feldman, T., Savage, K. J., Shustov, A. R., Diefenbach, C. S., Oki, Y., Palanca-Wessels, M. C., Uttarwar, M., Li, M., Yang, J., Jacobsen, E. D. 2016: 1-10

  Abstract

  This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had ≥1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that ≥1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).

  View details for PubMedID 27868471

• Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA SCIENCE TRANSLATIONAL MEDICINE Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. F., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C. A., Diehn, M., Alizadeh, A. A. 2016; 8 (364)

  Abstract

  Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

  View details for DOI 10.1126/scitranslmed.aai8545

  View details for Web of Science ID 000389448100006

  View details for PubMedID 27831904

• Classical Hodgkin Lymphoma with Reduced ß2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status. Cancer immunology research Roemer, M. G., Advani, R. H., Redd, R. A., Pinkus, G. S., Natkunam, Y., Ligon, A. H., Connelly, C. F., Pak, C. J., Carey, C. D., Daadi, S. E., Chapuy, B., De Jong, D., Hoppe, R. T., Neuberg, D. S., Shipp, M. A., Rodig, S. J. 2016; 4 (11): 910-916

  Abstract

  In classical Hodgkin lymphoma (cHL), malignant Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple mechanisms, including perturbed antigen presentation and enhanced PD-1 signaling. HRS cell expression of the PD-1 ligands is attributable, in part, to copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) Amplification of PD-L1/PD-L2 is associated with advanced clinical stage and inferior progression-free survival (PFS) following first-line (induction) therapy. The relationships between altered expression of β2-microglobulin (β2M), MHC class I, and MHC class II by HRS cells, PD-L1/PD-L2 amplification, and clinical outcome in cHL are poorly defined. We assessed these variables in diagnostic biopsy specimens from 108 patients with cHL who received uniform treatment and had long-term follow-up and found decreased/absent expression of β2M/MHC class I in 79% (85/108) and decreased/absent expression of MHC class II in 67% (72/108) of cases. Patients with decreased/absent β2M/MHC class I had shorter PFS, independent of PD-L1/PD-L2 amplification and advanced stage. Decreased or absent MHC class II was unrelated to outcome. These results suggest that MHC class I-mediated antigen presentation by HRS cells is an important component of the biological response to standard chemo/radiotherapy. The paucity of β2M/MHC class I expression on HRS cells also prompts speculation regarding alternative mechanisms of action of PD-1 blockade in cHL. Cancer Immunol Res; 4(11); 910-6. ©2016 AACR.

  View details for PubMedID 27737878

  View details for PubMedCentralID PMC5210180

• Template for Reporting Results of Biomarker Testing of Specimens From Patients With Diffuse Large B-Cell Lymphoma, Not Otherwise Specified ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Duncavage, E., Advani, R. H., Agosti, S., Foulis, P., Gibson, C., Kang, L., Khoury, J. D., Medeiros, L. J., Ohgami, R. S., O'Malley, D. P., Patel, K. P., Rosenbaum, J. N., Wilson, C. 2016; 140 (11): 1225-1227

  View details for DOI 10.5858/arpa.2015-0418-CP

  View details for Web of Science ID 000388360100011

  View details for PubMedID 27081876

• Template for Reporting Results of Biomarker Testing of Specimens From Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Duncavage, E., Advani, R. H., Agosti, S., Foulis, P., Gibson, C., Kang, L., Khoury, J. D., Medeiros, L. J., Ohgami, R. S., O'Malley, D. P., Patel, K. P., Rosenbaum, J. N., Wilson, C. 2016; 140 (11): 1228-1230

  View details for DOI 10.5858/arpa.2016-0045-CP

  View details for Web of Science ID 000388360100012

  View details for PubMedID 27081879

• Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by (90)Yibritumomab tiuxetan: Ten year follow-up of the phase 2 ECOG-ACRIN study E1499. Leukemia Smith, M. R., Hong, F., Li, H., Gordon, L. I., Gascoyne, R. D., Paietta, E. M., Advani, R. H., Forero-Torres, A., Horning, S. J., Kahl, B. S. 2016

  View details for DOI 10.1038/leu.2016.305

  View details for PubMedID 27780968

• Treatment recommendations from the Eighth International Workshop on Waldenström's Macroglobulinemia. Blood Leblond, V., Kastritis, E., Advani, R., Ansell, S. M., Buske, C., Castillo, J. J., García-Sanz, R., Gertz, M., Kimby, E., Kyriakou, C., Merlini, G., Minnema, M. C., Morel, P., Morra, E., Rummel, M., Wechalekar, A., Patterson, C. J., Treon, S. P., Dimopoulos, M. A. 2016; 128 (10): 1321-1328

  Abstract

  Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of the International Workshop on Waldenström's Macroglobulinemia (IWWM). At IWWM-8, a task force for treatment recommendations was impanelled to review recently published and ongoing clinical trial data as well as the impact of new mutations (MYD88 and CXCR4) on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives for WM patients. The panel concluded that therapeutic strategies in WM should be based on individual patient and disease characteristics. Chemoimmunotherapy combinations with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone provide durable responses and are still indicated in most patients. Approval of the BTK inhibitor ibrutinib in the United States and Europe represents a novel and effective treatment option for both treatment-naive and relapsing patients. Other B-cell receptor inhibitors, second-generation proteasome inhibitors (eg, carfilzomib), and mammalian target of rapamycin inhibitors are promising and may increase future treatment options. Active enrollment in clinical trials whenever possible was endorsed by the panel for most patients with WM.

  View details for DOI 10.1182/blood-2016-04-711234

  View details for PubMedID 27432877

• NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016. Journal of the National Comprehensive Cancer Network Horwitz, S. M., Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Lee Harris, N., Hernandez-Ilizaliturri, F., Hoppe, R. T., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H., Porcu, P. 2016; 14 (9): 1067-1079

  Abstract

  Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

  View details for PubMedID 27587620

• Non-Hodgkin's Lymphomas, Version 3.2016 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Horwitz, S. M., Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H., Porcu, P. 2016; 14 (9): 1067-1079

  Abstract

  Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

  View details for Web of Science ID 000382903900004

• 2 Gy?×?2 for palliative treatment of mantle cell lymphoma. Leukemia & lymphoma White, E. C., Advani, R., Hoppe, R. T. 2016; 57 (9): 2219-2221

  View details for DOI 10.3109/10428194.2015.1131274

  View details for PubMedID 26763352

• ACR Appropriateness Criteria® Hodgkin Lymphoma-Unfavorable Clinical Stage I and II. American journal of clinical oncology Roberts, K. B., Younes, A., Hodgson, D. C., Advani, R., Dabaja, B. S., Dhakal, S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Shapiro, R., Smith, S. M., Terezakis, S. A., Winkfield, K. M., Constine, L. S. 2016; 39 (4): 384-395

  Abstract

  These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for DOI 10.1097/COC.0000000000000294

  View details for PubMedID 27299425

• Ibrutinib in Waldenström macroglobulinemia: latest evidence and clinical experience. Therapeutic advances in hematology Castillo, J. J., Palomba, M. L., Advani, R., Treon, S. P. 2016; 7 (4): 179-186

  Abstract

  Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor, which has recently gained approval by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with symptomatic Waldenström macroglobulinemia (WM). Herein, we review the role of BTK in the pathophysiology of WM, and present the results of the preclinical and clinical studies that led to the initial investigation and later approval of ibrutinib in WM. We also discuss aspects associated with ibrutinib therapy in WM patients, especially focusing on genomic profiling and the impact on response to ibrutinib, and the management of adverse events.

  View details for DOI 10.1177/2040620716654102

  View details for PubMedID 27493708

• Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. Blood Matthews, J. M., Bhatt, S., Patricelli, M. P., Nomanbhoy, T. K., Jiang, X., Natkunam, Y., Gentles, A. J., Martinez, E., Zhu, D., Chapman, J. R., Cortizas, E., Shyam, R., Chinichian, S., Advani, R., Tan, L., Zhang, J., Choi, H. G., Tibshirani, R., Buhrlage, S. J., Gratzinger, D., Verdun, R., Gray, N. S., Lossos, I. S. 2016; 128 (2): 239-248

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), yet 40-50% of patients will eventually succumb to their disease demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNA's that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that Germinal Center Kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Since the majority of DLBCL tumors (~80%) exhibit activation of GCK, this therapy may be applicable to most patients.

  View details for DOI 10.1182/blood-2016-02-696856

  View details for PubMedID 27151888

• Diffuse Large B-Cell Lymphoma: Prospective Multicenter Comparison of Early Interim FLT PET/CT versus FDG PET/CT with IHP, EORTC, Deauville, and PERCIST Criteria for Early Therapeutic Monitoring RADIOLOGY Minamimoto, R., Fayad, L., Advani, R., Vose, J., Macapinlac, H., Meza, J., Hankins, J., Mottaghy, F., Juweid, M., Quon, A. 2016; 280 (1): 220-229

  Abstract

  Purpose To compare the performance characteristics of interim fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (after two cycles of chemotherapy) by using the most prominent standardized interpretive criteria (including International Harmonization Project [IHP] criteria, European Organization for Research and Treatment of Cancer [EORTC] criteria, and PET Response Criteria in Solid Tumors (PERCIST) versus those of interim (18)F fluorothymidine (FLT) PET/CT and simple visual interpretation. Materials and Methods This HIPAA-compliant prospective study was approved by the institutional review boards, and written informed consent was obtained. Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) underwent both FLT and FDG PET/CT 18-24 days after two cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin. For FDG PET/CT interpretation, IHP criteria, EORTC criteria, PERCIST, Deauville criteria, standardized uptake value, total lesion glycolysis, and metabolic tumor volume were used. FLT PET/CT images were interpreted with visual assessment by two reviewers in consensus. The interim (after cycle 2) FDG and FLT PET/CT studies were then compared with the end-of-treatment FDG PET/CT studies to determine which interim examination and/or criteria best predicted the result after six cycles of chemotherapy. Results From November 2011 to May 2014, there were 60 potential patients for inclusion, of whom 46 patients (24 men [mean age, 60.9 years ± 13.7; range, 28-78 years] and 22 women [mean age, 57.2 years ± 13.4; range, 25-76 years]) fulfilled the criteria. Thirty-four patients had complete response, and 12 had residual disease at the end of treatment. FLT PET/CT had a significantly higher positive predictive value (PPV) (91%) in predicting residual disease than did any FDG PET/CT interpretation method (42%-46%). No difference in negative predictive value (NPV) was found between FLT PET/CT (94%) and FDG PET/CT (82%-95%), regardless of the interpretive criteria used. FLT PET/CT showed statistically higher (P < .001-.008) or similar NPVs than did FDG PET/CT. Conclusion Early interim FLT PET/CT had a significantly higher PPV than standardized FDG PET/CT-based interpretation for therapeutic response assessment in DLBCL. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2015150689

  View details for Web of Science ID 000378721900024

  View details for PubMedID 26854705

• The 2016 revision of the World Health Organization classification of lymphoid neoplasms BLOOD Swerdlow, S. H., Campo, E., Pileri, S. A., Harris, N. L., Stein, H., Siebert, R., Advani, R., Ghielmini, M., Salles, G. A., Zelenetz, A. D., Jaffe, E. S. 2016; 127 (20): 2375-2390

  Abstract

  A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.

  View details for DOI 10.1182/blood-2016-01-643569

  View details for Web of Science ID 000378333900008

  View details for PubMedID 26980727

  View details for PubMedCentralID PMC4874220

• Speeding up PET/MR for cancer staging of children and young adults. European radiology Aghighi, M., Pisani, L. J., Sun, Z., Klenk, C., Madnawat, H., Fineman, S. L., Advani, R., von Eyben, R., Owen, D., Quon, A., Moseley, M., Daldrup-Link, H. E. 2016: -?

  Abstract

  Combining (18)F-FDG PET with whole-body MR for paediatric cancer staging is practically feasible if imaging protocols can be streamlined. We compared (18)F-FDG PET/STIR with accelerated (18)F-FDG PET/FSPGR for whole-body tumour imaging in children and young adults.Thirty-three children and young adults (17.5 ± 5.5 years, range 10-30) with malignant lymphoma or sarcoma underwent a (18)F-FDG PET staging examination, followed by ferumoxytol-enhanced STIR and FSPGR whole-body MR. (18)F-FDG PET scans were fused with MR data and the number and location of tumours on each integrated examination were determined. Histopathology and follow-up imaging served as standard of reference. The agreement of each MR sequence with the reference and whole-body imaging times were compared using Cohen's kappa coefficient and Student's t-test, respectively.Comparing (18)F-FDG PET/FSPGR to (18)F-FDG PET/STIR, sensitivities were 99.3 % for both, specificities were statistically equivalent, 99.8 versus 99.9 %, and the agreement with the reference based on Cohen's kappa coefficient was also statistically equivalent, 0.989 versus 0.992. However, the total scan-time for accelerated FSPGR of 19.8 ± 5.3 minutes was significantly shorter compared to 29.0 ± 7.6 minutes for STIR (p = 0.001).F-FDG PET/FSPGR demonstrated equivalent sensitivities and specificities for cancer staging compared to (18)F-FDG PET/STIR, but could be acquired with shorter acquisition time.• Breath-hold FSPGR sequences shorten the data acquisition time for whole-body MR and PET/MR. • Ferumoxytol provides long-lasting vascular contrast for whole-body MR and PET/MR. • (18) F-FDG PET/FSPGR data provided equal sensitivity and specificity for cancer staging compared to (18) F-FDG PET/STIR.

  View details for PubMedID 27048532

• Breast Imaging in Women Previously Irradiated for Hodgkin Lymphoma. American journal of clinical oncology Horst, K. C., Fero, K. E., Hancock, S. L., Advani, R. H., Ikeda, D. M., Daniel, B., Rosenberg, S. A., Donaldson, S. S., Hoppe, R. T. 2016; 39 (2): 114-119

  Abstract

  Women treated with mantle irradiation for Hodgkin lymphoma (HL) are at an increased risk of developing breast cancer (BC). Current guidelines recommend screening breast magnetic resonance imaging (MRI) as an adjunct to mammography (M) in these patients. There are limited data, however, as to the impact of breast MRI on cancer detection rates. The aim of the current study is to evaluate the use of breast MRI in survivors of HL treated and followed at a single institution.We retrospectively reviewed 980 female patients treated with mantle irradiation for HL between 1961 and 2008. Records were reviewed to determine age at radiotherapy treatment, radiotherapy dose, breast imaging (including M and breast MRI), biopsy results if applicable, and incidence of BC.A total of 118 patients had breast imaging performed at our institution. Median age at HL diagnosis was 28 years (range, 10 to 69 y). Median radiotherapy dose was 36 Gy (range, 20 to 45 Gy). Seventy-nine patients (67%) underwent M screening only, 1 (1%) breast MRI only, and 38 (32%) both M and breast MRI. Of these 38, 19 (50%) underwent 54 screening MRI studies (range per patient=1 to 8), 13 (34%) underwent preoperative MRI for workup of BC, and 6 (16%) initiated screening MRI of the contralateral breast only after diagnosed with BC. Fifty-nine biopsies were performed: 47 were prompted by suspicious M findings only, 10 by palpable findings on physical examination (PE), and 2 by suspicious breast MRI findings. Of the 47 biopsies prompted by M, 24 revealed malignant disease, whereas 23 proved to be benign. All 10 biopsies performed by palpation were malignant. Both biopsies prompted by MRI findings were benign. With M, there were 34 true-positive findings in 32 patients, 23 false-positive findings, and 1 false-negative finding. With screening MRI, there were 2 false-positive findings, 1 false-negative finding, and no true-positive findings.The role of screening breast MRI in women previously irradiated for HL is evolving. Further education of patients and physicians is important to increase awareness of more sensitive BC screening modalities in this high-risk population. Future studies are necessary to determine the appropriate integration of screening breast MRI into the ongoing follow-up of these women.

  View details for DOI 10.1097/COC.0000000000000025

  View details for PubMedID 24390271

  View details for PubMedCentralID PMC4079764

• Postibrutinib outcomes in patients with mantle cell lymphoma BLOOD Martin, P., Maddocks, K., Leonard, J. P., Ruan, J., Goy, A., Wagner-Johnston, N., Rule, S., Advani, R., Iberri, D., Phillips, T., Spurgeon, S., Kozin, E., Noto, K., Chen, Z., Jurczak, W., Auer, R., Chmielowska, E., Stilgenbauer, S., Bloehdorn, J., Portell, C., Williams, M. E., Dreyling, M., Barr, P. M., Chen-Kiang, S., DiLiberto, M., Furman, R. R., Blum, K. A. 2016; 127 (12): 1559-1563

  Abstract

  Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients that experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL that experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological, and radiological data, and therapies used pre and post ibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range 0-10). The MIPI scores at start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23%, respectively. Of patients with available data prior to ibrutinib and post-ibrutinib, 34/47 and 11/12 had a Ki67>30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% CI 1.6-4.9 months). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% C.I. 3.7 to 10.4 months). Multivariate Cox regression analysis of MIPI prior to post-ibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment following ibrutinib.

  View details for DOI 10.1182/blood-2015-10-673145

  View details for Web of Science ID 000373505600011

  View details for PubMedID 26764355

• A single-institution retrospective analysis of outcomes for stage I-II primary mediastinal large B-cell lymphoma treated with immunochemotherapy with or without radiotherapy LEUKEMIA & LYMPHOMA Binkley, M. S., Hiniker, S. M., Wu, S., Natkunam, Y., Mittra, E. S., Advani, R. H., Hoppe, R. T. 2016; 57 (3): 604-608

  Abstract

  As the optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) remains undefined, we evaluated outcomes of patients treated with standard and dose-intense rituximab-chemotherapy (R-CT) with and without radiotherapy (RT). We retrospectively identified 28 patients with stage I-II PMBCL in our lymphoma database, re-reviewed pathology slides and scored interim or post-chemotherapy PET/CTs using the Deauville scale. Fourteen patients received RT (36-45 Gy) preceded by either six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 12 weeks of rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (R-VACOP-B) with median follow-up of 94 months. Fourteen patients received 4-8 cycles of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab (DA-EPOCH-R) with median follow-up of 38 months; one of these received RT (36 Gy) due to post-chemotherapy PET/CT Deauville score 4. Following R-CT and RT or DA-EPOCH-R, 5-year and 3-year FFP and OS were both 100%. Both R-CHOP/R-VACOP-B with RT and DA-EPOCH-R demonstrate excellent outcomes.

  View details for DOI 10.3109/10428194.2015.1067700

  View details for Web of Science ID 000372499800016

• Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom Macroglobulinaemia BRITISH JOURNAL OF HAEMATOLOGY Xu, L., Hunter, Z. R., Tsakmaklis, N., Cao, Y., Yang, G., Chen, J., Liu, X., Kanan, S., Castillo, J. J., Tai, Y., Zehnder, J. L., Brown, J. R., Carrasco, R. D., Advani, R., Sabile, J. M., Argyropoulos, K., Palomba, M. L., Morra, E., Trojani, A., Greco, A., Tedeschi, A., Varettoni, M., Arcaini, L., Munshi, N. M., Anderson, K. C., Treon, S. P. 2016; 172 (5): 735-744

  Abstract

  CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.

  View details for DOI 10.1111/bjh.13897

  View details for Web of Science ID 000370959600008

  View details for PubMedID 26659815

• A single-institution retrospective analysis of outcomes for stage I-II primary mediastinal large B-cell lymphoma treated with immunochemotherapy with or without radiotherapy. Leukemia & lymphoma Binkley, M. S., Hiniker, S. M., Wu, S., Natkunam, Y., Mittra, E. S., Advani, R. H., Hoppe, R. T. 2016; 57 (3): 604-608

  Abstract

  As the optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) remains undefined, we evaluated outcomes of patients treated with standard and dose-intense rituximab-chemotherapy (R-CT) with and without radiotherapy (RT). We retrospectively identified 28 patients with stage I-II PMBCL in our lymphoma database, re-reviewed pathology slides and scored interim or post-chemotherapy PET/CTs using the Deauville scale. Fourteen patients received RT (36-45 Gy) preceded by either six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 12 weeks of rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (R-VACOP-B) with median follow-up of 94 months. Fourteen patients received 4-8 cycles of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab (DA-EPOCH-R) with median follow-up of 38 months; one of these received RT (36 Gy) due to post-chemotherapy PET/CT Deauville score 4. Following R-CT and RT or DA-EPOCH-R, 5-year and 3-year FFP and OS were both 100%. Both R-CHOP/R-VACOP-B with RT and DA-EPOCH-R demonstrate excellent outcomes.

  View details for DOI 10.3109/10428194.2015.1067700

  View details for PubMedID 26159046

• Diffuse Large B-Cell Lymphoma Version 1.2016. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Lee Harris, N., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2016; 14 (2): 196-231

  Abstract

  Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

  View details for PubMedID 26850490

• Diffuse Large B-Cell Lymphoma Version 1.2016 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2016; 14 (2): 196-231

  Abstract

  Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

  View details for Web of Science ID 000369634300011

• Ibrutinib-associated rash: a single-centre experience of clinicopathological features and management. British journal of haematology 2016

  View details for DOI 10.1111/bjh.14302

  View details for PubMedID 27539794

• ACR Appropriateness Criteria® Diffuse Large B-Cell Lymphoma. American journal of clinical oncology Dabaja, B. S., Advani, R., Hodgson, D. C., Dhakal, S., Flowers, C. R., Ha, C. S., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S. M., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2015; 38 (6): 610-620

  View details for DOI 10.1097/COC.0000000000000215

  View details for PubMedID 26583344

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  Abstract

  In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

  View details for PubMedCentralID PMC5089160

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

• Hodgkin Lymphoma: the Changing Role of Radiation Therapy in Early-Stage Disease-the Role of Functional Imaging. Current treatment options in oncology Iberri, D. J., Hoppe, R. T., Advani, R. H. 2015; 16 (9): 360-?

  View details for DOI 10.1007/s11864-015-0360-6

  View details for PubMedID 26187795

• Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: Characteristics, outcomes, and prognostication among a large multicenter cohort AMERICAN JOURNAL OF HEMATOLOGY Evens, A. M., Kanakry, J. A., Sehn, L. H., Kritharis, A., Feldman, T., Kroll, A., Gascoyne, R. D., Abramson, J. S., Petrich, A. M., Hernandez-Ilizaliturri, F. J., Al-Mansour, Z., Adeimy, C., Hemminger, J., Bartlett, N. L., Mato, A., Caimi, P. F., Advani, R. H., Klein, A. K., Nabhan, C., Smith, S. M., Fabregas, J. C., Lossos, I. S., Press, O. W., Fenske, T. S., Friedberg, J. W., Vose, J. M., Blum, K. A. 2015; 90 (9): 778-783

  View details for DOI 10.1002/ajh.24082

  View details for Web of Science ID 000360218000019

• Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20(+) lymphoid malignancies BRITISH JOURNAL OF HAEMATOLOGY Roberts, A. W., Advani, R. H., Kahl, B. S., Persky, D., Sweetenham, J. W., Carney, D. A., Yang, J., Busman, T. B., Enschede, S. H., Humerickhouse, R. A., Seymour, J. F. 2015; 170 (5): 669-678

  Abstract

  The oral BCL2 inhibitor navitoclax has moderate single-agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B-cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200-325 mg) daily and four standard weekly doses of rituximab. Twenty-nine patients were enrolled across three dose-escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19(+) counts were severely reduced, while CD3(+) cells (~ 20%) and serum immunoglobulin M levels (~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low-grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials.

  View details for DOI 10.1111/bjh.13487

  View details for Web of Science ID 000359606400007

  View details for PubMedID 25942994

• Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. American journal of hematology Evens, A. M., Kanakry, J. A., Sehn, L. H., Kritharis, A., Feldman, T., Kroll, A., Gascoyne, R. D., Abramson, J. S., Petrich, A. M., Hernandez-Ilizaliturri, F. J., Al-Mansour, Z., Adeimy, C., Hemminger, J., Bartlett, N. L., Mato, A., Caimi, P. F., Advani, R. H., Klein, A. K., Nabhan, C., Smith, S. M., Fabregas, J. C., Lossos, I. S., Press, O. W., Fenske, T. S., Friedberg, J. W., Vose, J. M., Blum, K. A. 2015; 90 (9): 778-783

  Abstract

  Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty-three percent of patients presented with MGZL, whereas 57% had non-MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0.001); >1 extranodal site (27% versus 8%, P = 0.014); and advanced stage disease (81% versus 13%, P = 0.0001); but they had less bulk (8% versus 44%, P = 0.0001), compared with MGZL patients. Common frontline treatments were cyclophosphamide-doxorubicin-vincristine-prednisone +/- rituximab (CHOP+/-R) 46%, doxorubicin-bleomycin-vinblastine-dacarbazine +/- rituximab (ABVD+/-R) 30%, and dose-adjusted etoposide-doxorubicin-cyclophosphamide-vincristine-prednisone-rituximab (DA-EPOCH-R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31-month median follow-up, 2-year progression-free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, outcomes in MGZL patients seemed similar compared with that of NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival for all patients. Additionally, patients treated with ABVD+/-R had markedly inferior 2-year PFS (22% versus 52%, P = 0.03) compared with DLBCL-directed therapy (CHOP+/-R and DA-EPOCH-R), which persisted on Cox regression (hazard ratio, 1.88; 95% confidence interval, 1.03-3.83; P = 0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (hazard ratio, 0.35; 95% confidence interval, 0.18-0.69; P = 0.002). Collectively, GZL is a heterogeneous and likely more common entity and often with nonmediastinal presentation, whereas outcomes seem superior when treated with a rituximab-based, DLBCL-specific regimen. Am. J. Hematol. 90:778-783, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajh.24082

  View details for PubMedID 26044261

• A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402 BRITISH JOURNAL OF HAEMATOLOGY Witzig, T. E., Hong, F., Micallef, I. N., Gascoyne, R. D., Dogan, A., Wagner, H., Kahl, B. S., Advani, R. H., Horning, S. J. 2015; 170 (5): 679-686

  Abstract

  Patients with early stage diffuse large B-cell lymphoma (DLBCL) receive RCHOP (rituximab cyclophosphamide, doxorubicin, vincristine, prednisone) alone or with involved field radiotherapy (IFRT). Anti-CD20 radioimmunotherapy (RIT) delivers radiation to microscopic sites outside of known disease. This phase II study aimed to achieve a functional complete response (CR) rate of ≥75% to RCHOP and (90) Yttrium-ibritumomab tiuxetan RIT. Patients with stages I/II DLBCL received 4-6 cycles of RCHOP followed by RIT [14·8 MBq/kg (0·4 mCi/kg)]; patients with positron emission tomographypositive sites of disease after RCHOP/RIT received 30 Gy IFRT. Of the 62 patients enrolled; 53 were eligible. 42% (22/53) had stage I/IE; 58% (31/53) stage II/IIE. After RCHOP, 79% (42/53) were in CR/unconfirmed CR. Forty-eight patients proceeded to RIT. One partial responder after RIT received IFRT and achieved a CR. The best response after RCHOP + RIT in all 53 patients was a functional CR rate of 89% (47/53; 95% confidence interval: 77-96%). With a median follow-up of 5·9 years, 7 (13%) patients have progressed and 4 (8%) have died (2 with DLBCL). At 5 years, 78% of patients remain in remission and 94% are alive. Chemoimmunotherapy and RIT is an active regimen for early stage DLBCL patients. Eighty-nine percent of patients achieved functional CR without the requirement of IFRT. This regimen is worthy of further study for early stage DLBCL in a phase III trial.

  View details for DOI 10.1111/bjh.13493

  View details for Web of Science ID 000359606400008

  View details for PubMedID 25974212

• Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results BLOOD Wang, M. L., Blum, K. A., Martin, P., Goy, A., Auer, R., Kahl, B. S., Jurczak, W., Advani, R. H., Romaguera, J. E., Williams, M. E., Barrientos, J. C., Chmielowska, E., Radford, J., Stilgenbauer, S., Dreyling, M., Jedrzejczak, W. W., Johnson, P., Spurgeon, S. E., Zhang, L., Baher, L., Cheng, M., Lee, D., Beaupre, D. M., Rule, S. 2015; 126 (6): 739-745

  Abstract

  Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391.

  View details for DOI 10.1182/blood-2015-03-635326

  View details for Web of Science ID 000360519600009

  View details for PubMedCentralID PMC4528064

• Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma NATURE MEDICINE Wilson, W. H., Young, R. M., Schmitz, R., Yang, Y., Pittaluga, S., Wright, G., Lih, C., Williams, P. M., Shaffer, A. L., Gerecitano, J., de Vos, S., Goy, A., Kenkre, V. P., Barr, P. M., Blum, K. A., Shustov, A., Advani, R., Fowler, N. H., Vose, J. M., Elstrom, R. L., Habermann, T. M., Barrientos, J. C., McGreivy, J., Fardis, M., Chang, B. Y., Clow, F., Munneke, B., Moussa, D., Beaupre, D. M., Staudt, L. M. 2015; 21 (8): 922-926

  Abstract

  The two major subtypes of diffuse large B cell lymphoma (DLBCL)-activated B cell-like (ABC) and germinal center B cell-like (GCB)-arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling. The ABC subtype has a ∼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies. We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL.

  View details for DOI 10.1038/nm.3884

  View details for Web of Science ID 000359181000019

  View details for PubMedID 26193343

• Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia Pfeifer, M., Zheng, B., Erdmann, T., Koeppen, H., McCord, R., Grau, M., STAIGER, A., Chai, A., Sandmann, T., MADLE, H., Dörken, B., Chu, Y., Chen, A. I., LEBOVIC, D., Salles, G. A., Czuczman, M. S., Palanca-Wessels, M. C., Press, O. W., Advani, R., Morschhauser, F., Cheson, B. D., Lenz, P., Ott, G., Polson, A. G., Mundt, K. E., Lenz, G. 2015; 29 (7): 1578-1586

  Abstract

  Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti-CD79B-MMAE treatment because of low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL.

  View details for DOI 10.1038/leu.2015.48

  View details for PubMedID 25708834

• Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes LEUKEMIA Pfeifer, M., Zheng, B., Erdmann, T., Koeppen, H., McCord, R., Grau, M., STAIGER, A., Chai, A., Sandmann, T., MADLE, H., Doerken, B., Chu, Y., Chen, A. I., LEBOVIC, D., Salles, G. A., Czuczman, M. S., Palanca-Wessels, M. C., Press, O. W., Advani, R., Morschhauser, F., Cheson, B. D., Lenz, P., Ott, G., Polson, A. G., Mundt, K. E., Lenz, G. 2015; 29 (7): 1578-1586

  Abstract

  Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti-CD79B-MMAE treatment because of low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL.

  View details for DOI 10.1038/leu.2015.48

  View details for Web of Science ID 000357623100018

• Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood Kurtz, D. M., Green, M. R., Bratman, S. V., Scherer, F., Liu, C. L., Kunder, C. A., Takahashi, K., Glover, C., Keane, C., Kihira, S., Visser, B., Callahan, J., Kong, K. A., Faham, M., Corbelli, K. S., Miklos, D., Advani, R. H., Levy, R., Hicks, R. J., Hertzberg, M., Ohgami, R. S., Gandhi, M. K., Diehn, M., Alizadeh, A. A. 2015; 125 (24): 3679-3687

  Abstract

  Recent studies have shown limited utility of routine surveillance imaging for diffuse large B-cell lymphoma (DLBCL) patients achieving remission. Detection of molecular disease by immunoglobulin high-throughput sequencing (Ig-HTS) from peripheral blood provides an alternate strategy for surveillance. We prospectively evaluated the utility of Ig-HTS within 311 blood and 105 tumor samples from 75 patients with DLBCL, comparing Ig-HTS from the cellular (circulating leukocytes) and acellular (plasma cell-free DNA) compartments of peripheral blood to clinical outcomes and (18)fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT; n = 173). Clonotypic immunoglobulin rearrangements were detected in 83% of patients with adequate tumor samples to enable subsequent monitoring in peripheral blood. Molecular disease measured from plasma, compared with circulating leukocytes, was more abundant and better correlated with radiographic disease burden. Before treatment, molecular disease was detected in the plasma of 82% of patients compared with 71% in circulating cells (P = .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P = .001). Detection of molecular disease in the plasma often preceded PET/CT detection of relapse in patients initially achieving remission. During surveillance time points before relapse, plasma Ig-HTS demonstrated improved specificity (100% vs 56%, P < .0001) and similar sensitivity (31% vs 55%, P = .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission.

  View details for DOI 10.1182/blood-2015-03-635169

  View details for PubMedID 25887775

  View details for PubMedCentralID PMC4463733

• Management of nodular lymphocyte predominant Hodgkin lymphoma HEMATOLOGICAL ONCOLOGY Advani, R. H., Hoppe, R. T. 2015; 33: 90-95

  View details for DOI 10.1002/hon.2226

  View details for Web of Science ID 000356094300017

  View details for PubMedID 26062064

• Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study LANCET ONCOLOGY Palanca-Wessels, M. C., Czuczman, M., Salles, G., Assouline, S., Sehn, L. H., Flinn, I., Patel, M. R., Sangha, R., Hagenbeek, A., Advani, R., Tilly, H., Casasnovas, O., Press, O. W., Yalamanchili, S., Kahn, R., Dere, R. C., Lu, D., Jones, S., Jones, C., Chu, Y., Morschhauser, F. 2015; 16 (6): 704-715

  Abstract

  Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL).In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549.Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL.Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL.Genentech.

  View details for DOI 10.1016/S1470-2045(15)70128-2

  View details for Web of Science ID 000355246600055

  View details for PubMedID 25925619

• Value of Surveillance Studies for Patients With Stage I to II Diffuse Large B-Cell Lymphoma in the Rituximab Era. International journal of radiation oncology, biology, physics Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Xu, G., Quon, A., Advani, R. H., Hoppe, R. T. 2015; 92 (1): 99-106

  Abstract

  The role of surveillance studies in limited-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been well defined. We sought to evaluate the use of imaging (computed tomography [CT] and positron emission tomography [PET]-CT) scans and lactate dehydrogenase (LDH) in surveillance of patients with stage I to II DLBCL.A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013.One hundred sixty-two consecutive patients with stage I to II DLBCL were treated with chemotherapy +/- rituximab, radiation, or combined modality therapy. The 5-year rates of overall survival (OS) and freedom from progression (FFP) were 81.2% and 80.8%, respectively. Of the 162 patients, 124 (77%) were followed up with at least 1 surveillance PET scan beyond end-of-treatment scans; of those, 94 of 124 (76%) achieved a complete metabolic response on PET scan after completion of chemotherapy, and this was associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3). Eighteen patients experienced relapse after initial response to therapy. Nine relapses were initially suspected by surveillance imaging studies (8 PET, 1 CT), and 9 were suspected clinically (5 by patient-reported symptoms and 4 by symptoms and physical examination). No relapses were detected by surveillance LDH. The median duration from initiation of treatment to relapse was 14.3 months among patients with relapses suspected by imaging, and 59.8 months among patients with relapses suspected clinically (P=.077). There was no significant difference in OS from date of first therapy or OS after relapse between patients whose relapse was suspected by imaging versus clinically. Thirteen of 18 patients underwent successful salvage therapy after relapse.A complete response on PET scan immediately after initial chemotherapy is associated with superior FFP and OS in stage I to II DLBCL. The use of PET scans as posttreatment surveillance is not associated with a survival advantage. LDH is not a sensitive marker for relapse. Our results argue for limiting the use of posttreatment surveillance in patients with limited-stage DLBCL.

  View details for DOI 10.1016/j.ijrobp.2015.01.039

  View details for PubMedID 25863757

• Hodgkin Lymphoma, Version 2.2015 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Benitez, C. M., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Huang, J., Johnston, P. B., Khan, N., Maloney, D. G., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Mulroney, C., Poppe, M., Rabinovitch, R., Seropian, S., Tsien, C., Winter, J. N., Yahalom, J., Burns, J. L., Sundar, H. 2015; 13 (5): 554-586

  Abstract

  Hodgkin lymphoma (HL) is an uncommon malignancy involving lymph nodes and the lymphatic system. Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma are the 2 main types of HL. CHL accounts for most HL diagnosed in the Western countries. Chemotherapy or combined modality therapy, followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale), is the standard initial treatment for patients with newly diagnosed CHL. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, has produced encouraging results in the treatment of relapsed or refractory disease. The potential long-term effects of treatment remain an important consideration, and long-term follow-up is essential after completion of treatment.

  View details for Web of Science ID 000354283800008

  View details for PubMedID 25964641

  View details for PubMedCentralID PMC4898052

• Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma in the Modern Era INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS King, M. T., Donaldson, S. S., Link, M. P., Natkunam, Y., Advani, R. H., Hoppe, R. T. 2015; 92 (1): 67-75

  Abstract

  To analyze treatment outcomes for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) at a single institution.Patients with newly diagnosed NLPHL between 1996 and 2013 were reviewed retrospectively. Patients treated before 1996 were excluded because the majority received extended field radiation therapy (RT) alone.Fifty-five patients (22 ≤ 21 years old) were identified. The median follow-up time was 6.8 years. Among 37 patients with limited-stage (I-II) disease, treatments included involved field RT at a median dose of 36 Gy (n=9), rituximab monotherapy (n=9), observation (n=3), and response-adaptive therapy (n=16), in which the RT dose was reduced from 25.5 Gy to 15 Gy or was eliminated based on interim imaging after chemotherapy. The 5-year progression-free survival (PFS) was 76.4% (95% confidence interval [CI], 63.1-92.4). Nine patients experienced progression, including 5 receiving rituximab, 2 undergoing observation, and 2 receiving response-adaptive therapy. Rituximab was associated with an inferior PFS compared with RT alone (P=.02). The difference in PFS between response-adaptive therapy and RT alone was not statistically significant (P=.39). Among 18 patients with advanced-stage (III-IV) disease, treatments included chemotherapy alone (n=3), combined modality therapy (CMT) (n=2), response-adaptive therapy (n=2), rituximab (n=7), and observation (n=4). The 5-year PFS was 29.9% (CI, 13.3-67.4). Twelve patients experienced progression, including 1 receiving chemotherapy, 1 receiving CMT, 6 receiving rituximab, and 4 undergoing observation. There was no significant PFS difference between rituximab and non-rituximab therapies (P=.19) within the caveat of small sample sizes. In the entire cohort, 9 patients (3 with limited disease, 6 with advanced disease) experienced large cell transformation (LCT). Seven patients died; of those, 5 died with LCT.For limited disease, response-adaptive therapy demonstrated comparable outcomes with RT alone. Rituximab monotherapy resulted in inferior outcomes for limited disease and a high relapse rate for advanced disease.

  View details for DOI 10.1016/j.ijrobp.2015.02.001

  View details for Web of Science ID 000353988200011

  View details for PubMedID 25863755

• A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma BRITISH JOURNAL OF HAEMATOLOGY Foss, F., Advani, R., Duvic, M., Hymes, K. B., Intragumtornchai, T., Lekhakula, A., Shpilberg, O., Lerner, A., Belt, R. J., Jacobsen, E. D., Laurent, G., Ben-Yehuda, D., Beylot-Barry, M., Hillen, U., Knoblauch, P., Bhat, G., Chawla, S., Allen, L. F., Pohlman, B. 2015; 168 (6): 811-819

  Abstract

  Belinostat is a pan-histone deacetylase inhibitor with antitumour and anti-angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000 mg/m(2) intravenously ×5 d of a 21-d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n = 24) had received a median of three prior systemic therapies (range 1-9) and 40% had stage IV disease. Patients with CTCL (n = 29) had received a median of one prior skin-directed therapy (range 0-4) and four prior systemic therapies (range 1-9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment-related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment-related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at www.clinicaltrials.gov as NCT00274651.

  View details for DOI 10.1111/bjh.13222

  View details for Web of Science ID 000351043400005

  View details for PubMedID 25404094

• Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Saad, A. A., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Wilson, L., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2015; 13 (3): 326-362

  View details for PubMedID 25736010

• Anxiety and Health-Related Quality of Life Among Patients With Low-Tumor Burden Non-Hodgkin Lymphoma Randomly Assigned to Two Different Rituximab Dosing Regimens: Results From ECOG Trial E4402 (RESORT) JOURNAL OF CLINICAL ONCOLOGY Wagner, L. I., Zhao, F., Hong, F., Williams, M. E., Gascoyne, R. D., Krauss, J. C., Advani, R. H., Go, R. S., Habermann, T. M., Leach, J. W., O'Connor, B., Schuster, S. J., Cella, D., Horning, S. J., Kahl, B. S. 2015; 33 (7)

  View details for DOI 10.1200/JCO.2014.57.6801

  View details for Web of Science ID 000352524200014

  View details for PubMedID 25605841

• Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT). Journal of clinical oncology Wagner, L. I., Zhao, F., Hong, F., Williams, M. E., Gascoyne, R. D., Krauss, J. C., Advani, R. H., Go, R. S., Habermann, T. M., Leach, J. W., O'Connor, B., Schuster, S. J., Cella, D., Horning, S. J., Kahl, B. S. 2015; 33 (7): 740-748

  Abstract

  The purpose of this study was to compare illness-related anxiety among participants in the Rituximab Extended Schedule or Retreatment Trial (RESORT) randomly assigned to maintenance rituximab (MR) versus rituximab re-treatment (RR). A secondary objective was to examine whether the superiority of MR versus RR on anxiety depended on illness-related coping style.Patients (N = 253) completed patient-reported outcome (PRO) measures at random assignment to MR or RR (baseline); at 3, 6, 12, 24, 36, and 48 months after random assignment; and at rituximab failure. PRO measures assessed illness-related anxiety and coping style, and secondary end points including general anxiety, worry and interference with emotional well-being, depression, and health-related quality of life (HRQoL). Patients were classified as using an active or avoidant illness-related coping style. Independent sample t tests and linear mixed-effects models were used to identify treatment arm differences on PRO end points and differences based on coping style.Illness-related anxiety was comparable between treatment arms at all time points (P > .05), regardless of coping style (active or avoidant). Illness-related anxiety and general anxiety significantly decreased over time on both arms. HRQoL scores were relatively stable and did not change significantly from baseline for both arms. An avoidant coping style was associated with significantly higher anxiety (18% and 13% exceeded clinical cutoff points at baseline and 6 months, respectively) and poorer HRQoL compared with an active coping style (P < .001), regardless of treatment arm assignment.Surveillance until RR at progression was not associated with increased anxiety compared with MR, regardless of coping style. Avoidant coping was associated with higher anxiety and poorer HRQoL.

  View details for DOI 10.1200/JCO.2014.57.6801

  View details for PubMedID 25605841

• Allogeneic transplant following brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma LEUKEMIA & LYMPHOMA Illidge, T., Bouabdallah, R., Chen, R., Gopal, A. K., Moskowitz, C. H., Ramchandren, R., Shustov, A. R., Tilly, H., Trippett, T. M., Gibb, A., Grove, L. E., Advani, R. 2015; 56 (3): 703-710

  Abstract

  Brentuximab vedotin is an antibody drug conjugate that induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Fifteen of 160 patients who participated in two pivotal phase 2 studies received a consolidative allogeneic stem cell transplant (allo-SCT) following brentuximab vedotin treatment. This case series describes their experience. The studies were approved by Institutional Review Boards prior to patient enrollment. Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks for up to 16 cycles. The estimated 2-year progression-free survival (PFS) rate was 66%, and the median PFS has not yet been reached. Eleven of the 15 patients were alive and the estimated 2-year survival rate was 80%. The safety of brentuximab vedotin treatment in this series was consistent with the known safety profile in this setting. Brentuximab vedotin is a compelling option for reducing tumor burden to facilitate a consolidative allo-SCT.

  View details for DOI 10.3109/10428194.2014.930852

  View details for Web of Science ID 000351144500025

  View details for PubMedID 24913507

• Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Saad, A. A., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Wilson, L., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2015; 13 (3): 326-362

  Abstract

  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL.

  View details for PubMedID 25736010

• Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression BLOOD Jacobsen, E. D., Sharman, J. P., Oki, Y., Advani, R. H., Winter, J. N., Bello, C. M., Spitzer, G., Palanca-Wessels, M. C., Kennedy, D. A., Levine, P., Yang, J., Bartlett, N. L. 2015; 125 (9): 1394-1402

  Abstract

  Several non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), variably express CD30. This phase 2, open-label study evaluated the efficacy of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in relapsed/refractory CD30(+) NHL. This planned subset analysis of B-cell NHLs includes 49 patients with DLBCL and 19 with other B-cell NHLs. Objective response rate was 44% for DLBCL, including 8 (17%) complete remissions (CRs) with a median duration of 16.6 months thus far (range, 2.7 to 22.7+ months). There was no statistical correlation between response and level of CD30 expression; however, all responding patients had quantifiable CD30 by computer-assisted assessment of immunohistochemistry. DLBCL patients were generally refractory to first-line (76%) and most recent therapies (82%), and 44% of these refractory patients responded (15% CRs). Patients with other B-cell lymphomas also responded: 1 CR, 2 partial responses (PRs) of 6 with gray zone, 1 CR of 6 with primary mediastinal B-cell, and 1 CR of 3 with posttransplant lymphoproliferative disorder. Adverse events were consistent with known toxicities. The combination of brentuximab vedotin with rituximab was generally well tolerated and had activity similar to brentuximab vedotin alone. Overall, significant activity with brentuximab vedotin was observed in relapsed/refractory DLBCL, and responses occurred across a range of CD30 expression. This study was registered at www.clinicaltrials.gov as #NCT01421667.

  View details for DOI 10.1182/blood-2014-09-598763

  View details for Web of Science ID 000350820900011

  View details for PubMedID 25573987

• Improved outcomes after autologous bone marrow transplantation for children with relapsed or refractory hodgkin lymphoma: twenty years experience at a single institution. Biology of blood and marrow transplantation Garfin, P. M., Link, M. P., Donaldson, S. S., Advani, R. H., Luna-Fineman, S., Kharbanda, S., Porteus, M., Weinberg, K. I., Agarwal-Hashmi, R. 2015; 21 (2): 326-334

  Abstract

  The purpose of this study is to evaluate the survival of pediatric patients undergoing autologous bone marrow transplantation (auBMT) for relapsed or refractory Hodgkin lymphoma (rrHL) and to identify factors that might contribute to their outcome. We reviewed the records and clinical course of 89 consecutive rrHL patients ≤ 21 years old who underwent auBMT at Stanford Hospitals and Clinics and the Lucile Packard Children's Hospital, Stanford between 1989 and 2012. We investigated, by multiple analyses, patient, disease, and treatment characteristics associated with outcome. Endpoints were 5-year overall and event-free survival. Our findings include that cyclophosphamide, carmustine, and etoposide (CBV) as a conditioning regimen for auBMT is effective for most patients ≤ 21 years old with rrHL (5-year overall survival, 71%). Transplantation after the year 2001 was associated with significantly improved overall survival compared with our earlier experience (80% compared with 65%). Patients with multiply relapsed disease or with disease not responsive to initial therapy fared less well compared with those with response to initial therapy or after first relapse. Administration of post-auBMT consolidative radiotherapy (cRT) also appears to contribute to improved survival. We are able to conclude that high-dose chemotherapy with CBV followed by auBMT is effective for the treatment of rrHL in children and adolescents. Survival for patients who undergo auBMT for rrHL has improved significantly. This improvement may be because of patient selection and improvements in utilization of radiotherapy rather than improvements in chemotherapy. Further investigation is needed to describe the role of auBMT across the entire spectrum of patients with rrHL and to identify the most appropriate preparative regimen with or without cRT therapy in the treatment of rrHL in young patients.

  View details for DOI 10.1016/j.bbmt.2014.10.020

  View details for PubMedID 25445024

• Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies CANCER CHEMOTHERAPY AND PHARMACOLOGY Marostica, E., Sukbuntherng, J., Loury, D., de Jong, J., de Trixhe, X. W., Vermeulen, A., De Nicolao, G., O'Brien, S., Byrd, J. C., Advani, R., McGreivy, J., Poggesi, I. 2015; 75 (1): 111-121

  Abstract

  Ibrutinib is an oral Bruton's tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients.Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25-12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling.A two-compartment PK model with sequential zero-first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively.The proposed population PK model was able to describe the plasma concentration-time profiles of ibrutinib across various trials. The linear model indicated that the compound's PK was dose independent and time independent.

  View details for DOI 10.1007/s00280-014-2617-3

  View details for Web of Science ID 000347153200012

  View details for PubMedID 25381051

• Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial. Leukemia & lymphoma Fayad, L., Ansell, S. M., Advani, R., Coiffier, B., Stuart, R., Bartlett, N. L., Forero-Torres, A., Kuliczkowski, K., Belada, D., Ng, E., Drachman, J. G. 2015; 56 (9): 2569-2578

  Abstract

  Single-agent dacetuzumab has demonstrated antitumor activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Preclinical data demonstrated improved dacetuzumab antitumor activity in combination with rituximab, ± chemotherapy. We designed a phase 2b, double-blind, placebo-controlled trial to compare rituximab, ifosfamide, carboplatin and etoposide (R-ICE) + dacetuzumab with R-ICE + placebo in patients with DLBCL who relapsed after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (ClinicalTrials.gov #NCT00529503). The primary endpoint was complete response (CR); additional endpoints included failure-free survival and overall survival (OS). Overall, 151 patients were randomized (75 dacetuzumab, 76 placebo). No notable differences between arms in demographics or subsequent treatment parameters were observed. Cytopenias, cough and infection were more frequent with dacetuzumab. Futility analysis failed to demonstrate higher CR rates with dacetuzumab (36% dacetuzumab, 42% placebo); consequently, enrollment was stopped. Unplanned post hoc analysis showed that patients who underwent subsequent autologous stem cell transplant experienced improvement in OS (hazard ratio = 0.195, p = 0.004), which may be explained by potential immunomodulatory effects of dacetuzumab on antigen-presenting cells.

  View details for DOI 10.3109/10428194.2015.1007504

  View details for PubMedID 25651427

• ACR Appropriateness Criteria Follow-up of Hodgkin Lymphoma JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Ha, C. S., Hodgson, D. C., Advani, R., Dabaja, B. S., Dhakal, S., Flowers, C. R., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2014; 11 (11): 1026-1033

  View details for DOI 10.1016/j.jacr.2014.07.038

  View details for Web of Science ID 000344834800008

• ACR appropriateness criteria follow-up of Hodgkin lymphoma. Journal of the American College of Radiology Ha, C. S., Hodgson, D. C., Advani, R., Dabaja, B. S., Dhakal, S., Flowers, C. R., Hoppe, B. S., Mendenhall, N. P., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Smith, S., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2014; 11 (11): 1026-1033 e3

  Abstract

  The main objectives of follow-up studies after completion of treatment for Hodgkin lymphoma are detection of recurrence for salvage therapy and monitoring for sequelae of treatment. The focus of the follow-up shifts, with time after treatment, from detection of recurrence to long-term sequelae. A majority of recurrence is detected by history and physical examination. The yield for routine imaging studies and blood tests is low. Although routine surveillance CT scan can detect recurrence not detected by history and physical examination, its benefit in ultimate survival and cost-effectiveness is not well defined. Although PET scan is a useful tool in assessing response to treatment, its routine use for follow-up is not recommended. Long-term sequelae of treatment include secondary malignancy, cardiovascular disease, pneumonitis, reproductive dysfunction, and hypothyroidism. Follow-up strategies for these sequelae need to be individualized, as their risks in general depend on the dose and volume of radiation to these organs, chemotherapy, age at treatment, and predisposing factors for each sequela. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is either lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for DOI 10.1016/j.jacr.2014.07.038

  View details for PubMedID 25278496

• Brentuximab Vedotin in the Front-Line Treatment of Patients With CD30(+) Peripheral T-Cell Lymphomas: Results of a Phase I Study JOURNAL OF CLINICAL ONCOLOGY Fanale, M. A., Horwitz, S. M., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Illidge, T., Huebner, D., Kennedy, D. A., Shustov, A. R. 2014; 32 (28): 3137-?

  View details for DOI 10.1200/JCO.2013.54.2456

  View details for Web of Science ID 000342671000009

• Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. Journal of clinical oncology Fanale, M. A., Horwitz, S. M., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Illidge, T., Huebner, D., Kennedy, D. A., Shustov, A. R. 2014; 32 (28): 3137-3143

  Abstract

  Front-line treatment of peripheral T-cell lymphomas (PTCL) involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50%. This phase I open-label study evaluated the safety and activity of brentuximab vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30(+) PTCL.Patients received sequential treatment (once every 3 weeks) with brentuximab vedotin 1.8 mg/kg (two cycles) followed by CHOP (six cycles) or brentuximab vedotin 1.8 mg/kg plus CHP (BV+CHP) for six cycles (once every 3 weeks). Responders received single-agent brentuximab vedotin for eight to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end points included objective response rate, complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no prespecified comparisons of the two treatment approaches.After sequential treatment, 11 (85%) of 13 patients achieved an objective response (CR rate, 62%; estimated 1-year PFS rate, 77%). Grade 3/4 adverse events occurred in eight (62%) of 13 patients. At the end of combination treatment, all patients (n = 26) achieved an objective response (CR rate, 88%; estimated 1-year PFS rate, 71%). All seven patients without anaplastic large-cell lymphoma achieved CR. Grade 3/4 adverse events (≥ 10%) in the combination-treatment group were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).Brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, had a manageable safety profile and exhibited substantial antitumor activity in newly diagnosed patients with CD30(+) PTCL. A randomized phase III trial is under way, comparing BV+CHP with CHOP (clinical trial No. NCT01777152).

  View details for DOI 10.1200/JCO.2013.54.2456

  View details for PubMedID 25135998

• Non-Hodgkin's Lymphomas, Version 4.2014. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Saad, A. A., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2014; 12 (9): 1282-1303

  Abstract

  Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

  View details for PubMedID 25190696

• Treatment recommendations for patients with Waldenstrom macroglobulinemia (WM) and related disorders: IWWM-7 consensus BLOOD Dimopoulos, M. A., Kastritis, E., Owen, R. G., Kyle, R. A., Landgren, O., Morra, E., Leleu, X., Garcia-Sanz, R., Munshi, N., Anderson, K. C., Terpos, E., Ghobrial, I. M., Morel, P., Maloney, D., Rummel, M., Leblond, V., Advani, R. H., Gertz, M. A., Kyriakou, C., Thomas, S. K., Barlogie, B., Gregory, S. A., Kimby, E., Merlini, G., Treon, S. P. 2014; 124 (9): 1404-1411

  Abstract

  Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

  View details for DOI 10.1182/blood-2014-03-565135

  View details for Web of Science ID 000342762100012

  View details for PubMedID 25027391

• Bruton's tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib. Therapeutic advances in hematology Aalipour, A., Advani, R. H. 2014; 5 (4): 121-133

  Abstract

  Aberrant signaling of the B-cell receptor pathway has been linked to the development and maintenance of B-cell malignancies. Bruton's tyrosine kinase (BTK), a protein early in this pathway, has emerged as a new therapeutic target in a variety of such malignancies. Ibrutinib, the most clinically advanced small molecule inhibitor of BTK, has demonstrated impressive tolerability and activity in a range of B-cell lymphomas which led to its recent approval for relapsed mantle cell lymphoma and chronic lymphocytic leukemia. This review focuses on the preclinical and clinical development of ibrutinib and discusses its therapeutic potential.

  View details for DOI 10.1177/2040620714539906

  View details for PubMedID 25360238

  View details for PubMedCentralID PMC4212313

• ACR appropriateness Criteria® pediatric Hodgkin lymphoma. Pediatric blood & cancer Terezakis, S. A., Metzger, M. L., Hodgson, D. C., Schwartz, C. L., Advani, R., Flowers, C. R., Hoppe, B. S., Ng, A., Roberts, K. B., Shapiro, R., Wilder, R. B., Yunes, M. J., Constine, L. S. 2014; 61 (7): 1305-1312

  Abstract

  Pediatric Hodgkin lymphoma is a highly curable malignancy and potential long-term effects of therapy need to be considered in optimizing clinical care. An expert panel was convened to reach consensus on the most appropriate approach to evaluation and treatment of pediatric Hodgkin lymphoma. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Four clinical variants were developed to assess common clinical scenarios and render recommendations for evaluation and treatment approaches to pediatric Hodgkin lymphoma. We provide a summary of the literature as well as numerical ratings with commentary. By combining available data in published literature and expert medical opinion, we present a consensus to the approach for management of pediatric Hodgkin lymphoma.

  View details for DOI 10.1002/pbc.24983

  View details for PubMedID 24616347

• A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors JOURNAL OF HEMATOLOGY & ONCOLOGY de Vos, S., Forero-Torres, A., Ansell, S. M., Kahl, B., Cheson, B. D., Bartlett, N. L., Furman, R. R., Winter, J. N., Kaplan, H., Timmerman, J., Whiting, N. C., Drachman, J. G., Advani, R. 2014; 7

  View details for DOI 10.1186/1756-8722-7-44

  View details for Web of Science ID 000338587000001

• Non-Hodgkin's lymphomas, version 2.2014. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2014; 12 (6): 916-946

  Abstract

  Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Follicular lymphoma (FL) is the most common subtype of indolent NHL, accounting for approximately 22% of all newly diagnosed cases of NHL. The incorporation of rituximab to chemotherapy regimens has become a widely accepted standard of care for first-line therapy for patients with FL. Maintenance and consolidation therapy with rituximab and radioimmunotherapy have also been associated with improved progression-free survival in patients experiencing response to first-line therapy. Despite therapeutic advances that have improved outcomes, FL is generally considered a chronic disease characterized by multiple recurrences with current therapies. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with FL.

  View details for PubMedID 24925202

• Non-Hodgkin's Lymphomas, Version 2.2014. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Fisher, R. I., Glenn, M. J., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2014; 12 (6): 916-946

  View details for PubMedID 24925202

• Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin BLOOD Horwitz, S. M., Advani, R. H., Bartlett, N. L., Jacobsen, E. D., Sharman, J. P., O'Connor, O. A., Siddiqi, T., Kennedy, D. A., Oki, Y. 2014; 123 (20): 3095-3100

  Abstract

  This phase 2, open-label, multicenter study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in relapsed/refractory CD30(+) non-Hodgkin lymphomas. The primary end point was objective response rate (ORR). Key secondary end points included safety, correlation of CD30 expression with response, response duration, and progression-free survival (PFS). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks until progression or unacceptable toxicity. This planned subset analysis included patients with peripheral T-cell lymphomas (PTCLs; n = 35), specifically angioimmunoblastic T-cell lymphoma (AITL; n = 13) and PTCL not otherwise specified (n = 22). Median age was 64 years; 63% were refractory to most recent therapy. Of 34 evaluable patients, ORR was 41% (8 complete remissions [CRs], 6 partial remissions [PRs]), and ORR was 54% in AITL (5 CRs, 2 PRs) with median PFS of 6.7 months thus far. No correlation between CD30 expression per central review and response was observed. Safety data were consistent with the known profile of brentuximab vedotin, and included at least grade 3 events of neutropenia (14%), peripheral sensory neuropathy, and hyperkalemia (9% each). In summary, brentuximab vedotin showed antitumor activity in patients with relapsed PTCL particularly AITL. This trial was registered at www.clinicaltrials.gov as #NCT01421667.

  View details for DOI 10.1182/blood-2013-12-542142

  View details for Web of Science ID 000335899400016

  View details for PubMedID 24652992

• A multicentre study of primary breast diffuse large B-cell lymphoma in the rituximab era BRITISH JOURNAL OF HAEMATOLOGY Hosein, P. J., Maragulia, J. C., Salzberg, M. P., Press, O. W., Habermann, T. M., Vose, J. M., Bast, M., Advani, R. H., Tibshirani, R., Evens, A. M., Islam, N., Leonard, J. P., Martin, P., Zelenetz, A. D., Lossos, I. S. 2014; 165 (3): 358-363

  Abstract

  Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow-up of 4·5 years (range 0·6-20·6 years), the Kaplan-Meier estimated median progression-free survival was 10·4 years (95% confidence interval [CI] 5·8-14·9 years), and the median overall survival was 14·6 years (95% CI 10·2-19 years). Twelve patients (16%) had CNS relapse. A low stage-modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage-modified IPI score is associated with survival.

  View details for DOI 10.1111/bjh.12753

  View details for Web of Science ID 000334031000011

  View details for PubMedID 24467658

• Bevacizumab and cyclosphosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology Group study (E2404). Leukemia & lymphoma Ganjoo, K., Hong, F., Horning, S. J., Gascoyne, R. D., Natkunam, Y., Swinnen, L. J., Habermann, T. M., Kahl, B. S., Advani, R. H. 2014; 55 (4): 768-772

  Abstract

  Peripheral T-cell lymphoma (PTCL) and natural killer (NK) cell lymphoma have poor survival with conventional cytotoxic chemotherapy. Because angiogenesis plays an important role in the biology of PTCL, a fully humanized anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab (A), was studied in combination with standard cyclosphosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy (ACHOP) to evaluate its potential to improve outcome in these patients. Patients were treated with 6-8 cycles of ACHOP followed by eight doses of maintenance A (15 mg/kg every 21 days). Forty-six patients were enrolled on this phase 2 study from July 2006 through March 2009. Forty-four patients were evaluable for toxicity and 39 were evaluable for response, progression and survival. A total of 324 cycles (range: 2-16, median 7) were administered to 39 evaluable patients and only nine completed all planned treatment. The overall response rate was 90% with 19 (49%) complete response/complete response unconfirmed (CR/CRu) and 16 (41%) a partial response (PR). The 1-year progression-free survival (PFS) rate was 44% at a median follow-up of 3 years. The median PFS and overall survival (OS) rates were 7.7 and 22 months, respectively. Twenty-three patients died (21 from lymphoma, two while in remission). Grade 3 or 4 toxicities included febrile neutropenia (n = 8), anemia (n = 3), thrombocytopenia (n = 5), congestive heart failure (n = 4), venous thrombosis (n = 3), gastrointestinal hemorrhage/perforation (n = 2), infection (n = 8) and fatigue (n = 6). Despite a high overall response rate, the ACHOP regimen failed to result in durable remissions and was associated with significant toxicities. Studies of novel therapeutics are needed for this patient population, whose clinical outcome remains poor.

  View details for DOI 10.3109/10428194.2013.816700

  View details for PubMedID 23786456

• Histologic subtypes of breast cancer following radiotherapy for Hodgkin lymphoma. Annals of oncology Horst, K. C., Hancock, S. L., OGNIBENE, G., Chen, C., Advani, R. H., Rosenberg, S. A., Donaldson, S. S., Hoppe, R. T. 2014; 25 (4): 848-851

  Abstract

  The purpose of the study was to determine whether breast cancers (BCs) that develop in women previously irradiated for Hodgkin lymphoma (HL) are biologically similar to sporadic BC.We retrospectively reviewed the charts of patients who developed BC after radiotherapy (RT) for HL. Tumors were classified as ductal carcinoma in situ (DCIS) or invasive carcinoma. Invasive carcinomas were further characterized according to the subtype: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. BCs after HL were compared with four age-matched sporadic, non-breast cancer (BRCA) I or II mutated BCs.One hundred forty-seven HL patients who were treated with RT between 1966 and 1999 and subsequently developed BCs were identified. Of these, 65 patients with 71 BCs had complete pathologic information. The median age at HL diagnosis was 23 (range, 10-48). The median age at BC diagnosis was 44 (range, 28-66). The median time to developing BC was 20 years. Twenty cancers (28%) were DCIS and 51 (72%) were invasive. Of the 51 invasive cancers, 24 (47%) were HR+/HER2-, 2 (4%) were HR+/HER2+, 5 (10%) were HR-/HER2+, and 20 (39%) were HR-/HER2-. There were no differences in BC histologic subtype according to the age at which patients were exposed to RT, the use of chemotherapy for HL treatment, or the time from RT exposure to the development of BC. In a 4 : 1 age-matched comparison to sporadic BCs, BCs after HL were more likely to be HR-/HER2- (39% versus 14%) and less likely to be HR+/HER2- (47% versus 61%) or HR+/HER2+ (4% versus 14%) (P = 0.0003).BCs arising in previously irradiated breast tissue were more likely to be triple negative compared with age-matched sporadic invasive cancers and less likely to be HR positive. Further studies will be important to determine the molecular pathways of carcinogenesis in breast tissue that is exposed to RT.

  View details for DOI 10.1093/annonc/mdu017

  View details for PubMedID 24608191

• Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies JOURNAL OF HEMATOLOGY & ONCOLOGY Bartlett, N. L., Chen, R., Fanale, M. A., Brice, P., Gopal, A., Smith, S. E., Advani, R., Matous, J. V., Ramchandren, R., Rosenblatt, J. D., Huebner, D., Levine, P., Grove, L., Forero-Torres, A. 2014; 7

  View details for DOI 10.1186/1756-8722-7-24

  View details for Web of Science ID 000334637200001

  View details for PubMedID 24642247

• Customized Targeted Therapy in Hodgkin Lymphoma: Hype or Hope? HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Diefenbach, C., Advani, R. 2014; 28 (1): 105-?

  Abstract

  Although most patients with Hodgkin lymphoma (HL) are cured with primary therapy, patients with primary refractory disease or relapse after initial treatment have poor outcomes and represent an unmet medical need. Recent advances in unraveling the biology of HL have yielded a plethora of novel targeted therapies. This review provides an overview of the data behind the hype generated by these advances and addresses the question of whether or not clinically these targeted therapies offer hope for patients with HL.

  View details for DOI 10.1016/j.hoc.2013.10.004

  View details for Web of Science ID 000329086300010

  View details for PubMedID 24287071

• A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors. Journal of hematology & oncology de Vos, S., Forero-Torres, A., Ansell, S. M., Kahl, B., Cheson, B. D., Bartlett, N. L., Furman, R. R., Winter, J. N., Kaplan, H., Timmerman, J., Whiting, N. C., Drachman, J. G., Advani, R. 2014; 7: 44-?

  Abstract

  Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study.A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies.Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity.Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development.ClinicalTrials.gov identifier NCT00435916.

  View details for DOI 10.1186/1756-8722-7-44

  View details for PubMedID 24919462

• Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. Journal of hematology & oncology Bartlett, N. L., Chen, R., Fanale, M. A., Brice, P., Gopal, A., Smith, S. E., Advani, R., Matous, J. V., Ramchandren, R., Rosenblatt, J. D., Huebner, D., Levine, P., Grove, L., Forero-Torres, A. 2014; 7: 24-?

  Abstract

  Brentuximab vedotin is a CD30-directed antibody-drug conjugate. Retreatment with brentuximab vedotin monotherapy was investigated in patients with CD30-positive Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (ALCL) who relapsed after achieving complete or partial remission (CR or PR) with initial brentuximab vedotin therapy in a previous study (ClinicalTrials.gov NCT00947856).Twenty-one patients with HL and 8 patients with systemic ALCL were retreated; 3 patients with systemic ALCL were retreated twice. Patients generally received brentuximab vedotin 1.8 mg/kg intravenously approximately every 3 weeks over 30 minutes as an outpatient infusion. The primary objectives of this study were to assess safety and to estimate antitumor activity of brentuximab vedotin retreatment.The objective response rate was 60% (30% CR) in HL patients and 88% (63% CR) in systemic ALCL patients. The estimated median duration of response for patients with an objective response was 9.5 months (range, 0.0+ to 28.0+ months) at the time of study closure. Of the 19 patients with objective response, 7 patients had not had an event of disease progression or death at the time of study closure; duration of response for these patients ranged from 3.5 to 28 months. Of the 11 patients with CR, 45% had response durations of over 1 year.Adverse events (AEs) occurring in ≥25% of patients during the retreatment period were generally similar in type and frequency to those observed in the pivotal trials of brentuximab vedotin monotherapy, with the exception of peripheral neuropathy, which is known to have a cumulative effect. Grade 3 or higher events were observed in 48% of patients; these were generally transient and managed by dose modifications or delays. Deaths due to AEs occurred in 3 HL patients; none were considered to be related to brentuximab vedotin retreatment.With the exception of a higher rate of peripheral motor neuropathy, retreatment with brentuximab vedotin was associated with similar side effects seen in the pivotal trials.Retreatment with brentuximab vedotin monotherapy is associated with response rates in 68% (39% CR) of patients with relapsed HL and systemic ALCL.United States registry and results database ClinicalTrials.gov NCT00947856.

  View details for DOI 10.1186/1756-8722-7-24

  View details for PubMedID 24642247

• Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. Journal of clinical oncology Evens, A. M., Advani, R., Press, O. W., Lossos, I. S., Vose, J. M., Hernandez-Ilizaliturri, F. J., Robinson, B. K., Otis, S., Nadav Dagan, L., Abdallah, R., Kroll-Desrosiers, A., Yarber, J. L., Sandoval, J., Foyil, K., Parker, L. M., Gordon, L. I., Blum, K. A., Flowers, C. R., Leonard, J. P., Habermann, T. M., Bartlett, N. L. 2013; 31 (32): 4132-4139

  View details for DOI 10.1200/JCO.2013.49.8220

  View details for PubMedID 24043736

• Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. Journal of clinical oncology Evens, A. M., Advani, R., Press, O. W., Lossos, I. S., Vose, J. M., Hernandez-Ilizaliturri, F. J., Robinson, B. K., Otis, S., Nadav Dagan, L., Abdallah, R., Kroll-Desrosiers, A., Yarber, J. L., Sandoval, J., Foyil, K., Parker, L. M., Gordon, L. I., Blum, K. A., Flowers, C. R., Leonard, J. P., Habermann, T. M., Bartlett, N. L. 2013; 31 (32): 4132-4139

  Abstract

  Lymphoma is the fourth most frequent cancer in pregnancy; however, current clinical practice is based largely on small series and case reports.In a multicenter retrospective analysis, we examined treatment, complications, and outcomes for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) occurring during pregnancy.Among 90 patients (NHL, n = 50; HL, n = 40), median age was 30 years (range, 18 to 44 years) and median diagnosis occurred at 24 weeks gestation. Of patients with NHL, 52% had advanced-stage versus 25% of patients with HL (P = .01). Pregnancy was terminated in six patients. Among the other 84 patients, 28 (33%) had therapy deferred to postpartum; these patients were diagnosed at a median 30 weeks gestation. This compared with 56 patients (67%) who received antenatal therapy with median lymphoma diagnosis at 21 weeks (P < .001); 89% of these patients received combination chemotherapy. The most common preterm complication was induction of labor (33%). Gestation went to full term in 56% of patients with delivery occurring at a median of 37 weeks. There were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy. At 41 months, 3-year progression-free survival (PFS) and overall survival (OS) for NHL were 53% and 82%, respectively, and 85% and 97%, respectively, for HL. On univariate analysis for NHL, radiotherapy predicted inferior PFS, and increased lactate dehydrogenase and poor Eastern Cooperative Oncology Group performance status (ECOG PS) portended worse OS. For HL patients, nulliparous status and "B" symptoms predicted inferior PFS.Standard (non-antimetabolite) combination chemotherapy administered past the first trimester, as early as 13 weeks gestation, was associated with few complications and expected maternal survival with lymphoma occurring during pregnancy.

  View details for DOI 10.1200/JCO.2013.49.8220

  View details for PubMedID 24043736

• Bruton tyrosine kinase inhibitors: a promising novel targeted treatment for B cell lymphomas. British journal of haematology Aalipour, A., Advani, R. H. 2013; 163 (4): 436-443

  Abstract

  Constitutive or aberrant signalling of the B cell receptor signalling cascade has been implicated in the propagation and maintenance of a variety of B cell malignancies. Small molecule inhibitors of Bruton tyrosine kinase (BTK), a protein early in this cascade and specifically expressed in B cells, have emerged as a new class of targeted agents. There are several BTK inhibitors, including ONO-WG-307, LFM-A13, dasatinib, CC-292, and PCI-32765 (ibrutinib), in preclinical and/or clinical development of which ibrutinib is currently in phase III trials. Recent clinical data suggest significant activity of ibrutinib as a first in class oral inhibitor of BTK. This review provides an overview of ongoing clinical studies of BTK inhibitors.

  View details for DOI 10.1111/bjh.12573

  View details for PubMedID 24111579

  View details for PubMedCentralID PMC4444436

• Management of B-cell non-Hodgkin lymphoma in Asia: resource-stratified guidelines LANCET ONCOLOGY Tan, D., Tan, S. Y., Lim, S. T., Kim, S. J., Kim, W., Advani, R., Kwong, Y. 2013; 14 (12): E548-E561

  Abstract

  Treatment of B-cell non-Hodgkin lymphomas has undergone substantial developments in the past 10 years. The introduction of rituximab has greatly improved survival outcomes in patients. Clinical practice guidelines based on current evidence have been developed to provide recommendations for standard treatment approaches. However, guidelines do not take into account resource limitations in resource-poor countries. The huge disparities in economy, health-care infrastructure, and access to novel drugs between Asian countries can hinder the delivery of optimum care to patients with lymphoma in Asia. We outline guidelines appropriate to different levels of health-care resources and expertise, aiming to provide advice on diagnosis and treatment, unify interpretation of results, and allow the design of future studies in Asia. In this resource-adapted consensus, we summarise recommendations for diagnosis, staging, risk stratification, and treatment of common B-cell non-Hodgkin lymphomas in Asia.

  View details for Web of Science ID 000326275300022

  View details for PubMedID 24176573

• ACR APPROPRIATENESS CRITERIA (R) Localized Nodal Indolent Lymphoma ONCOLOGY-NEW YORK Hoppe, B. S., Hodgson, D. C., Advani, R., Dabaja, B. S., Flowers, C. R., Ha, C. S., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2013; 27 (8): 786-794

  View details for Web of Science ID 000323686400009

• ACR Appropriateness Criteria: Localized nodal indolent lymphoma. Oncology (Williston Park, N.Y.) Hoppe, B. S., Hodgson, D. C., Advani, R., Dabaja, B. S., Flowers, C. R., Ha, C. S., Metzger, M. L., Plastaras, J. P., Roberts, K. B., Shapiro, R., Terezakis, S. A., Winkfield, K. M., Younes, A., Constine, L. S. 2013; 27 (8): 786-794

  Abstract

  The present guidelines review epidemiology, pathology, presentation, workup, staging, prognostic factors, and treatment options for patients with localized nodal indolent lymphoma, with an emphasis on radiation guidelines, including radiation dose, field design, and radiation techniques. Following a discussion of the current literature and available data for treatment and outcomes of patients with indolent lymphoma, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) by which the panel rates the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for PubMedID 24133827

• Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies CANCER CHEMOTHERAPY AND PHARMACOLOGY Han, T. H., Chen, R., Advani, R., Berryman, R. B., Smith, S. E., Forero-Torres, A., Rosenblatt, J. D., Smith, M. R., Zain, J., Hunder, N. N., Engert, A. 2013; 72 (1): 241-249

  Abstract

  Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization.Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF).There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies.There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.

  View details for DOI 10.1007/s00280-013-2192-z

  View details for Web of Science ID 000320889300025

  View details for PubMedID 23719719

• A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study LEUKEMIA & LYMPHOMA Foss, F. M., Sjak-Shie, N., Goy, A., Jacobsen, E., Advani, R., Smith, M. R., Komrokji, R., Pendergrass, K., Bolejack, V. 2013; 54 (7): 1373-1379

  Abstract

  This phase II study to determine the safety and efficacy of denileukin diftitox (DD) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) enrolled patients with newly diagnosed peripheral T-cell lymphoma (PTCL). Forty-nine received DD 18 μg/kg/day (days 1, 2) with CHOP (day 3) every 21 days for ≤ 6-8 cycles. Intent-to-treat (ITT) and safety populations comprised all patients. In the ITT population, the overall response rate was 65%, median duration of response was 30 months and median progression-free survival was 12 months. Median overall survival was not attained at the end of the study, and the overall survival rate was 63.3%. The two most frequent treatment-related adverse events (AEs) were fatigue and nausea. Most frequent AEs ≥ grade 3 within the hematologic system were lymphopenia (24.5%), neutropenia (20.4%) and leukopenia (18.4%). Three treatment-related deaths occurred. DD plus CHOP was well tolerated, and progression-free and overall survival improved versus historical comparison with CHOP alone. Confirmation in larger trials is warranted.

  View details for DOI 10.3109/10428194.2012.742521

  View details for Web of Science ID 000320698300009

  View details for PubMedID 23278639

• Non-Hodgkin's Lymphomas, Version 1.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M. A., Naganuma, M. 2013; 11 (3): 257-273

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

  View details for Web of Science ID 000316037400005

• Non-Hodgkin's lymphomas, version 1.2013. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M. A., Naganuma, M. 2013; 11 (3): 257-272

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

  View details for PubMedID 23486452

• Gene Expression-Based Model Using Formalin-Fixed Paraffin-Embedded Biopsies Predicts Overall Survival in Advanced-Stage Classical Hodgkin Lymphoma JOURNAL OF CLINICAL ONCOLOGY Scott, D. W., Chan, F. C., Hong, F., Rogic, S., Tan, K. L., Meissner, B., Ben-Neriah, S., Boyle, M., Kridel, R., Telenius, A., Woolcock, B. W., Farinha, P., Fisher, R. I., Rimsza, L. M., Bartlett, N. L., Cheson, B. D., Shepherd, L. E., Advani, R. H., Connors, J. M., Kahl, B. S., Gordon, L. I., Horning, S. J., Steidl, C., Gascoyne, R. D. 2013; 31 (6): 692-700

  Abstract

  Our aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET).Expression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry.A 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses.A gene expression-based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.

  View details for DOI 10.1200/JCO.2012.43.4589

  View details for Web of Science ID 000315086400017

  View details for PubMedID 23182984

  View details for PubMedCentralID PMC3574267

• Cancer Vaccines and T Cell Therapy BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Rezvani, K., Brody, J. D., Kohrt, H. E., Logan, A. C., Advani, R., Czerwinski, D. K., Weng, W., Negrin, R. S., Carlton, V., Faham, M., Levy, R., Barrett, J. 2013; 19 (1): S97-S101

  View details for DOI 10.1016/j.bbmt.2012.09.020

  View details for Web of Science ID 000313998100024

  View details for PubMedID 23041602

• Non-Hodgkin's Lymphomas, version 3.2012. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Naganuma, M., Dwyer, M. A. 2012; 10 (12): 1487-1498

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.

  View details for PubMedID 23221787

• Non-Hodgkin's Lymphomas, Version 3.2012 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L., Tsien, C., Vose, J. M., Yahalom, J., Zafar, N., Naganuma, M., Dwyer, M. A. 2012; 10 (12): 1487-1498

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.

  View details for Web of Science ID 000312114200005

• Mature Results From ECOG Study E1405-A Phase II Study of VcR-CVAD with Maintenance Rituximab for Previously Untreated Mantle Cell Lymphoma 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kahl, B. S., Li, H., Smith, M. R., Gascoyne, R. D., Yang, D. T., Paietta, E., Advani, R. H., Horning, S. J. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900306

• A Phase I Study of DCDT2980S, an Antibody-Drug Conjugate (ADC) Targeting CD22, in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL) 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Advani, R., Lebmic, D., Brunvand, M., Chen, A. I., Goy, A., Chang, J. E., Maeda, L. S., Ho, W., Kahn, R., Lu, D., Su, M., Chu, Y., Cheson, B. D. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900105

• Brentuximab Vedotin Demonstrates Significant Clinical Activity in Relapsed or Refractory Mycosis Fungoides with Variable CD30 Expression 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Krathen, M., Sundram, U., Bashey, S., Sutherland, K., Salva, K., Wood, G. S., Advani, R. H., Hoppe, R. T., Reddy, S., Armstrong, R., Nagpal, S., Pulitzer, M., Horwitz, S. M., Kim, Y. H. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900162

• A Phase I Study of the Anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A Targeting CD79b in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL) 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Palanca-Wessels, M. C., Flinn, I. W., Sehn, L. H., Patel, M., Sangha, R., Czuczman, M. S., Salles, G. A., Morschhauser, F., Advani, R., Press, O. W., Ho, W., Kahn, R., Lu, D., Su, Z., Chu, Y., Assouline, S. E. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900108

• Brentuximab Vedotin Administered Concurrently with Multi-Agent Chemotherapy As Frontline Treatment of ALCL and Other CD3O-Positive Mature T-Cell and NK-Cell Lymphomas 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Fanale, M. A., Shustov, A. R., Forero-Torres, A., Bartlett, N. L., Advani, R. H., Pro, B., Chen, R. W., Davies, A., Midge, T., Kennedy, D. A., Horwitz, S. M. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900104

• Second Cancers After Treatment with Stanford V Regimen in Eastern Cooperative Oncology Group (ECOG) Pilot Study E1492 At a Median Follow up of 17 Years 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Advani, R. H., Li, H., Hoppe, R. T., Bartlett, N. L., Bennett, J. M., Neuberg, D. S., Cassileth, P. A., Kahl, B. S., Horning, S. J. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049604223

• in Situ Vaccination for Patients with Previously Untreated Follicular Lymphoma: Analysis of Immune Responses 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Czerwinski, D. K., Brody, J., Kohrt, H. E., Hoppe, R. T., Advani, R. H., Levy, R. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049600215

• Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation BLOOD Gopal, A. K., Ramchandren, R., O'Connor, O. A., Berryman, R. B., Advani, R. H., Chen, R., Smith, S. E., Cooper, M., Rothe, A., Matous, J. V., Grove, L. E., Zain, J. 2012; 120 (3): 560-568

  Abstract

  Hodgkin lymphoma (HL) relapsing after allogeneic stem cell transplantation (alloSCT) presents a major clinical challenge. In the present investigation, we evaluated brentuximab vedotin, a CD30-directed Ab-drug conjugate, in 25 HL patients (median age, 32 years; range, 20-56) with recurrent disease after alloSCT (11 unrelated donors). Patients were > 100 days after alloSCT, had no active GVHD, and received a median of 9 (range, 5-19) prior regimens. Nineteen (76%) had refractory disease immediately before enrollment. Patients received 1.2 or 1.8 mg/kg of brentuximab vedotin IV every 3 weeks (median, 8 cycles; range, 1-16). Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median progression-free survival was 7.8 months, and the median overall survival was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events ≥ grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12%). Cytomegalovirus was detected in 5 patients (potentially clinically significant in 1). These results support the potential utility of brentuximab vedotin for selected patients with HL relapsing after alloSCT.

  View details for DOI 10.1182/blood-2011-12-397893

  View details for Web of Science ID 000307440100012

  View details for PubMedID 22510871

• Characteristics and outcomes of extranodal NK/t-cell lymphoma (ENKL): A North American (NA) multi-institutional experience. 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Maeda, L. S., Geiger, J. L., Savage, K. J., Rose, J., Pinter-Brown, L. C., Lunning, M. A., Abramson, J. S., Bartlett, N., Vose, J., Drape, J., Muffly, L. S., McMillan, A., Evens, A. M., Smith, S. M., Horwitz, S. M., Ansell, S. M., Advani, R. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009803765

• Single Cell Profiling of Circulating Tumor Cells: Transcriptional Heterogeneity and Diversity from Breast Cancer Cell Lines PLOS ONE Powell, A. A., Talasaz, A. H., Zhang, H., Coram, M. A., Reddy, A., Deng, G., Telli, M. L., Advani, R. H., Carlson, R. W., Mollick, J. A., Sheth, S., Kurian, A. W., Ford, J. M., Stockdale, F. E., Quake, S. R., Pease, R. F., Mindrinos, M. N., Bhanot, G., Dairkee, S. H., Davis, R. W., Jeffrey, S. S. 2012; 7 (5)

  Abstract

  To improve cancer therapy, it is critical to target metastasizing cells. Circulating tumor cells (CTCs) are rare cells found in the blood of patients with solid tumors and may play a key role in cancer dissemination. Uncovering CTC phenotypes offers a potential avenue to inform treatment. However, CTC transcriptional profiling is limited by leukocyte contamination; an approach to surmount this problem is single cell analysis. Here we demonstrate feasibility of performing high dimensional single CTC profiling, providing early insight into CTC heterogeneity and allowing comparisons to breast cancer cell lines widely used for drug discovery.We purified CTCs using the MagSweeper, an immunomagnetic enrichment device that isolates live tumor cells from unfractionated blood. CTCs that met stringent criteria for further analysis were obtained from 70% (14/20) of primary and 70% (21/30) of metastatic breast cancer patients; none were captured from patients with non-epithelial cancer (n = 20) or healthy subjects (n = 25). Microfluidic-based single cell transcriptional profiling of 87 cancer-associated and reference genes showed heterogeneity among individual CTCs, separating them into two major subgroups, based on 31 highly expressed genes. In contrast, single cells from seven breast cancer cell lines were tightly clustered together by sample ID and ER status. CTC profiles were distinct from those of cancer cell lines, questioning the suitability of such lines for drug discovery efforts for late stage cancer therapy.For the first time, we directly measured high dimensional gene expression in individual CTCs without the common practice of pooling such cells. Elevated transcript levels of genes associated with metastasis NPTN, S100A4, S100A9, and with epithelial mesenchymal transition: VIM, TGFß1, ZEB2, FOXC1, CXCR4, were striking compared to cell lines. Our findings demonstrate that profiling CTCs on a cell-by-cell basis is possible and may facilitate the application of 'liquid biopsies' to better model drug discovery.

  View details for DOI 10.1371/journal.pone.0033788

  View details for Web of Science ID 000305335000005

  View details for PubMedID 22586443

  View details for PubMedCentralID PMC3346739

• Hodgkin Lymphoma, Version 2.2012 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B., Duron, Y., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Maloney, D. G., Mansur, D., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Poppe, M., Pro, B., Winter, J. N., Yahalom, J., Sundar, H. 2012; 10 (5): 589-597

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin Lymphoma (HL) include the clinical management of classical HL and lymphocyte-predominant HL (LPHL). Major changes have been incorporated into these guidelines since their inception. In the 2012 NCCN Guidelines for HL, PET scans are not recommended for interim restaging of patients with stage I to II favorable disease. After reevaluating the available evidence on the use of interim PET imaging, the panel recommends the use of diagnostic CT scan of involved sites for interim restaging after completion of chemotherapy for this group of patients. Maintenance rituximab for 2 years is included as an option for patients with stage IB to IIB or stage III to IV LPHL treated with rituximab alone in the first-line setting. Brentuximab vedotin is included as an option for patients with progressive disease or relapsed disease after second-line chemotherapy or high-dose therapy with autologous stem cell rescue.

  View details for Web of Science ID 000303557700005

  View details for PubMedID 22570290

• Exploratory study of brentuximab vedotin (SGN-35), a novel monoclonal antibody-drug-conjugate against CD30, in mycosis fungoides (MF) and Sezary syndrome (SS) demonstrates clinical responses regardless of CD30 expression levels 75th Annual Meeting of the Society-for-Investigative-Dermatology Bashey, S., Krathen, M., Sutherland, K., Sundram, U., Lingala, B., Horwitz, S., Hoppe, R., Pulitzer, M., Advani, R., Kim, Y. NATURE PUBLISHING GROUP. 2012: S95–S95

  View details for Web of Science ID 000302866900562

• Interim-treatment quantitative PET parameters predict progression and death among patients with hodgkin's disease RADIATION ONCOLOGY Tseng, D., Rachakonda, L. P., Su, Z., Advani, R., Horning, S., Hoppe, R. T., Quon, A., Graves, E. E., Loo, B. W., Tran, P. T. 2012; 7

  Abstract

  We hypothesized that quantitative PET parameters may have predictive value beyond that of traditional clinical factors such as the International Prognostic Score (IPS) among Hodgkin's disease (HD) patients.Thirty HD patients treated at presentation or relapse had staging and interim-treatment PET-CT scans. The majority of patients (53%) had stage III-IV disease and 67% had IPS ≥ 2. Interim-treatment scans were performed at a median of 55 days from the staging PET-CT. Chemotherapy regimens used: Stanford V (67%), ABVD (17%), VAMP (10%), or BEACOPP (7%). Hypermetabolic tumor regions were segmented semiautomatically and the metabolic tumor volume (MTV), mean standardized uptake value (SUV mean), maximum SUV (SUV max) and integrated SUV (iSUV) were recorded. We analyzed whether IPS, absolute value PET parameters or the calculated ratio of interim- to pre-treatment PET parameters were associated with progression free survival (PFS) or overall survival (OS).Median follow-up of the study group was 50 months. Six of the 30 patients progressed clinically. Absolute value PET parameters from pre-treatment scans were not significant. Absolute value SUV max from interim-treatment scans was associated with OS as determined by univariate analysis (p < 0.01). All four calculated PET parameters (interim/pre-treatment values) were associated with OS: MTV int/pre (p < 0.01), SUV mean int/pre (p < 0.05), SUV max int/pre (p = 0.01), and iSUV int/pre (p < 0.01). Absolute value SUV max from interim-treatment scans was associated with PFS (p = 0.01). Three calculated PET parameters (int/pre-treatment values) were associated with PFS: MTV int/pre (p = 0.01), SUV max int/pre (p = 0.02) and iSUV int/pre (p = 0.01). IPS was associated with PFS (p < 0.05) and OS (p < 0.01).Calculated PET metrics may provide predictive information beyond that of traditional clinical factors and may identify patients at high risk of treatment failure early for treatment intensification.

  View details for DOI 10.1186/1748-717X-7-5

  View details for Web of Science ID 000301710700001

  View details for PubMedID 22260710

  View details for PubMedCentralID PMC3398283

• In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study BLOOD Kim, Y. H., Gratzinger, D., Harrison, C., Brody, J. D., Czerwinski, D. K., Ai, W. Z., Morales, A., Abdulla, F., Xing, L., Navi, D., Tibshirani, R. J., Advani, R. H., Lingala, B., Shah, S., Hoppe, R. T., Levy, R. 2012; 119 (2): 355-363

  Abstract

  We have developed and previously reported on a therapeutic vaccination strategy for indolent B-cell lymphoma that combines local radiation to enhance tumor immunogenicity with the injection into the tumor of a TLR9 agonist. As a result, antitumor CD8(+) T cells are induced, and systemic tumor regression was documented. Because the vaccination occurs in situ, there is no need to manufacture a vaccine product. We have now explored this strategy in a second disease: mycosis fungoides (MF). We treated 15 patients. Clinical responses were assessed at the distant, untreated sites as a measure of systemic antitumor activity. Five clinically meaningful responses were observed. The procedure was well tolerated and adverse effects consisted mostly of mild and transient injection site or flu-like symptoms. The immunized sites showed a significant reduction of CD25(+), Foxp3(+) T cells that could be either MF cells or tissue regulatory T cells and a similar reduction in S100(+), CD1a(+) dendritic cells. There was a trend toward greater reduction of CD25(+) T cells and skin dendritic cells in clinical responders versus nonresponders. Our in situ vaccination strategy is feasible also in MF and the clinical responses that occurred in a subset of patients warrant further study with modifications to augment these therapeutic effects. This study is registered at www.clinicaltrials.gov as NCT00226993.

  View details for DOI 10.1182/blood-2011-05-355222

  View details for Web of Science ID 000299268900012

  View details for PubMedID 22045986

  View details for PubMedCentralID PMC3257006

• A Phase I Weekly Dosing Study of Brentuximab Vedotin in Patients with Relapsed/Refractory CD30-Positive Hematologic Malignancies CLINICAL CANCER RESEARCH Fanale, M. A., Forero-Torres, A., Rosenblatt, J. D., Advani, R. H., Franklin, A. R., Kennedy, D. A., Han, T. H., Sievers, E. L., Bartlett, N. L. 2012; 18 (1): 248-255

  Abstract

  The antibody-drug conjugate (ADC) brentuximab vedotin comprises a CD30-directed antibody covalently attached to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. This study explored the safety, maximum-tolerated dose (MTD), and activity of weekly dosing of brentuximab vedotin in patients with relapsed or refractory CD30-positive hematologic malignancies.In this phase I dose-escalation study, brentuximab vedotin was administered intravenously on Days 1, 8, and 15, of each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg. Forty-four patients were enrolled: 38 with Hodgkin lymphoma, five with systemic anaplastic large cell lymphoma, and one with peripheral T-cell lymphoma not otherwise specified. Doses were escalated in increments of 0.2 mg/kg until dose-limiting toxicity (DLT) was observed. Patients were monitored for antitherapeutic antibodies and pharmacokinetic parameters. Antitumor assessments were carried out every two cycles.The MTD was 1.2 mg/kg. The most common adverse events were peripheral sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. Tumor regression occurred in 85% of patients and the overall objective response rate was 59% (n = 24), with 34% (n = 14) complete remissions. The median duration of response was not reached at a median follow-up of 45 weeks on study.Weekly administration of brentuximab vedotin resulted in tumor regression and durable remissions in patients with CD30-positive malignancies. This ADC was associated with manageable toxicity, including peripheral neuropathy. Further study in CD30-positive malignancies is warranted.

  View details for DOI 10.1158/1078-0432.CCR-11-1425

  View details for Web of Science ID 000298758900026

  View details for PubMedID 22080439

• Optimal Therapy of Advanced Hodgkin Lymphoma HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM Advani, R. 2011: 310-316

  View details for DOI 10.1182/asheducation-2011.1.310

  View details for Web of Science ID 000208759700047

• Lymphoma in Pregnancy: Excellent Fetal Outcomes and Maternal Survival in a Large Multicenter Analysis 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Evens, A. M., Advani, R., Lossos, I. S., Press, O. W., Vose, J. M., Hernandez-Ilizaliturri, F. J., Robinson, B. K., Otis, S., Dagan, L. N., Abdallah, R., Kroll, A., Sandoval, J., Yarber, J. L., Foyil, K. V., Parker, L. M., Gordon, L. I., Leonard, J. P., Habermann, T. M., Bartlett, N. L. AMER SOC HEMATOLOGY. 2011: 45–46

  View details for Web of Science ID 000299597100095

• A Phase II Trial of Ofatumumab in Subjects with Waldenstrom's Macroglobulinemia 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Furman, R. R., Eradat, H., DiRienzo, C. G., Hayman, S. R., Hofmeister, C. C., Avignon, N. A., Leonard, J. P., Coleman, M., Advani, R., Switzky, J. C., Liao, Q., Shah, D. N., Lisby, S., Lin, T. S. AMER SOC HEMATOLOGY. 2011: 1581–81

  View details for Web of Science ID 000299597105429

• Immunotransplant for Mantle Cell Lymphoma: Phase I/II Study Preliminary Results 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Brody, J. D., Czerwinski, D. K., Carlton, V., Moorhead, M., Zheng, J., Klinger, M., Faham, M., Advani, R., Kohrt, H. E., Alizadeh, A. A., Negrin, R. S., Weng, W., Sheehan, K., Levy, R. AMER SOC HEMATOLOGY. 2011: 1323–23

  View details for Web of Science ID 000299597104419

• Validation of the Elderly IPI (E-IPI) for Patients with Diffuse Large B Cell Lymphoma Using An Independent Data Set From the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Advani, R. H., Hong, F., Li, H., Kahl, B. S., Pfreundschuh, M., Ziepert, M. AMER SOC HEMATOLOGY. 2011: 681–81

  View details for Web of Science ID 000299597102163

• Prospective, Multicenter Study of the MTOR Inhibitor Everolimus (RAD001) As Primary Therapy in Waldenstrom's Macroglobulinemia 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Treon, S. P., Tripsas, C. K., Ioakimidis, L., Warren, D., Patterson, C., Heffner, L., Eradat, H., Gregory, S. A., Thomas, S., Advani, R., Baz, R., Badros, A. Z., Matous, J., Anderson, K. C., Ghobrial, I. M. AMER SOC HEMATOLOGY. 2011: 1273–74

  View details for Web of Science ID 000299597104302

• The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Wang, L., Martin, P., Blum, K. A., Kahl, B. S., Maeda, L. S., Advani, R., Williams, M. E., Rule, S., Rodriguez, S., Pang, C., Hedrick, E., Goy, A. AMER SOC HEMATOLOGY. 2011: 203–4

  View details for Web of Science ID 000299597100443

• Allogeneic Transplant Following Brentuximab Vedotin Treatment in Patients with Relapsed or Refractory CD30+Lymphomas 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Illidge, T., Bouabdallah, R., Chen, R. W., Gopal, A. K., Moskowitz, C. H., Ramchandren, R., Rosenblatt, J. D., Shustov, A. R., Tilly, H., Trippett, T., Grove, L. E., Advani, R. H. AMER SOC HEMATOLOGY. 2011: 1335–36

  View details for Web of Science ID 000299597104442

• Patterns of Failure in Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma (HL) Treated with ABVD plus Radiotherapy or the Stanford V Regimen in the Randomized Phase III North American Intergroup Trial: E2496 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Advani, R., Hong, F., Gordon, L. I., Gascoyne, R. D., Wagner, H., Hoppe, R. T., Fisher, R. I., Bartlett, N. L., Kahl, B. S., Stiff, P., Cheson, B. D., Belch, A. R., Friedberg, J. W., Kassis, J., Blum, K. A., Habermann, T. M., Tuscano, J., Horning, S. J. AMER SOC HEMATOLOGY. 2011: 696–97

  View details for Web of Science ID 000299597102198

• Multicenter Phase I Trial of Intraventricular Immuno-Chemotherapy in Recurrent CNS Lymphoma 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Rubenstein, J. L., Chen, L., Advani, R., Drappatz, J., Gerstner, E., Batchelor, T., Krouwer, H., Kadoch, C., Munster, P., Cha, S., Shuman, M. A., Damon, L. E. AMER SOC HEMATOLOGY. 2011: 438–39

  View details for Web of Science ID 000299597101230

• Prolonged Treatment with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL) 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Forero-Torres, A., Berryman, R. B., Advani, R. H., Bartlett, N. L., Chen, R. W., Fanale, M. A., Gopal, A. K., O'Connor, O. A., Olshefski, R., Smith, S. E., Grove, L. E., Matous, J. AMER SOC HEMATOLOGY. 2011: 1585–86

  View details for Web of Science ID 000299597105439

• Phase I trial of oblimersen (GenasenseA (R)) and gemcitabine in refractory and advanced malignancies INVESTIGATIONAL NEW DRUGS Galatin, P. S., Advani, R. H., Fisher, G. A., Francisco, B., Julian, T., Losa, R., Sierra, M. I., Sikic, B. I. 2011; 29 (5): 971-977

  Abstract

  Overexpression of Bcl-2 is associated with worse prognosis for a number of cancer types. The present study was designed to determine the maximum tolerated dose (MTD) of oblimersen (antisense Bcl-2) and gemcitabine when administered to patients with refractory malignancies.Sixteen patients with advanced solid tumors refractory to standard therapies were treated with escalating doses of oblimersen continuous, 120-h intravenous infusion given every 14 days, with a fixed-dose-rate intravenous infusion of gemcitabine administered on day 5 of each cycle. Serial plasma samples were collected to calculate the pharmacokinetics of oblimersen and gemcitabine, and also to measure the effect of oblimersen on Bcl-2 expression.7 women and 9 men, median age 55 years (range 35-74 years), received a 5-day infusion of oblimersen at dose levels of 5 mg/kg/day (n = 4) or 7 mg/kg/day (n = 12). On the 5th day of the infusion, gemcitabine was given at 10 mg/m(2)/h for a total dose of 1,000 mg/m(2) (n = 7; cohorts I and II), 1,200 mg/m(2) (n = 3; cohort III), or 1,500 mg/m(2) (n = 6; cohort IV). Edema was the dose-limiting toxicity (DLT), necessitating expansion of cohort IV. No subsequent DLTs were noted. Thus, the maximum planned doses were well tolerated, and a formal MTD was not determined. Most hematologic toxicities were grade 1 or 2. There was low-grade fatigue, nausea/vomiting, and myalgias/arthralgias. Oblimersen C(ss) and AUC increased in relation to the dose escalation, but gemcitabine triphosphate levels did not correlate well with dose. There were no objective responses, though 5 patients had stable disease. A >75% reduction in Bcl-2 expression in peripheral blood mononuclear leucocytes was seen more frequently in patients who achieved stable disease than in progressing patients.The maximal planned dose levels of oblimersen and gemcitabine in combination were well tolerated. Only one DLT (edema) occurred. There was a correlation between Bcl-2 reduction and stable disease. The recommended doses of the drugs for future studies are 7 mg/kg/day of oblimersen on days 1-5, and gemcitabine 1,500 mg/m(2) on day 5, every two weeks.

  View details for DOI 10.1007/s10637-010-9416-4

  View details for Web of Science ID 000294223500027

  View details for PubMedID 20349264

• Hodgkin lymphoma. Journal of the National Comprehensive Cancer Network Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Bello, C. M., Bierman, P. J., Blum, K. A., Dabaja, B., Duron, Y., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Maloney, D. G., Mansur, D., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Poppe, M., Pro, B., Weiss, L., Winter, J. N., Yahalom, J. 2011; 9 (9): 1020-1058

  View details for PubMedID 21917626

• NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Bello, C. M., Bierman, P. J., Blum, K. A., Dabaja, B., Duron, Y., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Maloney, D. G., Mansur, D., Mauch, P. M., Metzger, M., Moore, J. O., Morgan, D., Moskowitz, C. H., Poppe, M., Pro, B., Weiss, L., Winter, J. N., Yahalom, J. 2011; 9 (9): 1020-1058

  View details for Web of Science ID 000294584900007

• Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment BLOOD Alizadeh, A. A., Gentles, A. J., Alencar, A. J., Liu, C. L., Kohrt, H. E., Houot, R., Goldstein, M. J., Zhao, S., Natkunam, Y., Advani, R. H., Gascoyne, R. D., Briones, J., Tibshirani, R. J., Myklebust, J. H., Plevritis, S. K., Lossos, I. S., Levy, R. 2011; 118 (5): 1350-1358

  Abstract

  Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell-of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.

  View details for DOI 10.1182/blood-2011-03-345272

  View details for Web of Science ID 000293510000028

  View details for PubMedID 21670469

  View details for PubMedCentralID PMC3152499

• Lymphoma in Pregnancy Initially Diagnosed as Vaginal Intraepithelial Neoplasia and Lichen Planus OBSTETRICS AND GYNECOLOGY Thuong-Thuong Nguyen, T. T., Gubens, M., Arber, D. A., Advani, R., Juretzka, M., Aziz, N. 2011; 118 (2): 486-489

  Abstract

  Non-Hodgkin's lymphoma presenting as a vaginal mass in pregnancy is uncommon.A 38-year-old primigravid woman presented at 27 weeks of gestation with vaginal lesions, bleeding, and discharge. Previous vaginal biopsies had been consistent with vaginal intraepithelial neoplasia 1 and lichen planus. After admission for this enlarging vaginal mass and bleeding, she was noted to have a newly palpable breast mass. Biopsy of the breast mass and subsequent re-evaluation of original vaginal biopsies were consistent with diffuse large B-cell lymphoma. She was treated with chemoimmunotherapy during pregnancy and delivered a viable neonate at term.Although benign vaginal conditions are common, non-Hodgkin's lymphoma should be considered in the differential diagnosis of persistent or enlarging vaginal lesions in pregnancy.

  View details for DOI 10.1097/AOG.0b013e3182234d12

  View details for Web of Science ID 000293115000027

  View details for PubMedID 21768862

• PHASE II STUDY OF R-CHOP FOLLOWED BY Y-90-IBRITUMOMAB TIUXETAN IN UNTREATED MANTLE CELL LYMPHOMA (MCL): 5 YEAR FOLLOW-UP OF EASTERN COOPERATIVE ONCOLOGY GROUP E1499 11th International Conference on Malignant Lymphoma Smith, M. R., Li, H., Gordon, L., Gascoyne, R., Paietta, E., Forero-Torres, A., Kahl, B., Advani, R., Hong, F., Horning, S. OXFORD UNIV PRESS. 2011: 86–87

  View details for Web of Science ID 000291996300034

• IMMUNOTRANSPLANT FOR MANTLE CELL LYMPHOMA: PHASE I/II STUDY PRELIMINARY RESULTS 11th International Conference on Malignant Lymphoma Brody, J., Advani, R., Czerwinski, D., Negrin, R., Levy, R. OXFORD UNIV PRESS. 2011: 102–102

  View details for Web of Science ID 000291996300079

• OUTCOME OF LYMPHOMA DURING PREGNANCY: AN INDIVIDUALIZED THERAPEUTIC APPROACH RESULTS IN EXCELLENT PATIENT OUTCOMES AND MINIMAL OBSTETRIC OR FETAL COMPLICATIONS 11th International Conference on Malignant Lymphoma YARBER, J. L., Otis, S. A., Robinson, B. K., Gordon, L. I., Winter, J. N., Advani, R. H., Evens, A. M. OXFORD UNIV PRESS. 2011: 191–191

  View details for Web of Science ID 000291996300337

• Non-Hodgkin's Lymphomas JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Bellam, N., Byrd, J. C., Czuczman, M. S., Fayad, L. E., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kelsey, C. R., Kim, Y. H., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Pro, B., Reddy, N., Sokol, L., Swinnen, L. J., Tsien, C., Vose, J. M., Wierda, W. G., Yahalom, J., Zafar, N. 2011; 9 (5): 484-560

  View details for Web of Science ID 000290292400005

  View details for PubMedID 21550968

• ACR Appropriateness Criteria (R) on Hodgkin's Lymphoma-Unfavorable Clinical Stage I and II JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Das, P., Ng, A., Constine, L. S., Advani, R., Flowers, C., Friedberg, J., Hodgson, D. C., Schwartz, C. L., Wilder, R. B., Wilson, L. D., Yunes, M. J. 2011; 8 (5): 302-308

  Abstract

  Combined-modality therapy, consisting of chemotherapy followed by radiation therapy (RT), represents the standard of care for most patients with unfavorable-prognosis early-stage Hodgkin's lymphoma. The most widely accepted chemotherapy regimen is ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine); however, recent trials have evaluated other regimens such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and Stanford V. After chemotherapy, the standard radiation field is involved-field RT, although there is increasing interest now in involved-node RT. The authors review recent trials on chemotherapy and RT for unfavorable-prognosis early-stage Hodgkin's lymphoma. This article presents illustrative clinical cases, with treatment recommendations from an expert panel of radiation oncologists and medical oncologists.

  View details for DOI 10.1016/j.jacr.2011.01.009

  View details for Web of Science ID 000306201300006

  View details for PubMedID 21531305

• CD40 Pathway Activation Status Predicts Response to CD40 Therapy in Diffuse Large B Cell Lymphoma SCIENCE TRANSLATIONAL MEDICINE Burington, B., Yue, P., Shi, X., Advani, R., Lau, J. T., Tan, J., Stinson, S., Stinson, J., Januario, T., de Vos, S., Ansell, S., Forero-Torres, A., Fedorowicz, G., Yang, T. T., Elkins, K., Du, C., Mohan, S., Yu, N., Modrusan, Z., Seshagiri, S., Yu, S., Pandita, A., Koeppen, H., French, D., Polson, A. G., Offringa, R., Whiting, N., Ebens, A., Dornan, D. 2011; 3 (74)

  Abstract

  The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.

  View details for DOI 10.1126/scitranslmed.3001620

  View details for Web of Science ID 000292974200002

  View details for PubMedID 21411738

• Sezary syndrome: Immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC) JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Olsen, E. A., Rook, A. H., Zic, J., Kim, Y., Porcu, P., Querfeld, C., Wood, G., Demierre, M., Pittelkow, M., Wilson, L. D., Pinter-Brown, L., Advani, R., Parker, S., Kim, E. J., Junkins-Hopkins, J. M., Foss, F., Cacchio, P., Duvic, M. 2011; 64 (2): 352-404

  Abstract

  Sézary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

  View details for DOI 10.1016/j.jaad.2010.08.037

  View details for Web of Science ID 000286780400016

  View details for PubMedID 21145619

• Prediction of Survival In Diffuse Large B-Cell Lymphoma Based On the Expression of Two Genes Reflecting Tumor and Microenvironment 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Alizadeh, A. A., Gentles, A. J., Alencar, A. J., Kohrt, H. E., Houot, R., Goldstein, M. J., Zhao, S., Natkunam, Y., Advani, R., Gascoyne, R. D., Briones, J., Tibshirani, R. J., Myklebust, J. H., Plevritis, S. K., Lossos, I. S., Levy, R. AMER SOC HEMATOLOGY. 2010: 836–37

  View details for Web of Science ID 000289662202229

• Navitoclax (ABT-263) Plus Rituximab: Interim Results of a Phase 1 Study In Patients with CD20-Positive Lymphoid Malignancies 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kahl, B., Roberts, A. W., Seymour, J. F., Advani, R. H., Persky, D. O., Yang, J., Cui, Y., Busman, T., Krivoshik, A., Enschede, S., Humerickhouse, R. AMER SOC HEMATOLOGY. 2010: 1608–

  View details for Web of Science ID 000289662204363

• Clinical and Pathological Features of Non-Hodgkin Lymphomas Harboring Concurrent t(14;18) and 8q24 Anomalies 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Alizadeh, A. A., Anderson, M., Kohrt, H. E., Shyam, R. M., Bangs, C. D., Cherry, A. M., Advani, R., Natkunam, Y., Levy, R. AMER SOC HEMATOLOGY. 2010: 1291–92

  View details for Web of Science ID 000289662203465

• In Situ Vaccination with TLR9 Agonist Combined with Local Radiation In Mycosis Fungoides: Analysis of Phase I/II Study 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kim, Y. H., Gratzinger, D., Harrison, C., Brody, J., Czerwinski, D., Xing, L., Morales, A., Ai, W., Abdulla, F., Navi, D., Tibshirani, R. J., Advani, R., Natkunam, Y., Hoppe, R. T., Levy, R. AMER SOC HEMATOLOGY. 2010: 130–30

  View details for Web of Science ID 000289662200287

• In Situ Vaccination With a TLR9 Agonist Induces Systemic Lymphoma Regression: A Phase I/II Study JOURNAL OF CLINICAL ONCOLOGY Brody, J. D., Ai, W. Z., Czerwinski, D. K., Torchia, J. A., Levy, M., Advani, R. H., Kim, Y. H., Hoppe, R. T., Knox, S. J., Shin, L. K., Wapnir, I., Tibshirani, R. J., Levy, R. 2010; 28 (28): 4324-4332

  Abstract

  Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.

  View details for DOI 10.1200/JCO.2010.28.9793

  View details for Web of Science ID 000282272700032

  View details for PubMedID 20697067

  View details for PubMedCentralID PMC2954133

• Classical Hodgkin Lymphoma in First Complete Remission: Is There a Role for F-18 FDG PET/CT Surveillance? 23rd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) Lagaru, A., Maeda, L. S., Lin, F. I., Hoppe, R. T., Rosenberg, S. A., Gambhir, S. S., Advani, R. H. SPRINGER. 2010: S212–S213

  View details for Web of Science ID 000283023800065

• PHASE 1 STUDY OF NAVITOCLAX (ABT-263) PLUS RITUXIMAB IN CD20-POSITIVE LYMPHOID MALIGNANCIES 15th Annual Meeting of the European-Hematology-Association Roberts, W., Advani, R., Kahl, B., Persky, D., Xiong, H., Cui, Y., Busman, T., Krivoshik, A., Enschede, S., Humerickhouse, R. FERRATA STORTI FOUNDATION. 2010: 371–371

  View details for Web of Science ID 000279051301215

• ACR Appropriateness Criteria (R): Follow-Up of Hodgkin's Lymphoma CURRENT PROBLEMS IN CANCER Ng, A., Constine, L. S., Advani, R., Das, P., Flowers, C., Friedberg, J., Hodgson, D. C., Schwartz, C. L., Wilder, R. B., Wilson, L. D., Yunes, M. J. 2010; 34 (3): 211-227

  Abstract

  In the follow-up of Hodgkin's lymphoma patients, the focus in the first 5 years is to detect recurrence, while after 5 years, the focus is on limiting and detecting late effects of treatment. In the first 5 years post-treatment, routine history and physical and computed tomography (CT) imaging (more frequent in the first 2 years) are generally appropriate. However, there are limited data to support the role of positron emission tomography scanning as routine follow-up. Beyond 5 years post-treatment, annual history and physical is appropriate, although there is no longer a role for routine imaging for recurrences. Women irradiated to the chest area at a young age (<35) would benefit from annual mammogram screening given the increased breast cancer risk. Magnetic resonance imaging can be considered, although there is a lack of data supporting its role in this population. Low-dose chest CT for lung cancer screening in patients with history of mediastinal irradiation and/or alkylating chemotherapy exposures and a smoking history can be considered, although data on its utility is lacking. Cardiac screening with echocardiogram and exercise tolerance tests in patients with history of mediastinal irradiation and/or adriamycin exposure may be appropriate, although the optimal screening interval would depend on mediastinal dose, adriamycin dose, presence of other cardiac risk factors and findings at the baseline screening. Patients at risk for cardiac disease due to treatment exposure would also benefit from lipid screening every 1-3 years.

  View details for DOI 10.1016/j.currproblcancer.2010.04.007

  View details for Web of Science ID 000279038500006

  View details for PubMedID 20541059

• Voreloxin, a First-in-Class Anticancer Quinolone Derivative, in Relapsed/Refractory Solid Tumors: A Report on Two Dosing Schedules CLINICAL CANCER RESEARCH Advani, R. H., Hurwitz, H. I., Gordon, M. S., Ebbinghaus, S. W., Mendelson, D. S., Wakelee, H. A., Hoch, U., Silverman, J. A., Havrilla, N. A., Berman, C. J., Fox, J. A., Allen, R. S., Adelman, D. C. 2010; 16 (7): 2167-2175

  Abstract

  Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity.Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history.In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m(2)). At 60 mg/m(2), four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m(2), two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for >29 days (n = 1). Therefore, the MTD was 48 mg/m(2) (HP patients) and 60 mg/m(2) (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m(2)). At 18 mg/m(2), two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m(2). Voreloxin exhibited low clearance (2 L/h/m(2)), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria.Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia.

  View details for DOI 10.1158/1078-0432.CCR-09-2236

  View details for Web of Science ID 000278595800021

  View details for PubMedID 20233886

• Non-Hodgkin's Lymphomas JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Abramson, J. S., Advani, R. H., Andreadis, C. B., Byrd, J. C., Czuczman, M. S., Fayad, L., Forero, A., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kim, Y. H., LaCasce, A. S., Mughal, T. I., Nademanee, A., Porcu, P., Press, O., Prosnitz, L., Reddy, N., Smith, M. R., Sokol, L., Swinnen, L., Vose, J. M., Wierda, W. G., Yahalom, J., Yunus, F. 2010; 8 (3): 288-334

  View details for Web of Science ID 000275349900005

• NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's lymphomas. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Abramson, J. S., Advani, R. H., Andreadis, C. B., Byrd, J. C., Czuczman, M. S., Fayad, L., Forero, A., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kim, Y. H., LaCasce, A. S., Mughal, T. I., Nademanee, A., Porcu, P., Press, O., Prosnitz, L., Reddy, N., Smith, M. R., Sokol, L., Swinnen, L., Vose, J. M., Wierda, W. G., Yahalom, J., Yunus, F. 2010; 8 (3): 288-334

  View details for PubMedID 20202462

• Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study BLOOD Horning, S. J., Juweid, M. E., Schoeder, H., Wiseman, G., McMillan, A., Swinnen, L. J., Advani, R., Gascoyne, R., Quon, A. 2010; 115 (4): 775-777

  Abstract

  Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET(+) interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: kappa statistic = 0.445 using ECOG criteria, and kappa statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924 [corrected].

  View details for DOI 10.1182/blood-2009-08-234351

  View details for Web of Science ID 000274086600008

  View details for PubMedID 19767508

• Mid-treatment Metabolic Tumor Volume Predicts Progression and Death among Patients with Hodgkin's Disease 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Tseng, D., Rachakonda, L. P., Su, Z., Advani, R., Horning, S., Rosenberg, S. A., Hoppe, R. T., Quon, A., Graves, E. E., Loo, B. W., Tran, P. T. ELSEVIER SCIENCE INC. 2010: S546–S547

  View details for Web of Science ID 000288775701265

• Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R-CHOP) BRITISH JOURNAL OF HAEMATOLOGY Gratzinger, D., Advani, R., Zhao, S., Talreja, N., Tibshirani, R. J., Shyam, R., Horning, S., Sehn, L. H., Farinha, P., Briones, J., Lossos, I. S., Gascoyne, R. D., Natkunam, Y. 2010; 148 (2): 235-244

  Abstract

  Diffuse large B cell lymphoma (DLBCL) is clinically and biologically heterogeneous. In most cases of DLBCL, lymphoma cells co-express vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2, suggesting autocrine in addition to angiogenic effects. We enumerated microvessel density and scored lymphoma cell expression of VEGF, VEGFR1, VEGFR2 and phosphorylated VEGFR2 in 162 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone)-like regimens. VEGFR2 expression correlated with shorter overall survival (OS) independent of International Prognostic Index (IPI) (P = 0.0028). Phosphorylated VEGFR2 (detected in 13% of cases) correlated with shorter progression-free survival (PFS, P = 0.044) and trended toward shorter OS on univariate analysis. VEGFR1 was not predictive of survival on univariate analysis, but it did correlate with better OS on multivariate analysis with VEGF, VEGFR2 and IPI (P = 0.036); in patients with weak VEGFR2, lack of VEGFR1 coexpression was significantly correlated with poor OS independent of IPI (P = 0.01). These results are concordant with our prior finding of an association of VEGFR1 with longer OS in DLBCL treated with chemotherapy alone. We postulate that VEGFR1 may oppose autocrine VEGFR2 signalling in DLBCL by competing for VEGF binding. In contrast to our prior results with chemotherapy alone, microvessel density was not prognostic of PFS or OS with R-CHOP-like therapy.

  View details for DOI 10.1111/j.1365-2141.2009.07942.x

  View details for Web of Science ID 000272884100006

  View details for PubMedID 19821819

  View details for PubMedCentralID PMC2809124

• CD40 Pathway Activation Status Predicts Response to CD40 Targeted Therapy in Diffuse Large b-Cell Lymphoma. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Dornan, D., Burington, B., Yue, P., Shi, X., Advani, R., Yu, N., Lau, J. T., Yu, S., de Vos, S., Ansell, S. M., Forero-Torres, A., Modrusan, Z., Koeppen, H., Yang, T., Du, C., Elkins, K., Polson, A. G., Offringa, R., Whiting, N., Ebens, A. J. AMER SOC HEMATOLOGY. 2009: 1065–65

  View details for Web of Science ID 000272725803276

• A Phase I Dose Escalation Study of the Btk Inhibitor PCI-32765 in Relapsed and Refractory B Cell Non-Hodgkin Lymphoma and Use of a Novel Fluorescent Probe Pharmacodynamic Assay. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Pollyea, D. A., Smith, S., Fowler, N., Boyd, T. E., Smith, A. M., Sirisawad, M., Honigberg, L. A., Hamdy, A., Advani, R. AMER SOC HEMATOLOGY. 2009: 1430–30

  View details for Web of Science ID 000272725804377

• Role or FDG-PET/CT Surveillance for Patients with Classical Hodgkin's Disease in First Complete Response: The Stanford University Experience. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Maeda, L. S., Horning, S. J., Iagaru, A. H., Lin, F. I., Hoppe, R. T., Rosenberg, S. A., Advani, R. H. AMER SOC HEMATOLOGY. 2009: 626–26

  View details for Web of Science ID 000272725801743

• The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405-A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Kahl, B. S., Li, H., Smith, M. R., Gascoyne, R. D., Paietta, E., Advani, R., Horning, S. J. AMER SOC HEMATOLOGY. 2009: 663–63

  View details for Web of Science ID 000272725802029

• The emerging role for rituximab in the treatment of nodular lymphocyte predominant Hodgkin lymphoma CURRENT OPINION IN ONCOLOGY Maeda, L. S., Advani, R. H. 2009; 21 (5): 397-400

  Abstract

  Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subset of Hodgkin lymphoma that is distinct from classical Hodgkin lymphoma (cHL). The unique malignant 'popcorn' cells express the B-cell antigen CD20 and lack expression of the cHL markers CD15 and CD30. Traditionally, NLPHL has been included with cHL in clinical trials with excellent prognosis reported in several series. The reliable expression of CD20 has led to the evaluation of the chimeric monoclonal anti-CD20 antibody rituximab in several recent trials.Three series have reported the efficacy of 4 weekly doses of rituximab in all stages of NLPHL, both in the treatment-naive and relapsed settings. Emerging data also suggest that longer courses of antibody therapy may improve the duration of response.Rituximab appears to offer a nonchemotherapy-based effective treatment option, which is well tolerated. Ongoing studies are required to further define the optimal patient population who may benefit from rituximab and evaluate its role in maintenance as well as in combination with radiotherapy and chemotherapy.

  View details for DOI 10.1097/CCO.0b013e32832f3ca3

  View details for Web of Science ID 000269172400002

  View details for PubMedID 19606035

• Prognostic Factors in Primary Cutaneous Anaplastic Large Cell Lymphoma Characterization of Clinical Subset With Worse Outcome 49th Annual Meeting of the American-Society-of-Hematology Woo, D. K., Jones, C. R., Vanoli-Storz, M. N., Kohler, S., Reddy, S., Advani, R., Hoppe, R. T., Kim, Y. H. AMER MEDICAL ASSOC. 2009: 667–74

  Abstract

  To identify prognostic factors in primary cutaneous anaplastic large cell lymphoma (pcALCL), focusing on extensive limb disease (ELD), defined as initial presentation or progression to multiple skin tumors in 1 limb or contiguous body regions, and to study gene expression profiles of patients with pcALCL.Retrospective cohort study.The Stanford Comprehensive Cancer Center and dermatology ambulatory clinics.A total of 48 patients with pcALCL evaluated from 1990 through 2005.Hazard ratios (HRs) for prognostic factors for overall survival (OS) and disease-specific survival (DSS) and risk factors for progression to extracutaneous disease were identified using Cox regression. Gene expression profiles of 9 typical pcALCL and 3 ELD samples were investigated using complementary DNA microarrays.Univariate analysis demonstrated age, ELD, and progression to extracutaneous disease as significant prognostic factors for OS, whereas ELD and progression to extracutaneous disease were significant for DSS. In multivariate analysis, age (HR, 1.83; 95% confidence interval [CI], 1.02-3.26) and progression to extracutaneous disease (HR, 6.42; 95% CI, 1.39-29.68) remained significant for OS, whereas ELD (HR, 29.31; 95% CI, 1.72-500.82) and progression to extracutaneous disease (HR, 13.12; 95% CI, 1.03-167.96) remained independent prognostic factors for DSS. Presentation with T3 disease was a risk factor for progression to extracutaneous disease (HR, 10.20; 95% CI, 1.84-56.72). Microarray data revealed that patients with ELD and typical pcALCL formed distinct clusters.Patients with ELD have a more aggressive course associated with a differential gene expression profile. More aggressive treatments may be indicated for patients with ELD and those whose disease progresses to extracutaneous disease because they have poorer outcomes.

  View details for Web of Science ID 000267010900006

  View details for PubMedID 19528422

• Prognostic significance of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), and vascularity in diffuse large B-cell lymphoma treated with immunochemotherapy (R-CHOP) 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Gratzinger, D., Advani, R., Zhao, S., Talreja, N., Tibshirani, R. J., Horning, S. J., Levy, R., Lossos, I. S., Gascoyne, R. D., Natkunam, Y. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605490

• Dynamic CD8 T-cell responses to tumor-associated Epstein-Barr virus (EBV) antigens in patients with EBV-negative Hodgkin's disease 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Kohrt, H. E., Advani, R., Hoppe, R., Rosenberg, S., Horning, S., Lee, P. P. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605482

• Targeting CD40 in Waldenstrom's Macroglobulinemia 5th International Workshop on Waldenstroms Macroglobulinemia Lee, M., Advani, R. CIG MEDIA GROUP, LP. 2009: 87–89

  Abstract

  CD40 is a member of the tumor necrosis factor (TNF) receptor family and is expressed in a majority of B-cell malignancies. In Waldenström's macroglobulinemia (WM), CD40 expression is a common feature of bone marrow infiltrating lymphoplasmacytic cells, and preclinical evidence suggests that CD40 signaling is functionally important for WM growth and survival. Two antibodies targeting CD40 (SGN-40 and HCD 122 [Chir 12.12]) are currently undergoing clinical testing in multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody while SGN-40 is a humanized IgG1 partial agonistic antibody. Both agents have demonstrated activity in preclinical models and are potent mediators of antibodydependent cellular cytotoxicity (ADCC). Clinically, phase I data suggest both agents are well tolerated with no immunogenicity and have early evidence of single-agent clinical activity in relapsed and refractory NHL and MM. These observations support the testing of CD40-targeted agents in WM.

  View details for DOI 10.3816/CLM.2009.n.023

  View details for Web of Science ID 000264628200023

  View details for PubMedID 19362983

• Extranodal natural killer/T-cell lymphoma: current concepts in biology and treatment LEUKEMIA & LYMPHOMA Kohrt, H., Advani, R. 2009; 50 (11): 1773-1784

  Abstract

  Natural killer/T-cell (NK/T) lymphomas represent a group of rare tumors of NK and NK-T cells. The World Health Organization classifies NK-cell tumors into three types, extranodal NK/T-cell lymphomas (ENKL, nasal and non-nasal), NK-cell leukemias, and a blastic variant (CD4-positive, CD56-positive hematodermic neoplasms). We focus our review to the current concepts in biology and treatment of ENKL. Though considerable advances have been made in our understanding of NK-cell biology, malignant transformation including the role of Epstein-Barr virus, and prognosis, the rare nature of ENKL and its heterogeneity limit the ability to standardize therapy. Radiotherapy is fundamental to treatment of early-stage disease with a role for chemoradiotherapy among high-risk patients. The clinical course of advanced disease is highly aggressive with frequent chemotherapy resistance and a poor prognosis. Therapeutic approaches to advanced-stage or relapsed and refractory disease, including the appropriate sequence of chemotherapy, combined modality therapy, and stem cell transplantation is not well-established. International and multicenter clinical trials are needed for this rare and aggressive disease.

  View details for DOI 10.3109/10428190903186502

  View details for Web of Science ID 000272145000014

  View details for PubMedID 19883307

• CD81 Protein Is Expressed in Normal Germinal Center B-Cells and in Subtypes of Human Non-Hodgkin Lymphomas 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Luo, R. F., Zhao, S., Tibshirani, R., Lossos, I. S., Advani, R., Gratzinger, D., Wong, A., Talrega, N., Levy, R., Levy, S., Natkunam, Y. NATURE PUBLISHING GROUP. 2009: 275A–275A

  View details for Web of Science ID 000262371501249

• Dynamic CD8 T-Cell Responses to Tumor-Associated Epstein-Barr Virus Antigens in Patients With Epstein-Barr Virus-Negative Hodgkin's Disease ONCOLOGY RESEARCH Kohrt, H., Johannsen, A., Hoppe, R., Horning, S. J., Rosenberg, S. A., Advani, R., Lee, P. P. 2009; 18 (5-6): 287-292

  Abstract

  In almost half of patients diagnosed with Hodgkin's disease (HD), the malignant Reed-Sternberg (RS) cells express Epstein-Barr virus (EBV) antigens. Multiple translational efforts are actively investigating antitumor immune strategies by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. In an effort to explore the EBV-specific immune response, here we characterize EBV-specific CTL responses to lytic and latent EBV antigens in 12 consecutive EBV carriers with EBV-negative HD. Compared to healthy donors, we detected weak, baseline EBV-specific responses to both lytic and latent antigens by IFN-gamma ELISPOT in patients with EBV-negative HD at diagnosis. Chemoradiotherapy was associated temporally with a decrease EBV-specific responses. At final follow-up (24 months), recovery of EBV-specific CTL responses was observed with robustness of lytic-specific response equivalent to healthy controls. We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment. Our observation challenges prior belief that patients with HD remain immunodeficient following therapy and argues that the clinical significance of the EBV-specific immune response in EBV-negative HD should be further investigated.

  View details for DOI 10.3727/096504009X12596189659169

  View details for Web of Science ID 000274459900010

  View details for PubMedID 20225766

• Indolent primary cutaneous B-cell lymphoma: Experience using systemic rituximab JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Morales, A. V., Advani, R., Horwitz, S. M., Riaz, N., Reddy, S., Hoppe, R. T., Kim, Y. H. 2008; 59 (6): 953-957

  Abstract

  Optimal treatment of indolent primary cutaneous B-cell lymphoma (CBCL), marginal zone lymphoma, and follicle center lymphoma, presenting as multiple lesions, has yet to be established. Rituximab is a chimeric monoclonal IgG1 antibody directed against the CD20 antigen of B cells. Clinical efficacy of systemic rituximab in CBCL has yet to be established.We sought to assess the efficacy of systemic rituximab in the treatment of CBCL.This was a retrospective study of 15 patients with indolent CBCL treated with intravenous rituximab (375 mg/m(2)) as a single agent. Variable maintenance regimen was used in a subset of patients. Responses were categorized as complete response, partial response, stable disease, or progressive disease. The efficacy end points included were objective response rate, time to response, time to progression, and duration of response.Ten patients with follicle center lymphoma and 5 with marginal zone lymphoma were included. The objective response rate was 87% (60% complete response, 27% partial response). All patients with follicle center lymphoma had a response with 80% achieving complete response. Of the patients with marginal zone lymphoma, 3 had a response, one stable disease, and one progressive disease. Median follow-up was 36 months. Median time to response, duration of response, and time to progression was 30 days, 24 months, and 24 months, respectively.The study was limited by the small sample size and retrospective design.This study, although small, suggests that rituximab is a reasonable first-line treatment option for indolent CBCL with multiple lesions where local treatment is not effective or desirable.

  View details for DOI 10.1016/j.jaad.2008.08.005

  View details for Web of Science ID 000261141600006

  View details for PubMedID 18817999

• Evaluation and management of angioimmunoblastic T-cell lymphoma: a review of current approaches and future strategies. Clinical advances in hematology & oncology : H&O Alizadeh, A. A., Advani, R. H. 2008; 6 (12): 899-909

  Abstract

  Angioimmunoblastic T-cell lymphoma (AITL) is a rare and complex lymphoproliferative disorder, clinically characterized by widespread lymphadenopathy, extranodal disease, immune-mediated hemolysis, and polyclonal hypergammaglobulinemia. Significant progress has been made in the understanding of AITL since its recognition as a clonal T-cell disorder with associated deregulation of B-cells and endothelial cells within a unique malignant microenvironment. However, as the responses to conventional chemotherapy have not been durable, prognosis with current treatment approaches has remained dismal. Here we review the clinical presentation, prognosis, and management of patients with AITL. We discuss recent developments in the understanding of the pathogenesis of AITL at a cellular and molecular level, including the implication of the follicular helper T-cell as the corresponding cell of origin, the roles of Epstein-Barr virus, B-cell deregulation, angiogenesis, and other signaling pathways in AITL, and the therapeutic implications of these findings. Finally, we discuss recent clinical trials and novel treatment approaches in the management of patients with AITL.

  View details for PubMedID 19209140

• LMO2 Protein Expression Predicts Survival in Patients with Diffuse Large B-Cell Lymphoma Treated with Immunochemotherapy (RCHOP): A Multicenter Validation Study. 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Advani, R., Talreja, N., Tibshirani, R., Zhao, S., Alizadeh, A., Briones, J., Bordes, R., Cohen, J., Horning, S., Levy, R., Lossos, I. S., Natkunam, Y. AMER SOC HEMATOLOGY. 2008: 1291–91

  View details for Web of Science ID 000262104704387

• A Phase 1/2A Open-Label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lympboprolifierative Malignancies 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Horwitz, S. M., Vose, J. M., Advani, R., Sankhala, K., Padmanabhan, S., Hamlin, P. A., Chen, A., Wilroy, S., Zain, J. M., Wright, D., Weissbrot, H., Hohenstein, M., Cagnoni, P. J., Saunders, M. E., O'Connor, O. A. AMER SOC HEMATOLOGY. 2008: 557–57

  View details for Web of Science ID 000262104701791

• Hodgkin disease/lymphoma. Journal of the National Comprehensive Cancer Network Hoppe, R. T., Advani, R. H., Ambinder, R. F., Bierman, P. J., Bloomfield, C. D., Blum, K., Dabaja, B., Djulbegovic, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hudson, M. M., Kaminski, M. S., Love, G., Maloney, D. G., Mansur, D., Mauch, P. M., Moore, J. O., Schilder, R. J., Weiss, L. M., Winter, J. N., Yahalom, J., Zelenetz, A. D. 2008; 6 (6): 594-622

  View details for PubMedID 18597713

• Paraffin-based 6-gene model predicts outcome in diffuse large B-cell lymphoma patients treated with R-CHOP BLOOD Malumbres, R., Chen, J., Tibshirani, R., Johnson, N. A., Sehn, L. H., Natkunam, Y., Briones, J., Advani, R., Connors, J. M., Byrne, G. E., Levy, R., Gascoyne, R. D., Lossos, I. S. 2008; 111 (12): 5509-5514

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by variable clinical outcomes. Outcome prediction at the time of diagnosis is of paramount importance. Previously, we constructed a 6-gene model for outcome prediction of DLBCL patients treated with anthracycline-based chemotherapies. However, the standard therapy has evolved into rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Herein, we evaluated the predictive power of a paraffin-based 6-gene model in R-CHOP-treated DLBCL patients. RNA was successfully extracted from 132 formalin-fixed paraffin-embedded (FFPE) specimens. Expression of the 6 genes comprising the model was measured and the mortality predictor score was calculated for each patient. The mortality predictor score divided patients into low-risk (below median) and high-risk (above median) subgroups with significantly different overall survival (OS; P = .002) and progression-free survival (PFS; P = .038). The model also predicted OS and PFS when the mortality predictor score was considered as a continuous variable (P = .002 and .010, respectively) and was independent of the IPI for prediction of OS (P = .008). These findings demonstrate that the prognostic value of the 6-gene model remains significant in the era of R-CHOP treatment and that the model can be applied to routine FFPE tissue from initial diagnostic biopsies.

  View details for DOI 10.1182/blood-2008-02-136374

  View details for Web of Science ID 000256786500021

  View details for PubMedID 18445689

  View details for PubMedCentralID PMC2424149

• Clinical and immunologic responses to a novel in situ lymphoma vaccine maneuver: Results of a phase II trial of intra-tumoral CPG-[PF-3512676] 10th International Conference on Malignant Lymphoma Brody, J. D., Ai, W. Z., Czerwinski, D. K., Advani, R., Horning, S. J., Hoppe, R. T., Levy, R. OXFORD UNIV PRESS. 2008: 158–158

  View details for Web of Science ID 000256693500263

• Attitudes and beliefs towards surviorship issues in Hodgkin's disease (HD). Results of focus group discussions with patients treated at stanford university 10th International Conference on Malignant Lymphoma Advani, R., Rosenberg, S., Talreja, N., Hoppe, R., Horning, S. OXFORD UNIV PRESS. 2008: 137–137

  View details for Web of Science ID 000256693500185

• Improved prognosis after histologic transformation (HT) of follicular lymphoma (FL): The Stanford experience 1960-2003 10th International Conference on Malignant Lymphoma Tan, D., Rosenberg, S. A., Lavori, P., Levy, R., Hoppe, R., Warnke, R., Advani, R., Natkuunam, Y., Yuen, A., Horning, S. J. OXFORD UNIV PRESS. 2008: 111–112

  View details for Web of Science ID 000256693500106

• Closing the gap: A comparison of observed versus expected survival in follicular lymphoma (FL) at Stanford University from 1960-2003 Tan, D., Rosenberg, S. A., Lavori, P., Sigal, B. M., Levy, R., Hoppe, R. T., Warnke, R., Advani, R., Natkunam, Y., Plevritis, S. K., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457403064

• Clinical and immunologic responses to a novel in situ lymphoma vaccine maneuver: Preliminary results of a phase II trial of intra-tumoral CpG 7909 Brody, J., Ai, W. Z., Czerwinski, D., Advani, R., Horning, S. J., Ganjoo, K. N., Levy, R. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457400598

• Beyond the guidelines in the treatment of peripheral T-cell lymphoma: new drug development. Journal of the National Comprehensive Cancer Network Chen, A. I., Advani, R. H. 2008; 6 (4): 428-435

  Abstract

  Peripheral T-cell lymphomas (PTCLs) are a rare and diverse group of neoplasms with a poor prognosis. Management of these disorders has been largely extrapolated from the treatment of aggressive B-cell lymphomas; however, therapeutic responses to this approach are neither adequate nor durable for most patients with PTCL. Given the rarity of PTCL, much of the literature consists of studies with small sample size and anecdotal case reports. Therefore, no consensus exists on the best therapeutic strategy for either newly diagnosed or relapsed/refractory PTCL. This article reviews promising novel approaches in the treatment of PTCL and its subtypes. Investigation into the pathogenesis of PTCL has also identified new targets for treatment. These emerging therapies include new uses of existing agents and the development of novel agents specifically targeted against T-cell lymphoma. Results using antimetabolites, immunotherapies, and histone deacetylase inhibitors have been particularly encouraging. These novel therapies are being tested as single agents and in combination with conventional lymphoma regimens in the frontline and salvage settings. Because of the rarity and heterogeneity of PTCL, national and international cooperation is needed to conduct the clinical studies required for the development of more effective treatment paradigms. These efforts are ongoing and will hopefully guide new strategies to improve the historically poor outcome of PTCL.

  View details for PubMedID 18433608

• Non-Hodgkin's lymphomas. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Advani, R. H., Byrd, J. C., Czuczman, M. S., Damon, L. E., Duvic, M., Fayad, L., Forero, A., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kim, Y. H., LaCasce, A. S., Nademanee, A., Olsen, E. A., Porcu, P., Press, O., Prosnitz, L., Smith, M. R., Sotomayor, E. M., Vose, J. M., Yahalom, J., Yunus, F. 2008; 6 (4): 356-421

  View details for PubMedID 18433606

• Denileukin diftitox (ONTAK) plus CHOP chemotherapy in patients with peripheral T-Cell lymphomas (PTCL), the CONCEPT trial 49th Annual Meeting of the American-Society-of-Hematology Foss, F., Sjak-Shie, N., Goy, A., Jacobsen, E., Advani, R., Smith, M., Komrokji, R., Pendergrass, K., Bolejack, V., Watts, K., Acosta, M. AMER SOC HEMATOLOGY. 2007: 1011A–1011A

  View details for Web of Science ID 000251100804486

• Belinostat (PXD101) in patients with recurrent or refractory peripheral or cutaneous T-Cell lymphoma: Results of a phase II study 49th Annual Meeting of the American-Society-of-Hematology Advani, R., Hymes, K., Pohlman, B., Jacobsen, E., McDonnell, J., Belt, R., LERNER, A., Kim, Y., MUNDIS, R., MANSFIELD, T., Buhl-Jensen, P., Ooi, C. E., Duvic, M., Foss, F. AMER SOC HEMATOLOGY. 2007: 1012A–1012A

  View details for Web of Science ID 000251100804490

• Phase II study of R-CHOP followed by Y-90-ibritumomab tiuxetan in untreated mantle cell lymphoma: Eastern cooperative oncology group study E1499 49th Annual Meeting of the American-Society-of-Hematology Smith, M. R., Zhang, L., Gordon, L. I., Foran, J., Kahl, B., Gascoyne, R. D., Advani, R., Paietta, E., Weller, E., Horning, S. J. AMER SOC HEMATOLOGY. 2007: 121A–121A

  View details for Web of Science ID 000251100800390

• Stage I/II Hodgkin's disease: Comparison of outcomes of patients with bulky mediastinal disease versus other risk factors; the Stanford V experience Advani, R. H., Hoppe, R. T., Rosenberg, S. A., Horning, S. J. AMER SOC HEMATOLOGY. 2007: 685A–685A

  View details for Web of Science ID 000251100803098

• Survival in follicular lymphoma: The Stanford experience, 1960-2003. 49th Annual Meeting of the American-Society-of-Hematology Tan, D., Rosenberg, S. A., Levy, R., Lavori, P., Tibshirani, R., Hoppe, R. T., Warnke, R., Advani, R., Natkunam, Y., Yuen, A., Horning, S. J. AMER SOC HEMATOLOGY. 2007: 1005A–1005A

  View details for Web of Science ID 000251100804465

• Prognostic factors in primary cutaneous anaplastic large cell lymphoma: Clinical and molecular characterization of a subset with worse outcome 49th Annual Meeting of the American-Society-of-Hematology Woo, D., Jones, C., Vanoli-Storz, M., Kohler, S., Reddy, S., Advani, R., Hoppe, R., Kim, Y. AMER SOC HEMATOLOGY. 2007: 1045A–1045A

  View details for Web of Science ID 000251100804610

• Stage I/II Hodgkin's disease (HD) with bulky mediastinal disease or other risk factors (RF) the Stanford V experience 7th International Symposium on Hodgkins Lymphoma Advani, R. H., Hoppe, R. T., Rosenberg, S. A., Horning, S. J. FERRATA STORTI FOUNDATION. 2007: 27–27

  View details for Web of Science ID 000250470800070

• A prospective trial of involved field radiation (IFRT) plus chemotherapy vs extended field (EFRT) radiation for favorable Hodgkin's disease (HD): Long-term follow-up and implications for current combined modality therapy 7th International Symposium on Hodgkins Lymphoma Horning, S. J., Hoppe, R. T., Advani, R. H., Breslin, S., McCormick, E., Allen, J., Hancock, S. L., Rosenberg, S. A. FERRATA STORTI FOUNDATION. 2007: 53–53

  View details for Web of Science ID 000250470800147

• Intra-CSF rituximab for lymhomatous meningitis - Reply JOURNAL OF CLINICAL ONCOLOGY Rubenstein, J., Abrey, L., Advani, R., Shuman, M., Tsai, T., O'Brien, J. 2007; 25 (28): 4509-4511

  View details for DOI 10.1200/JCO.2007.13.1284

  View details for Web of Science ID 000251073300039

• Non-Hodgkin lymphoma of the breast CANCER Ganjoo, K., Advani, R., Mariappan, M. R., McMillan, A., Horning, S. 2007; 110 (1): 25-30

  Abstract

  Primary lymphoma of the breast has been reported to have a high local and central nervous system recurrence (CNS) rate, suggesting the need for consolidation radiotherapy and CNS prophylaxis. A retrospective study was done to evaluate the institutional experience in this patient population.In all, 37 patients with lymphoma involving the breast at initial diagnosis and managed at Stanford University from 1981-2005 were included. Diagnostic tissue biopsies were obtained either from the breast mass or an involved lymph node. Treatment and response data, patterns of recurrence, and outcomes were reviewed.Diffuse large B cell lymphoma (DLBCL) was the most common histologic subtype seen in 18 of 37 (49%) patients. Follicular and marginal zone subtypes were seen in 38%. Most patients presented with an incidental breast mass in stage I(E) or II(E). Four (11%) patients presented with bilateral breast involvement, with only 1 patient presenting with CNS disease. DLBCL patients received doxorubicin-based chemotherapy, with 70% receiving involved field radiotherapy and a single patient receiving intrathecal therapy. No recurrences occurred in the involved breast and a single parenchymal CNS recurrence was recorded. Among the DLBCL patients, the 5-year progression-free survival (PFS) was 61%, with a median follow-up of 3.8 years (range, 5 months to 19 years) and the 5-year overall survival (OS) was estimated at 82%. Patients with indolent lymphoma had an estimated 5-year PFS of 76% and an OS of 92%.DLBCL of the breast was successfully treated with doxorubicin-based chemotherapy alone or with involved field radiotherapy in an estimated 61% of patients at 5 years. A single CNS recurrence was observed in our series of patients, most of whom presented with limited disease.

  View details for DOI 10.1002/cncr.22753

  View details for Web of Science ID 000247384200003

  View details for PubMedID 17541937

• Multicenter clinical trial of bortezomib in relapsed/refractory Waldenstrom's macroglobulinemia: Results of WMCTG trial 03-248 CLINICAL CANCER RESEARCH Treon, S. P., Hunter, Z. R., Matous, J., Joyce, R. M., Mannion, B., Advani, R., Cook, D., Songer, J., Hill, J., Kaden, B. R., Sharon, D., Steiss, R., Leleu, X., Branagan, A. R., Badros, A. 2007; 13 (11): 3320-3325

  Abstract

  Waldenstrom's macroglobulinemia (WM) is a B-cell disorder. Despite advances in the therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM.In this multicenter study, 27 patients with WM received up to eight cycles of bortezomib at 1.3 mg/m(2) on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease.Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (P < 0.0001). The overall response rate was 85%, with 10 and 13 patients achieving minor and major responses, respectively. Responses were prompt and occurred at median of 1.4 months. The median time to progression for all responding patients was 7.9 (range, 3-21.4+) months. The most common grade III/IV toxicities occurring in > or =5% of patients were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy.The results of these studies show that bortezomib is an active agent in relapsed and refractory WM.

  View details for DOI 10.1158/1078-0432.CCR-06-2511

  View details for Web of Science ID 000246788700030

  View details for PubMedID 17545538

• Phase II study of rituximab plus CHOP followed by Y-90-ibritumomab tiuxetan in patients with previously untreated mantle cell lymphoma: An Eastern Cooperative Oncology Group Study (E1499). 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Smith, M. R., Chen, H., Gordon, L., Foran, J., Kahl, B., Advani, R., Gascoyne, R. D., Weller, E., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2006: 422S–422S

  View details for Web of Science ID 000239009402559

• Incidence of secondary leukemia/myelodysplasia (AML/MDS) in Hodgkin's disease (HD) with three generations of therapy at Stanford University. 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Advani, R. H., Hoppe, R. T., Rosenberg, S. A., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2006: 426S–426S

  View details for Web of Science ID 000239009403005

• Treatment of mantle cell lymphoma: Current approach and future directions CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY Brody, J., Advani, R. 2006; 58 (3): 257-265

  Abstract

  Although mantle cell lymphoma has been described as "moderately aggressive" it has become clear that it carries a worse long-term prognosis than other subtypes of non-Hodgkin's lymphoma. In recent years, this has prompted numerous clinical trials of novel and more aggressive therapies in hopes of impacting these poor outcomes. These include more intensive combination chemotherapy regimens, monoclonal antibody therapy in conjunction with other treatments or conjugated to radioactive isotopes, high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation, and newer targeted therapies based on increasing understanding of the molecular pathways of this malignancy.

  View details for DOI 10.1016/j.critrevonc.2005.10.001

  View details for Web of Science ID 000238633200007

  View details for PubMedID 16751087

• Staging accuracy in mycosis fungoides and Sezary syndrome using integrated positron emission tomography and computed tomography 65th Annual Meeting of the Society-for-Investigative-Dermatology Tsai, E. Y., Taur, A., Espinosa, L., Quon, A., Johnson, D., Dick, S., Chow, S., Advani, R., Warnke, R., Kohler, S., Hoppe, R. T., Kim, Y. H. AMER MEDICAL ASSOC. 2006: 577–84

  Abstract

  To evaluate the usefulness of integrated positron emission tomography and computed tomography (PET/CT) in staging mycosis fungoides (MF) and Sézary syndrome and to correlate PET/CT data with histopathologic diagnosis of lymph nodes (LNs).A single-center, prospective cohort analysis.Academic referral center for cutaneous lymphoma.Thirteen patients with MF and SS at risk for secondary LN involvement. Interventions Patients were clinically evaluated based on general physical examination, total body skin examination, and laboratory screening. They underwent integrated PET/CT followed by excisional biopsy of LNs.We used PET/CT to assess LN size and metabolic activity. Enlarged LNs were defined as axillary or inguinal LNs with a short axis 1.5 cm or larger; or cervical LN, with a short axis 1.0 cm or larger. We classified LN pathologic results according to National Cancer Institute (LN1-4) and World Health Organization (WHO 1-3) criteria. We quantified PET activity using standardized uptake value (SUV) and correlated with LN grade.Based on CT size criteria alone, only 5 patients had enlarged LNs, whereas PET revealed hypermetabolic LNs in all 13 patients. Six patients had LN1-3, and 7 had effacement of LN architecture by lymphoma cells (LN4). Of the 7 patients with LN4 nodes, 4 had SS, and 3 had tumorous MF. Two patients with LN4 nodes had inguinal LNs smaller than 1.5 cm and would have been assigned an N0 classification without the use of integrated PET/CT. Correlation of SUV with LN grade revealed that LN1-3 nodes were associated with a mean SUV of 2.7 (median SUV, 2.2; range, 2.0-4.7) and LN4 nodes were associated with a mean SUV of 5.4 (median SUV, 3.9; range, 2.1-11.8). Patients with large cell transformation had the highest SUVs.For staging MF and SS, PET/CT was more sensitive in detecting LN involved by lymphoma compared with CT data alone and thus may provide more accurate staging and prognostic information. The intensity of PET activity correlated with histologic LN grade.

  View details for Web of Science ID 000237543100006

  View details for PubMedID 16702495

• Management of advanced stage Hodgkin lymphoma. Journal of the National Comprehensive Cancer Network Advani, R., Ai, W. Z., Horning, S. J. 2006; 4 (3): 241-247

  Abstract

  Although advanced Hodgkin lymphoma is highly curable, balancing the high cure rate with long-term toxicity is challenging. ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) is the standard chemotherapy regimen, producing a high cure rate with acceptable toxicity. Stanford V and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) are new regimens with encouraging results and are undergoing randomized clinical trials. The International Prognostic Score provides a clinical tool that may help identify patients with high-risk disease who may require a more aggressive regimen. Consolidative radiation's role in managing advanced Hodgkin lymphoma is still controversial, but it is most accepted for bulky or residual disease or after brief chemotherapy. The development and integration of newer imaging tools, such as fluorodeoxyglucose-positron emission tomography imaging, may allow a more precise evaluation of disease and help define which patients might benefit from consolidative treatment.

  View details for PubMedID 16507271

• Non-Hodgkin's lymphoma. Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Zelenetz, A. D., Advani, R. H., Buadi, F., Cabanillas, F., Caligiuri, M. A., Czuczman, M. S., Damon, L. E., Fayad, L., Flinn, I. W., Forero, A., Glenn, M. J., Gockerman, J. P., Gordon, L. I., Harris, N. L., Hoppe, R. T., Kaminski, M. S., LaCasce, A. S., Nademanee, A., Porcu, P., Press, O., Prosnitz, L., Smith, M. R., Sotomayor, E. M., Vose, J. M., Yahalom, J. 2006; 4 (3): 258-310

  View details for PubMedID 16507273

• Hodgkin disease/lymphoma. Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Hoppe, R. T., Advani, R. H., Bierman, P. J., Bloomfield, C. D., Buadi, F., Djulgegovic, B., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Kaminski, M. S., Love, G., Maloney, D. G., Mauch, P. M., Moore, J. O., Schilder, R. J., Weiss, L., Winter, J. N., Yahalom, J., Zelenetz, A. D. 2006; 4 (3): 210-230

  View details for PubMedID 16507269

• A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance ANNALS OF ONCOLOGY Advani, R., Lum, B. L., Fisher, G. A., Halsey, J., Chin, D. L., Jacobs, C. D., Sikic, B. I. 2005; 16 (12): 1968-1973

  Abstract

  The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel.Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m2 for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed.The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted.The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.

  View details for DOI 10.1093/annonc/mdi396

  View details for Web of Science ID 000233489600018

  View details for PubMedID 16126736

• Motexafin gadolinium (MGd) has clinical activity in relapsed/refractory low grade lymphomas (LG) and relapsed/refractory chronic lymphocytic leukemia (CLL). 47th Annual Meeting of the American-Society-of-Hematology Kahl, B. S., Advani, R., Kay, N., Lossos, I. S., Evens, A., Gordon, L., MILLER, R. A., Phan, S. C. AMER SOC HEMATOLOGY. 2005: 269B–270B

  View details for Web of Science ID 000233426101460

• Phase II study of bortezomib in Waldenstrom's Macroglobulinemia: Results of WMCTG trial 03-248. 47th Annual Meeting of the American-Society-of-Hematology Treon, S., Hunter, Z. R., Matous, J., Badros, A., Joyce, R. M., Mannion, B., Advani, R., Cook, D., Songer, J., Hill, J., Kaden, B. R., Sharon, D., Steiss, R., Branagan, A. R., Patterson, C. J. AMER SOC HEMATOLOGY. 2005: 147A–147A

  View details for Web of Science ID 000233426000491

• Bexarotene is highly active in the treatment of subcutaneous Panniculitis-like T-cell lymphoma. 47th Annual Meeting of the American-Society-of-Hematology Molina, A. M., Advani, R., Reddy, S., Hoppe, R., Friedberg, J. W., Sadan, S., Myskowski, P., Kim, Y. H., Horwitz, S. M. AMER SOC HEMATOLOGY. 2005: 934A–934A

  View details for Web of Science ID 000233426006128

• Assessment of favorable (F) versus unfavorable (U) early stage Hodgkin's disease (HD); the Stanford V plus radiotherapy (RT) experience. 47th Annual Meeting of the American-Society-of-Hematology Advani, R., Maeda, L., Hoppe, R. T., Breslin, S., Rosenberg, S. A., Baer, D., Mason, J., Horning, S. J. AMER SOC HEMATOLOGY. 2005: 548A–548A

  View details for Web of Science ID 000233426003294

• A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-alpha administered as a 24-hour weekly infusion schedule in patients with advanced cancer 36th Annual Meeting of the American-Society-of-Clinical-Oncology Advani, R., Lum, B. L., Fisher, G. A., Halsey, J., Geary, R. S., Holmlund, J. T., Kwoh, T. J., DORR, F. A., Sikic, B. I. SPRINGER. 2005: 467–77

  Abstract

  A phase I study was performed to determine the maximum tolerated dose (MTD), safety profile and pharmacology of aprinocarsen (ISIS 3521), an antisense oligonucleotide to protein kinase C-alpha, in patients with refractory solid tumors.Fourteen patients were treated in sequential cohorts of aprinocarsen by 24-hour continuous infusion (CIV), weekly, at doses of 6, 12, 18 and 24 mg/kg.One grade 4 toxicity was observed, transient grade 4 neutropenia at 18 mg/kg. Grade 3 toxicities included neutropenia at 12 mg/kg, fever and hemorrhage at 18 mg/kg, and neutropenia, nausea, and chills at 24 mg/kg. Grade 2 toxicities included thrombocytopenia myalgias, chills, headache, fatigue, fever and nausea/vomiting. Mean prothrombin times and activated partial thromboplastin times (aPTT) increased by 10% and 29% from baseline (p = 0.006 and 0.005). Mean complement split products (Bb and C3a) increased 1.6-fold and 3.6-fold (from p = 0.014 and 0.004, respectively). These changes correlated with dose and were transient with recovery to baseline by day 7. Steady state plasma concentrations (Css) of aprinocarsen were achieved within four hours. Css better described changes in aPTT than dose. Clinical evidence of complement activation was not observed.In contrast to 21-day protracted infusion schedules, delivery of aprinocarsen over a 24-hour infusion schedule showed concentration-dependent effects on coagulation and complement, which are consistent with nonclinical toxicology studies performed in the phosphorothioate DNA antisense drug class. These coagulation and complement changes resulted in a maximum tolerated dose 24 mg/kg.

  View details for DOI 10.1007/s10637-005-2906-0

  View details for Web of Science ID 000231245000008

  View details for PubMedID 16133798

• A phase I trial of oblimersen and gemcitabine in refractory and advanced malignancies 41st Annual Meeting of the American-Society-of-Clinical-Oncology Fisher, G., Advani, R., Wakelee, H., Jacobs, C., Gladysheva, K., Fitzgerald, A. M., Sikic, B. AMER SOC CLINICAL ONCOLOGY. 2005: 234S–234S

  View details for Web of Science ID 000230326601349

• PET status after Stanford V chemotherapy predicts outcome in Hodgkins disease 9th International Conference on Malignant Lymphoma Advani, R., Maeda, L., Lavori, P., Hoppe, R., Breslin, S., Rosenberg, S., Horning, S. OXFORD UNIV PRESS. 2005: 121–121

  View details for Web of Science ID 000233670100285

• A Phase I Trial of Aprinocarsen (ISIS 3521/LY900003), an Antisense Inhibitor of Protein Kinase C-alpha Administered as a 24-hour Weekly Infusion Schedule in Patients with Advanced Cancer. Investigational New Drugs, Advani R, Lum BL, Fisher GA, Halsey J, Geary RS, Holmlund JT, Kwoh TJ, Dorr FA, Sikic BI. 2005; In Press
• Efficacy and late effects of Stanford V chemotherapy and radiotherapy in untreated Hodgkin's disease: Mature data in early and advanced stage patients. 46th Annual Meeting of the American-Society-of-Hematology Horning, S. J., Hoppe, R. T., Advani, R., Warnke, R., Baer, D., Mason, J., Rosenberg, S. A. AMER SOC HEMATOLOGY. 2004: 92A–92A

  View details for Web of Science ID 000225127500310

• A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. 40th Annual Meeting of the American-Society-of-Clinical-Oncology Fishe, G. A., Kuo, T., Cho, C. D., Halsey, J., Jambalos, C. N., Schwartz, E. J., Robert, R. V., Advani, R. H., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2004: 248S–248S

  View details for Web of Science ID 000223512400981

• Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: A phase III trial (E2995) JOURNAL OF CLINICAL ONCOLOGY Greenberg, P. L., Lee, S. J., Advani, R., Tallman, M. S., Sikic, B. I., Letendre, L., Dugan, K., Lum, B., Chin, D. L., Dewald, G., Paietta, E., Bennett, J. M., Rowe, J. M. 2004; 22 (6): 1078-1086

  Abstract

  To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n=66) versus MEC (n=63) to treat patients with relapsed or refractory AML and high-risk MDS.For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P=not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased--35% versus 15% for the remaining patients (P=.018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients' overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR- patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P=.09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents.CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.

  View details for DOI 10.1200/JCO.2004.07.048

  View details for Web of Science ID 000220287900017

  View details for PubMedID 15020609

• A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Cho, C. D., Fisher, G. A., Halsey, J., Jambalos, C. N., Schwartz, E. J., Rouse, R. V., Advani, R. H., Wakelee, H. A., Lum, B. L., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2003: 6103S–6103S

  View details for Web of Science ID 000187467300140

• Phase I and pharmacokinetic study of BMS-188797, a new taxane analog, administered on a weekly schedule in patients with advanced malignancies CLINICAL CANCER RESEARCH Advani, R., Fisher, G. A., Lum, B. L., Jambalos, C., Cho, C. D., Cohen, M., Gollerkeri, A., Sikic, B. I. 2003; 9 (14): 5187-5194

  Abstract

  The purpose of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary activity of BMS-188797 administered weekly.Patients with advanced malignancies were treated with escalating doses of BMS-188797 on a weekly schedule as a 1-h i.v. infusion. Plasma sampling was performed to characterize the pharmacokinetics of BMS-188797.Eighteen patients with advanced malignancies were enrolled at three dose levels ranging from 35 to 65 mg/m(2). The number of patients evaluated at each dose level was as follows: 35 mg/m(2) (n = 3); 50 mg/m(2) (n = 9); and 65 mg/m(2) (n = 6). At 65 mg/m(2), three of six patients had a DLT (one had grade 4 neutropenia lasting >7 days, and two had grade 3 diarrhea). Expansion of the 50-mg/m(2) dose cohort to nine patients established this dose as the MTD, with one patient experiencing a DLT (grade 4 neutropenia with fever). Two partial responses were observed (lung cancer, 7+ months; ovarian cancer, 6+ months durations), as well as two minor responses (esophageal cancer, 5 months; ovarian cancer, 5 months). Both patients with partial responses had been clinically resistant to paclitaxel. Plasma pharmacokinetic mean values of maximum concentration (C(max)) and area under the curve (AUC(0-48)) increased in a dose-dependent manner within the range of doses used in this study, and in three of four patients, the DLTs correlated with AUC.The MTD and the recommended Phase II dose of weekly BMS-188797 is 50 mg/m(2). The drug demonstrates antitumor activity in taxane-refractory solid tumors and is now being evaluated in combination with carboplatin.

  View details for Web of Science ID 000186558400017

  View details for PubMedID 14613998

• A phase I study of ZD 1839 (Iressa) in combination with oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) in advanced solid malignancies 14th EORTC/NCI/AACR Symposium on Molecular Targets and Cancer Therapeutics Fisher, G. A., Cho, C. D., Halsey, J. Z., Advani, R. H., Yuen, A. R., Lum, B. L., Sikic, B. I. ELSEVIER SCI LTD. 2002: S63–S63

  View details for Web of Science ID 000179895700204

• The effect of oral valspodar (psc 833), a modulator of multidrug resistance, on the pharmacokinetics of liposomal doxorubicin. Lum, B. L., Chin, D. L., Cho, C. D., Advani, R., Fisher, G. A., Halsey, J., Sikic, B. I. NATURE PUBLISHING GROUP. 2002: P48–P48

  View details for Web of Science ID 000174178600176

• A phase I trial of doxorubicin, paclitaxel, and valspodar (PSC 833), a modulator of multidrug resistance 34th Annual Meeting of the American-Society-of-Clinical-Oncology Advani, R., Fisher, G. A., Lum, B. L., Hausdorff, J., Halsey, J., Litchman, M., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2001: 1221–29

  Abstract

  P-glycoprotein is an efflux pump for many drugs including doxorubicin and paclitaxel. This study evaluated the coadministration of these drugs with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of determining: (a) maximum tolerated doses (MTDs) of doxorubicin followed by paclitaxel (DP); (b) the MTD of DP combined with PSC 833 (DPV), without and with filgrastim (G-CSF); and (c) the pharmacokinetic interactions of PSC 833 with doxorubicin and paclitaxel.For the first cycle, patients received doxorubicin as a 15-min infusion followed by paclitaxel as a 1-h infusion. For the second cycle, patients received reduced doses of DP with PSC 833 at 5 mg/kg p.o., four times a day for 12 doses.Thirty-three patients with various refractory malignancies were enrolled and assessable. The MTD of DP without PSC 833 was 35 mg/m(2) doxorubicin and 150 mg/m(2) paclitaxel. The MTD of DPV without G-CSF was 12.5 mg/m(2) doxorubicin and 70 mg/m(2) paclitaxel. The dose-limiting toxicity for both DP and DPV was neutropenia without thrombocytopenia. With G-CSF, the MTD for DPV was 20 mg/m(2) doxorubicin and 90 mg/m(2) paclitaxel. No grade 4 nonhematological toxicities were observed. Five partial and two minor tumor remissions were observed. Paired pharmacokinetics with and without PSC 833 revealed substantial drug interactions with both doxorubicin and paclitaxel.PSC 833 can be administered safely with doxorubicin and paclitaxel. The pharmacokinetic profiles of these drugs are significantly affected by PSC 833, requiring approximately 60% dose reductions for equivalent degrees of myelosuppression.

  View details for Web of Science ID 000168768500018

  View details for PubMedID 11350887

• Treatment of refractory/relapsed AML with PSC833 plus mitoxantrone, etoposide, cytarabine (PSC-MEC) vs MEC: Randomized phase III trial (E2995). Greenberg, P., Advani, R., Tallman, M., Letendre, L., Saba, H., Dugan, K., Lee, S. J., Lum, B., Sikic, B. I., Paietta, E., Bennett, J., Rowe, J. M. AMER SOC HEMATOLOGY. 1999: 383A–383A

  View details for Web of Science ID 000083790301752

• Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). Blood Advani R, Saba HI, Tallman M, Rowe JM, Wiernik PH, Ramek J, Dugan K, Lum B, Villena J, Sikic BI, Davis E, Paietta E, Litchman M , Greenberg P. 1999; 93: 787-95