Steven Coutre

All Publications

• Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables BLOOD Roberts, A. W., Ma, S., Kipps, T. J., Coutre, S. E., Davids, M. S., Eichhorst, B., Hallek, M., Byrd, J. C., Humphrey, K., Zhou, L., Chyla, B., Nielsen, J., Potluri, J., Kim, S., Verdugo, M., Stilgenbauer, S., Wierda, W. G., Seymour, J. F. 2019; 134 (2): 111–22

  View details for DOI 10.1182/blood.2018882555

  View details for Web of Science ID 000474864100008

• Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. The New England journal of medicine Shanafelt, T. D., Wang, X. V., Kay, N. E., Hanson, C. A., O'Brien, S., Barrientos, J., Jelinek, D. F., Braggio, E., Leis, J. F., Zhang, C. C., Coutre, S. E., Barr, P. M., Cashen, A. F., Mato, A. R., Singh, A. K., Mullane, M. P., Little, R. F., Erba, H., Stone, R. M., Litzow, M., Tallman, M. 2019; 381 (5): 432–43

  Abstract

  Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001).The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

  View details for DOI 10.1056/NEJMoa1817073

  View details for PubMedID 31365801

• A one-two punch with VO KOs CLL. Blood Coutre, S. 2019; 133 (26): 2737–38

  View details for DOI 10.1182/blood-2019-04-901116

  View details for PubMedID 31248874

• Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. The New England journal of medicine Woyach, J. A., Ruppert, A. S., Heerema, N. A., Zhao, W., Booth, A. M., Ding, W., Bartlett, N. L., Brander, D. M., Barr, P. M., Rogers, K. A., Parikh, S. A., Coutre, S., Hurria, A., Brown, J. R., Lozanski, G., Blachly, J. S., Ozer, H. G., Major-Elechi, B., Fruth, B., Nattam, S., Larson, R. A., Erba, H., Litzow, M., Owen, C., Kuzma, C., Abramson, J. S., Little, R. F., Smith, S. E., Stone, R. M., Mandrekar, S. J., Byrd, J. C. 2018

  Abstract

  BACKGROUND: Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy.METHODS: Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met.RESULTS: A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen).CONCLUSIONS: Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872 .).

  View details for PubMedID 30501481

• Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression Free Survival (PFS) Compared with Bendamustine Plus Rituximab in Untreated Older Patients with Chronic Lymphocytic Leukemia (CLL): Results of Alliance North American Intergroup Study A041202 Woyach, J. A., Ruppert, A. S., Heerema, N. A., Zhao, W., Booth, A. M., Ding, W., Bartlett, N. L., Brander, D. M., Barr, P., Rogers, K. A., Parikh, S. A., Coutre, S., Hurria, A., Lozanski, G., Nattam, S., Larson, R. A., Erba, H. P., Litzow, M. R., Owen, C., Atkins, J., Abramson, J. S., Little, R. F., Smith, S. E., Stone, R. M., Mandrekar, S. J., Byrd, J. C. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-116653

  View details for Web of Science ID 000454837600060

• Survival adjusting for crossover: phase 3 study of ibrutinib vs. chlorambucil in older patients with untreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Haematologica Coutre, S., Tedeschi, A., Robak, T., Barr, P. M., Owen, C., Bairey, O., Burger, J., Zhou, C., Styles, L., James, D. F., Kipps, T. J. 2018; 103 (6): e249–e251

  View details for PubMedID 29170253

• Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Stilgenbauer, S., Eichhorst, B., Schetelig, J., Hillmen, P., Seymour, J. F., Coutre, S., Jurczak, W., Mulligan, S. P., Schuh, A., Assouline, S., Wendtner, C., Roberts, A. W., Davids, M. S., Bloehdorn, J., Munir, T., Bottcher, S., Zhou, L., Salem, A. H., Desai, M., Chyla, B., Arzt, J., Kim, S. Y., Verdugo, M., Gordon, G., Hallek, M., Wierda, W. G. 2018: JCO2017766840

  Abstract

  Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10-4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10-4 was achieved in this high-risk population.

  View details for PubMedID 29715056

• Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience BLOOD O'Brien, S., Furman, R. R., Coutre, S., Flinn, I. W., Burger, J. A., Blum, K., Sharman, J., Wierda, W., Jones, J., Zhao, W., Heerema, N. A., Johnson, A. J., Luan, Y., James, D. F., Chu, A. D., Byrd, J. C. 2018; 131 (17): 1910–19

  Abstract

  We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naïve (TN) older patients (≥65 years of age) and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients. The median progression-free survival (PFS) was not reached in TN patients. The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups. Survival outcomes were less robust for R/R patients with del(17p) and those who received more prior therapies. The onset of grade ≥3 cytopenias, such as neutropenia and thrombocytopenia, decreased over time. Treatment--limiting adverse events were more frequent during the first year compared with subsequent periods. These results demonstrate sustained efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL. These trials were registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01109069.

  View details for PubMedID 29437592

  View details for PubMedCentralID PMC5921964

• Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy BLOOD Coutre, S., Choi, M., Furman, R. R., Eradat, H., Heffner, L., Jones, J. A., Chyla, B., Zhou, L., Agarwal, S., Waskiewicz, T., Verdugo, M., Humerickhouse, R. A., Potluri, J., Wierda, W. G., Davids, M. S. 2018; 131 (15): 1704–11

  Abstract

  B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi before enrollment. Venetoclax was initiated at 20 mg daily, followed by intrapatient ramp-up to 400 mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received idelalisib (ORR, 67% [24/36]); 2 patients achieved complete remission, and 1 had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached; estimated 12-month PFS was 79%. The most common adverse events (AEs; all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after idelalisib therapy. This trial was registered at www.clinicaltrials.gov as #NCT02141282.

  View details for PubMedID 29305552

  View details for PubMedCentralID PMC5922273

• Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial LANCET ONCOLOGY Jones, J. A., Mato, A. R., Wierda, W. G., Davids, M. S., Choi, M., Cheson, B. D., Furman, R. R., Lamanna, N., Barr, P. M., Zhou, L., Chyla, B., Salem, A., Verdugo, M., Humerickhouse, R. A., Potluri, J., Coutre, S., Woyach, J., Byrd, J. C. 2018; 19 (1): 65–75

  Abstract

  Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy.In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282.Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8-18) for all 91 patients, 19 months (9-27) for the main cohort, and 12 months (8-15) for the expansion cohort. 59 (65%, 95% CI 53-74) of 91 patients had an overall response, including 30 (70%, 54-83) of 43 patients in the main cohort and 29 (60%, 43-72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred.The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019.AbbVie, Genentech.

  View details for PubMedID 29246803

• Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study LANCET ONCOLOGY O'Brien, S., Jones, J. A., Coutre, S. E., Mato, A. R., Hillmen, P., Tam, C., Osterborg, A., Siddiqi, T., Thirman, M. J., Furman, R. R., Ilhan, O., Keating, M. J., Call, T. G., Brown, J. R., Stevens-Brogan, M., Li, Y., Clow, F., James, D. F., Chu, A. D., Hallek, M., Stilgenbauer, S. 2016; 17 (10): 1409-1418

  Abstract

  The TP53 gene, encoding tumour suppressor protein p53, is located on the short arm of chromosome 17 (17p). Patients with 17p deletion (del17p) chronic lymphocytic leukaemia have poor responses and survival after chemoimmunotherapy. We assessed the activity and safety of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma.We did a multicentre, international, open-label, single-arm study at 40 sites in the USA, Canada, Europe, Australia, and New Zealand. Patients (age ≥18 years) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis. Preplanned exploratory analyses were progression-free survival, overall survival, sustained haematological improvement, and immunological improvement. Patient enrolment is complete, but follow-up is ongoing. Treatment discontinuation owing to adverse events, unacceptable toxicity, or death were collected as a single combined category. This study is registered with ClinicalTrials.gov, number NCT01744691.Between Jan 29, 2013, and June 19, 2013, 145 patients were enrolled. The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug, with a median age of 64 years (IQR 57-72) and a median of two previous treatments (IQR 1-3). At the prespecified primary analysis after a median follow-up of 11·5 months (IQR 11·1-13·8), 92 (64%, 95% CI 56-71) of 144 patients had an overall response according to independent review committee assessment; 119 patients (83%, 95% CI 76-88) had an overall response according to investigator assessment. In an extended analysis with median follow-up of 27·6 months (IQR 14·6-27·7), the investigator-assessed overall response was reported in 120 patients (83%, 95% CI 76-89). 24-month progression-free survival was 63% (95% CI 54-70) and 24-month overall survival was 75% (67-81). Sustained haematological improvement was noted in 72 (79%) of 91 patients with any baseline cytopenia. No clinically relevant changes were noted from baseline to 6 months or 24 months in IgA (median 0·4 g/L at baseline, 0·6 g/L at 6 months, and 0·7 g/L at 24 months), IgG (5·0 g/L, 5·3 g/L, and 4·9 g/L), or IgM (0·3 g/L at each timepoint) concentrations. Common reasons for treatment discontinuation were progressive disease in 34 (24%) patients and adverse events, unacceptable toxicity, or death in 24 (17%) patients. Major bleeding occurred in 13 (9%) patients (11 [8%] grade 3-4). Grade 3 or worse infections occurred in 43 (30%) patients, including pneumonia in 19 (13%) patients. In the extended analysis, 38 patients died, 18 as a result of adverse events (four pneumonia, three chronic lymphocytic leukaemia, two Richter's syndrome, two sepsis, and one each of acute myocardial infarction, septic shock, encephalopathy, general deterioration in physical health, abnormal hepatic function, myocardial infarction, and renal infarction).A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable, providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. Ibrutinib represents a clinical advance in the treatment of patients with del17p chronic lymphocytic leukaemia and has been incorporated into treatment algorithms as a primary treatment for these patients.Pharmacyclics LLC, an AbbVie Company.

  View details for DOI 10.1016/S1470-2045(16)30212-1

  View details for Web of Science ID 000387055800042

  View details for PubMedID 27637985

• A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia BLOOD O'Brien, S. M., Lamanna, N., Kipps, T. J., Flinn, I., Zelenetz, A. D., Burger, J. A., Keating, M., Mitra, S., Holes, L., Yu, A. S., Johnson, D. M., Miller, L. L., Kim, Y., Dansey, R. D., Dubowy, R. L., Coutre, S. E. 2015; 126 (25): 2686-2694

  View details for DOI 10.1182/blood-2015-03-630947

  View details for Web of Science ID 000368429600010

• Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. New England journal of medicine Byrd, J. C., Brown, J. R., O'Brien, S., Barrientos, J. C., Kay, N. E., Reddy, N. M., Coutre, S., Tam, C. S., Mulligan, S. P., Jaeger, U., Devereux, S., Barr, P. M., Furman, R. R., Kipps, T. J., Cymbalista, F., Pocock, C., Thornton, P., Caligaris-Cappio, F., Robak, T., Delgado, J., Schuster, S. J., Montillo, M., Schuh, A., de Vos, S., Gill, D., Bloor, A., Dearden, C., Moreno, C., Jones, J. J., Chu, A. D., Fardis, M., McGreivy, J., Clow, F., James, D. F., Hillmen, P. 2014; 371 (3): 213-223

  Abstract

  In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

  View details for DOI 10.1056/NEJMoa1400376

  View details for PubMedID 24881631

• Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. New England journal of medicine Furman, R. R., Sharman, J. P., Coutre, S. E., Cheson, B. D., Pagel, J. M., Hillmen, P., Barrientos, J. C., Zelenetz, A. D., Kipps, T. J., Flinn, I., Ghia, P., Eradat, H., Ervin, T., Lamanna, N., Coiffier, B., Pettitt, A. R., Ma, S., Stilgenbauer, S., Cramer, P., Aiello, M., Johnson, D. M., Miller, L. L., Li, D., Jahn, T. M., Dansey, R. D., Hallek, M., O'Brien, S. M. 2014; 370 (11): 997-1007

  Abstract

  Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population.In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy.The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab.The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).

  View details for DOI 10.1056/NEJMoa1315226

  View details for PubMedID 24450857

• Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial LANCET ONCOLOGY O'Brien, S., Furman, R. R., Coutre, S. E., Sharman, J. P., Burger, J. A., Blum, K. A., Grant, B., Richards, D. A., Coleman, M., Wierda, W. G., Jones, J. A., Zhao, W., Heerema, N. A., Johnson, A. J., Izumi, R., Hamdy, A., Chang, B. Y., Graef, T., Clow, F., Buggy, J. J., James, D. F., Byrd, J. C. 2014; 15 (1): 48-58

  Abstract

  Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia.In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247.Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22.1 months (IQR 18.4-23.2), 22 (71%) of 31 patients achieved an objective response (95% CI 52.0-85.8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response.The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials.Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.

  View details for DOI 10.1016/S1470-2045(13)70513-8

  View details for PubMedID 24332241

• Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia NEW ENGLAND JOURNAL OF MEDICINE Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Grant, B., Sharman, J. P., Coleman, M., Wierda, W. G., Jones, J. A., Zhao, W., Heerema, N. A., Johnson, A. J., Sukbuntherng, J., Chang, B. Y., Clow, F., Hedrick, E., Buggy, J. J., James, D. F., O'Brien, S. 2013; 369 (1): 32-42

  Abstract

  The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).

  View details for DOI 10.1056/NEJMoa1215637

  View details for Web of Science ID 000321263500008

  View details for PubMedID 23782158

• The Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naive (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Patients Including Patients with High-Risk (HR) Disease: New and Updated Results of 116 Patients in a Phase Ib/II Study 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Byrd, J. C., Furman, R. R., Coutre, S., Flinn, I. W., Burger, J. A., Blum, K. A., Sharman, J., Grant, B., Jones, J. A., Wierda, W. G., Zhao, W., Heerema, N. A., Johnson, A. J., Anh Tran, A., Clow, F., Kunkel, L., James, D. F., O'Brien, S. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900268

• Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study LANCET ONCOLOGY Kantarjian, H., Faderl, S., Garcia-Manero, G., Luger, S., Venugopal, P., Maness, L., Wetzler, M., Coutre, S., Stock, W., Claxton, D., Goldberg, S. L., Arellano, M., Strickland, S. A., Seiter, K., Schiller, G., Jabbour, E., Chiao, J., Plunkett, W. 2012; 13 (11): 1096-1104

  Abstract

  Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML.In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187.Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment.Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML.Cyclacel Limited.

  View details for DOI 10.1016/S1470-2045(12)70436-9

  View details for Web of Science ID 000310570900040

  View details for PubMedID 23075701

• Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia JOURNAL OF CLINICAL ONCOLOGY Kreitman, R. J., Tallman, M. S., Robak, T., Coutre, S., Wilson, W. H., Stetler-Stevenson, M., FitzGerald, D. J., Lechleider, R., Pastan, I. 2012; 30 (15): 1822-1828

  Abstract

  To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL).Eligible patients had relapsed/refractory HCL after ≥ two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 μg/kg every other day for three doses (QOD ×3), with up to 16 cycles repeating at ≥ 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies.Twenty-eight patients were enrolled, including three patients each at 5, 10, 20, and 30 μg/kg, four patients at 40 μg/kg, and 12 patients at 50 μg/kg QOD ×3 for one to 16 cycles each (median, four cycles). Dose-limiting toxicity was not observed. Two patients had transient laboratory abnormalities consistent with grade 2 hemolytic uremic syndrome with peak creatinine of 1.53 to 1.66 mg/dL and platelet nadir of 106,000 to 120,000/μL. Drug-related toxicities in 25% to 64% of the 28 patients included (in decreasing frequency) grade 1 to 2 hypoalbuminemia, aminotransferase elevations, edema, headache, hypotension, nausea, and fatigue. Of 26 patients evaluable for immunogenicity, 10 patients (38%) made antibodies neutralizing more than 75% of the cytotoxicity of 1,000 ng/mL of immunotoxin, but this immunogenicity was rare (5%) after cycle 1. The overall response rate was 86%, with responses observed at all dose levels, and 13 patients (46%) achieved complete remission (CR). Only 1 CR lasted less than 1 year, with the median disease-free survival time not yet reached at 26 months.Moxetumomab pasudotox at doses up to 50 μg/kg QOD ×3 has activity in relapsed/refractory HCL and has a safety profile that supports further clinical development for treatment of this disease.

  View details for DOI 10.1200/JCO.2011.38.1756

  View details for Web of Science ID 000304427600017

  View details for PubMedID 22355053

• The Bruton's Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) O'Brien, S., Burger, J. A., Blum, K. A., Furman, R. R., Coutre, S. E., Sharman, J., Flinn, I. W., Grant, B., Heerema, N. A., Johnson, A. J., Navarro, T., Holmgren, E., Hedrick, E., Byrd, J. C. AMER SOC HEMATOLOGY. 2011: 449–50

  View details for Web of Science ID 000299597101254

• Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710 BLOOD Powell, B. L., Moser, B., Stock, W., Gallagher, R. E., Willman, C. L., Stone, R. M., Rowe, J. M., Coutre, S., Feusner, J. H., Gregory, J., Couban, S., Appelbaum, F. R., Tallman, M. S., Larson, R. A. 2010; 116 (19): 3751-3757

  Abstract

  Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

  View details for DOI 10.1182/blood-2010-02-269621

  View details for Web of Science ID 000284110400014

  View details for PubMedID 20705755

• Optimizing therapy for acute myeloid leukemia. Journal of the National Comprehensive Cancer Network Kohrt, H. E., Coutre, S. E. 2008; 6 (10): 1003-1016

  Abstract

  The 10-year overall survival for younger patients with newly diagnosed acute myeloid leukemia has improved threefold in the past 2 decades. This improvement has occurred in large part because of advances in supportive care and efforts to optimize standard induction and consolidation therapies applied in a stratified approach based on predictors of individual patient risk. Innovations in diagnostic technologies have broadened the understanding of key prognostic factors, including cytogenetic and molecular status, which define the extensive interpatient heterogeneity of this clonal disease. Despite this progress, only approximately 25% of patients who experience a complete remission with cytotoxic chemotherapy (50%-70% of patients with newly diagnosed disease) remain disease-free. Efforts to develop novel agents are actively ongoing, particularly for older patients (age > or = 60), and targeted therapies, for specific subsets of patients are being based on a better understanding of the biology of the disease.

  View details for PubMedID 19176198

• Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study BLOOD Ottmann, O., Dombret, H., Martinelli, G., Simonsson, B., Guilhot, F., Larson, R. A., Rege-Cambrin, G., Radich, J., Hochhaus, A., Apanovitch, A. M., Gollerkeri, A., Coutre, S. 2007; 110 (7): 2309-2315

  Abstract

  Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.

  View details for DOI 10.1182/blood-2007-02-073528

  View details for Web of Science ID 000249800900025

  View details for PubMedID 17496201

• Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801 BLOOD DeAngelo, D. J., Yu, D., Johnson, J. L., Coutre, S. E., Stone, R. M., Stopeck, A. T., Gockerman, J. P., Mitchell, B. S., Appelbaum, F. R., Larson, R. A. 2007; 109 (12): 5136-5142

  Abstract

  Nelarabine (506U78) is a soluble pro-drug of 9-beta-D-arabinofuranosylguanine (ara-G), a deoxyguanosine derivative. We treated 26 patients with T-cell acute lymphoblastic leukemia (T-ALL) and 13 with T-cell lymphoblastic lymphoma (T-LBL) with nelarabine. All patients were refractory to at least one multiagent regimen or had relapsed after achieving a complete remission. Nelarabine was administered on an alternate day schedule (days 1, 3, and 5) at 1.5 g/m(2)/day. Cycles were repeated every 22 days. The median age was 34 years (range, 16-66 years); 32 (82%) patients were male. The rate of complete remission was 31% (95% confidence interval [CI], 17%, 48%) and the overall response rate was 41% (95% CI, 26%, 58%). The principal toxicity was grade 3 or 4 neutropenia and thrombocytopenia, occurring in 37% and 26% of patients, respectively. There was only one grade 4 adverse event of the nervous system, which was a reversible depressed level of consciousness. The median disease-free survival (DFS) was 20 weeks (95% CI, 11, 56), and the median overall survival was 20 weeks (95% CI, 13, 36). The 1-year overall survival was 28% (95% CI, 15%, 43%). Nelarabine is well tolerated and has significant antitumor activity in relapsed or refractory T-ALL and T-LBL.

  View details for DOI 10.1182/blood-2006-11-056754

  View details for Web of Science ID 000247360200020

  View details for PubMedID 17344466

  View details for PubMedCentralID PMC1941786

• Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis BLOOD Cortes, J., Rousselot, P., Kim, D., Ritchie, E., Hamerschlak, N., Coutre, S., Hochhaus, A., Guilhot, F., Saglio, G., Apperley, J., Ottmann, O., Shah, N., Erben, P., Branford, S., Agarwal, P., Gollerkeri, A., Baccarani, M. 2007; 109 (8): 3207-3213

  Abstract

  The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.

  View details for DOI 10.1182/blood-2006-09-046888

  View details for Web of Science ID 000245658500022

  View details for PubMedID 17185463

• Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation BLOOD Gotlib, J., Berube, C., Growney, J. D., Chen, C. C., George, T. I., Williams, C., Kajiguchi, T., Ruan, J., Lilleberg, S. L., Durocher, J. A., Lichy, J. H., Wang, Y. F., Cohen, P. S., Arber, D. A., Heinrich, M. C., Neckers, L., GALLI, S. J., Gilliland, D. G., Coutre, S. E. 2005; 106 (8): 2865-2870

  Abstract

  The majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.

  View details for DOI 10.1182/blood-2005-04-1568

  View details for PubMedID 15972446

• Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. Seminars in cancer biology Coutré, S., Gotlib, J. 2004; 14 (4): 307-315

  Abstract

  Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.

  View details for PubMedID 15305431

• The HP1L1-PDIGFR alpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management BLOOD Gotlib, J., Cools, J., Malone, J. M., Schrier, S. L., Gilliland, D. G., Coutre, S. E. 2004; 103 (8): 2879-2891

  Abstract

  Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.

  View details for DOI 10.1182/blood-2003-06-1824

  View details for Web of Science ID 000222163500012

  View details for PubMedID 15070659

• A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome NEW ENGLAND JOURNAL OF MEDICINE Cools, J., DeAngelo, D. J., Gotlib, J., Stover, E. H., Legare, R. D., Cortes, J., Kutok, J., Clark, J., Galinsky, I., GRIFFIN, J. D., Cross, N. C., Tefferi, A., MALONE, J., Alam, R., Schrier, S. L., Schmid, J., Rose, M., Vandenberghe, P., Verhoef, G., Boogaerts, M., Wlodarska, I., Kantarjian, H., Marynen, P., Coutre, S. E., Stone, R., Gilliland, D. G. 2003; 348 (13): 1201-1214

  Abstract

  Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRalpha (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRalpha is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

  View details for Web of Science ID 000181790800002

  View details for PubMedID 12660384

• Long-Term Studies Assessing Outcomes of Ibrutinib Therapy in Patients With Del(11q) Chronic Lymphocytic Leukemia. Clinical lymphoma, myeloma & leukemia Kipps, T. J., Fraser, G., Coutre, S. E., Brown, J. R., Barrientos, J. C., Barr, P. M., Byrd, J. C., O'Brien, S. M., Dilhuydy, M., Hillmen, P., Jaeger, U., Moreno, C., Cramer, P., Stilgenbauer, S., Chanan-Khan, A. A., Mahler, M., Salman, M., Eckert, K., Solman, I. G., Balasubramanian, S., Cheng, M., Londhe, A., Ninomoto, J., Howes, A., James, D. F., Hallek, M. 2019

  Abstract

  BACKGROUND: Certain genomic features, such as del(11q), expression of unmutated immunoglobulin heavy-chain variable region (IGHV) gene, or complex karyotype, predict poorer outcomes to chemotherapy in patients with chronic lymphocytic leukemia (CLL).PATIENTS AND METHODS: We examined the pooled long-term follow-up data from PCYC-1115 (RESONATE-2), PCYC-1112 (RESONATE), and CLL3001 (HELIOS), comprising a total of 1238 subjects, to determine the prognostic significance of these markers in patients treated with ibrutinib.RESULTS: With a median follow-up of 47 months, ibrutinib-treated patients had longer progression-free survival (PFS) than patients treated in the comparator arm, regardless of genomic risk factors. Among patients treated with ibrutinib, we found that high-risk genomic features were not associated with shorter PFS (63-75% across all subgroups at 42 months) or overall survival (79-83% across all subgroups at 42 months). Surprisingly, we observed that ibrutinib-treated patients with del(11q) actually had a significantly longer PFS than ibrutinib-treated patients without del(11q) (42-month PFS rate 70% vs. 65%, P= .02).CONCLUSION: These analyses not only demonstrate that genomic risk factors previously associated with poor outcomes lose their adverse prognostic significance but also that del(11q) can be associated with a superior PFS with ibrutinib therapy.

  View details for DOI 10.1016/j.clml.2019.07.004

  View details for PubMedID 31447270

• Tumour debulking and reduction in predicted risk of tumour lysis syndrome with single-agent ibrutinib in patients with chronic lymphocytic leukaemia BRITISH JOURNAL OF HAEMATOLOGY Wierda, W. G., Byrd, J. C., O'Brien, S., Coutre, S., Barr, P. M., Furman, R. R., Kipps, T. J., Burger, J. A., Stevens, D. A., Sharman, J., Ghia, P., Flinn, I. W., Zhou, C., Ninomoto, J., James, D. F., Tam, C. S. 2019; 186 (1): 184–88

  View details for DOI 10.1111/bjh.15791

  View details for Web of Science ID 000472576700033

• Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab BLOOD Byrd, J. C., Hillmen, P., O'Brien, S., Barrientos, J. C., Reddy, N. M., Coutre, S., Tam, C. S., Mulligan, S. P., Jaeger, U., Barr, P. M., Furman, R. R., Kipps, T. J., Thornton, P., Moreno, C., Montillo, M., Pagel, J. M., Burger, J. A., Woyach, J. A., Dai, S., Vezan, R., James, D. F., Brown, J. R. 2019; 133 (19): 2031–42

  View details for DOI 10.1182/blood-2018-08-870238

  View details for Web of Science ID 000467385500009

• Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis AMERICAN JOURNAL OF HEMATOLOGY O'Brien, S. M., Byrd, J. C., Hillmen, P., Coutre, S., Brown, J. R., Barr, P. M., Barrientos, J. C., Devereux, S., Robak, T., Reddy, N. M., Kipps, T. J., Tedeschi, A., Cynnbalista, F., Ghia, P., Chang, S., Ninomoto, J., James, D. F., Burger, J. A. 2019; 94 (5): 554–62

  View details for DOI 10.1002/ajh.25436

  View details for Web of Science ID 000468303900006

• Acute Lymphoblastic Leukemia, Version 1.2019 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Brown, P. A., Wieduwilt, M., Logan, A., DeAngelo, D. J., Wang, E. S., Fathi, A., Cassaday, R. D., Litzow, M., Advani, A., Aoun, P., Bhatnagar, B., Boyer, M. W., Bryan, T., Burke, P. W., Coccia, P. F., Coutre, S. E., Jain, N., Kirby, S., Liu, A., Massaro, S., Mattison, R. J., Oluwole, O., Papadantonakis, N., Park, J., Rubnitz, J. E., Uy, G. L., Gregory, K. M., Ogba, N., Shah, B. 2019; 17 (5): 414–23

  Abstract

  Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

  View details for DOI 10.6004/jnccn.2019.0024

  View details for Web of Science ID 000468989400003

  View details for PubMedID 31085755

• Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Sharman, J. P., Coutre, S. E., Furman, R. R., Cheson, B. D., Pagel, J. M., Hillmen, P., Barrientos, J. C., Zelenetz, A. D., Kipps, T. J., Flinn, I. W., Ghia, P., Eradat, H., Ervin, T., Lamanna, N., Coiffier, B., Pettitt, A. R., Ma, S., Tausch, E., Cramer, P., Huang, J., Mitra, S., Hallek, M., O'Brien, S. M., Stilgenbauer, S. 2019: JCO1801460

  Abstract

  PURPOSE: A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies.PATIENTS AND METHODS: Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety.RESULTS: The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases.CONCLUSION: IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.

  View details for DOI 10.1200/JCO.18.01460

  View details for PubMedID 30995176

• Utility of PET-CT in patients with chronic lymphocytic leukemia following B-cell receptor pathway inhibitor therapy. Haematologica Mato, A. R., Wierda, W. G., Davids, M. S., Cheson, B. D., Coutre, S. E., Choi, M., Furman, R. R., Heffner, L., Barr, P. M., Eradat, H., Ford, S. M., Zhou, L., Verdugo, M., Humerickhouse, R. A., Potluri, J., Byrd, J. C. 2019

  Abstract

  The utility of PET-CT in distinguishing Richter's transformation versus chronic lymphocytic leukemia progression after ibrutinib and/or idelalisib was assessed in a post-hoc analysis of a phase 2 study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter's transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, 8 had Richter's transformation, 2 had another malignancy, and 25 had chronic lymphocytic leukemia. A PET-CT maximum standardized uptake value ≥10 had 71% sensitivity and 50% specificity for detecting Richter's transformation (odds ratio, 2.5 [95% CI: .4-15]; p=.318). Response rate to venetoclax was similar for screening maximum standardized uptake value <10 versus ≥10 (65% vs 62%) (n=127 enrolled), though median progression-free survival was longer with <10 (24.7 vs 15.4 months; p=.0335). Six developed Richter's transformation on venetoclax, of whom 2 had screening biopsy demonstrating chronic lymphocytic leukemia (others did not have biopsy) and 5 had screening maximum standardized uptake value <10. We have defined the test characteristics for PET-CT to distinguish progression of chronic lymphocytic leukemia as compared to Richter's transformation when biopsied in patients treated with B-cell receptor signaling pathway inhibitors. Overall diminished sensitivity and specificity as compared to prior reports of patients treated with chemotherapy/chemoimmunotherapy, suggest it has diminished ability to discriminate these two diagnoses using a maximum standardized uptake value ≥10 cutoff. This cutoff did not identify venetoclax-treated patients with an inferior response but may be predictive of inferior progression-free survival. ClinicalTrials.gov; NCT02141282.

  View details for PubMedID 30923097

• Long-term follow-up of the RESONATE phase 3 trial of ibrutinib versus ofatumumab. Blood Byrd, J. C., Hillmen, P., O'Brien, S., Barrientos, J. C., Reddy, N. M., Coutre, S., Tam, C. S., Mulligan, S. P., Jaeger, U., Barr, P. M., Furman, R. R., Kipps, T. J., Thornton, P., Moreno, C., Montillo, M., Pagel, J. M., Burger, J. A., Woyach, J. A., Dai, S., Vezan, R., James, D. F., Brown, J. R. 2019

  Abstract

  Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the US and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR] 0.133; 95% CI, 0.099-0.178) was observed. Overall survival benefit continues (HR 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS versus without these factors. Median duration of ibrutinib was 41 months with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL, and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as NCT01578707.

  View details for PubMedID 30842083

• Durability of Response to Venetoclax (VEN) in Patients with CLL Relapsed/Refractory to Ibrutinib and/or Idelalisib Byrd, J., Wierda, W., Davids, M., Choi, M., Furman, R., Mato, A., Zhou, L., Verdugo, M., Potluri, J., Coutre, S. WILEY. 2019: 83–84

  View details for Web of Science ID 000462529200122

• LONG-TERM FOLLOW-UP OF SINGLE-AGENT IBRUTINIB IN FIRST-LINE AND RELAPSED/REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA Reid, M., Settlemire, J., Liu, E., Amaya-Chanaga, C., Coutre, S., Byrd, J. ONCOLOGY NURSING SOC. 2019

  View details for Web of Science ID 000461140000152

• Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with CLL: phase 3 analysis. American journal of hematology O'Brien, S. M., Byrd, J. C., Hillmen, P., Coutre, S., Brown, J. R., Barr, P. M., Barrientos, J. C., Devereux, S., Robak, T., Reddy, N. M., Kipps, T. J., Tedeschi, A., Cymbalista, F., Ghia, P., Chang, S., Ninomoto, J., James, D. F., Burger, J. A. 2019

  Abstract

  The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first-line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher-risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib-treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single-agent ibrutinib: RESONATE (PCYC-1112) in patients with R/R CLL and RESONATE-2 (PCYC-1115) in patients with treatment-naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib-treated non-del(17p) patients with CLL (136 TN and 135 R/R). Median progression-free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow-up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow-up 18 months, n=51) and was not reached in TN patients (median follow-up 10 months, n=30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy. Clinicaltrials.gov: NCT01578707, NCT01722487. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30767298

• Tumour debulking and reduction in predicted risk of tumour lysis syndrome with single-agent ibrutinib in patients with chronic lymphocytic leukaemia. British journal of haematology Wierda, W. G., Byrd, J. C., O'Brien, S., Coutre, S., Barr, P. M., Furman, R. R., Kipps, T. J., Burger, J. A., Stevens, D. A., Sharman, J., Ghia, P., Flinn, I. W., Zhou, C., Ninomoto, J., James, D. F., Tam, C. S. 2019

  View details for PubMedID 30740654

• Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood advances Coutre, S. E., Byrd, J. C., Hillmen, P., Barrientos, J. C., Barr, P. M., Devereux, S., Robak, T., Kipps, T. J., Schuh, A., Moreno, C., Furman, R. R., Burger, J. A., O'Dwyer, M., Ghia, P., Valentino, R., Chang, S., Dean, J. P., James, D. F., O'Brien, S. M. 2019; 3 (12): 1799–1807

  Abstract

  Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

  View details for DOI 10.1182/bloodadvances.2018028761

  View details for PubMedID 31196847

• NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019. Journal of the National Comprehensive Cancer Network : JNCCN Wierda, W. G., Byrd, J. C., Abramson, J. S., Bilgrami, S. F., Bociek, G., Brander, D., Brown, J., Chanan-Khan, A. A., Chavez, J. C., Coutre, S. E., Davis, R. S., Fletcher, C. D., Hill, B., Kahl, B. S., Kamdar, M., Kaplan, L. D., Khan, N., Kipps, T. J., Ma, S., Malek, S., Mato, A., Mosse, C., Neppalli, V. T., Shadman, M., Siddiqi, T., Stephens, D., Wagner, N., Dwyer, M. A., Sundar, H. 2019; 17 (1): 12–20

  Abstract

  Chronic lymphocytic leukemia (CLL) is generally characterized by an indolent disease course. Histologic transformation (also known as Richter's transformation) to more aggressive lymphomas, such as diffuse large B-cell lymphoma or Hodgkin lymphoma, occurs in approximately 2% to 10% of patients and is associated with a poor prognosis. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with histologic transformation.

  View details for PubMedID 30659125

• Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Tallman, M. S., Wang, E. S., Altman, J. K., Appelbaum, F. R., Bhatt, V. R., Bixby, D., Coutre, S. E., De Lima, M., Fathi, A. T., Fiorella, M., Foran, J. M., Hall, A. C., Jacoby, M., Lancet, J., LeBlanc, T. W., Mannis, G., Marcucci, G., Martin, M. G., Mims, A., O'Donnell, M. R., Olin, R., Peker, D., Perl, A., Pollyea, D. A., Pratz, K., Prebet, T., Ravandi, F., Shami, P. J., Stone, R. M., Strickland, S. A., Wieduwilt, M., Gregory, K. M., Hammond, L., Ogba, N. 2019; 17 (6): 721–49

  Abstract

  Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

  View details for DOI 10.6004/jnccn.2019.0028

  View details for PubMedID 31200351

• Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood Roberts, A. W., Ma, S., Kipps, T. J., Coutre, S. E., Davids, M. S., Eichhorst, B., Hallek, M., Byrd, J. C., Humphrey, K., Zhou, L., Chyla, B., Nielsen, J., Potluri, J., Kim, S. Y., Verdugo, M., Stilgenbauer, S., Wierda, W. G., Seymour, J. F. 2019

  Abstract

  To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment-effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in four early phase trials were pooled. Rates of response, complete remission (CR/CRi) and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n=436) and for those patients who were planned to receive 400 mg/day monotherapy (n=347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time-to-progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy ({greater than or equal to}5cm), and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation, and NOTCH1 mutation were consistently associated with shorter DoR but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.

  View details for PubMedID 31023700

• Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis. British journal of haematology Brown, J. R., Moslehi, J., Ewer, M. S., O'Brien, S. M., Ghia, P., Cymbalista, F., Shanafelt, T. D., Fraser, G., Rule, S., Coutre, S. E., Dilhuydy, M., Cramer, P., Jaeger, U., Dreyling, M., Byrd, J. C., Treon, S., Liu, E. Y., Chang, S., Bista, A., Vempati, R., Boornazian, L., Valentino, R., Reddy, V., Mahler, M., Yang, H., Graef, T., Burger, J. A. 2018

  Abstract

  Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N=1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13months vs. 6months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.

  View details for PubMedID 30506764

• Improvement in Parameters of Hematologic and Immunologic Function and Patient Well-being in the Phase III RESONATE Study of Ibrutinib Versus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Barrientos, J. C., O'Brien, S., Brown, J. R., Kay, N. E., Reddy, N. M., Coutre, S., Tam, C., Mulligan, S., Jaeger, U., Devereux, S., Pocock, C., Robak, T., Schuster, S. J., Schuh, A., Gill, D., Bloor, A., Dearden, C., Moreno, C., Cull, G., Hamblin, M., Jones, J. A., Eckert, K., Solman, I. G., Suzuki, S., Hsu, E., James, D. F., Byrd, J. C., Hillmen, P. 2018; 18 (12): 803-+

  Abstract

  Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization.With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P < .0001). Higher rates of clinically meaningful improvement were demonstrated with ibrutinib versus ofatumumab for FACIT-F and EORTC global health. Greater improvement was observed in disease-related weight loss, fatigue, night sweats, and abdominal discomfort with ibrutinib versus ofatumumab. Hospitalizations in the first 30 days occurred less frequently with ibrutinib than ofatumumab (0.087 vs. 0.184 events/patient; P = .0198). New-onset diarrhea was infrequent with ibrutinib after the first 6 months (47% at ≤6 months vs. 5% at 12-18 months). With ibrutinib, grade ≥ 3 hypertension occurred in 6%, grade ≥ 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients.Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.

  View details for PubMedID 30249389

• Up to 7 Years of Follow-up of Single-Agent Ibrutinib in the Phase 1b/2 PCYC-1102 Trial of First Line and Relapsed/Refractory Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Byrd, J. C., Furman, R. R., Coutre, S., Flinn, I. W., Burger, J. A., Blum, K. A., Sharman, J., Wierda, W. G., Zhao, W., Heerema, N. A., Luan, Y., Liu, E. A., Dean, J. P., O'Brien, S. M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-110847

  View details for Web of Science ID 000454842800284

• Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naive patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies AMERICAN JOURNAL OF HEMATOLOGY Robak, T., Burger, J. A., Tedeschi, A., Barr, P. M., Owen, C., Bairey, O., Hillmen, P., Simpson, D., Grosicki, S., Devereux, S., McCarthy, H., Coutre, S. E., Quach, H., Gaidano, G., Maslyak, Z., Stevens, D. A., Moreno, C., Gill, D. S., Flinn, I. W., Gribben, J. G., Mokatrin, A., Cheng, M., Styles, L., James, D. F., Kipps, T. J., Ghia, P. 2018; 93 (11): 1402–10

  Abstract

  Chemoimmunotherapy (CIT) and targeted therapy with single-agent ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with ibrutinib. Grade ≥ 3 neutropenia was 12% for ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings.

  View details for PubMedID 30129285

• Safety Analysis of Four Randomized Controlled Studies of Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or Mantle Cell Lymphoma CLINICAL LYMPHOMA MYELOMA & LEUKEMIA O'Brien, S., Hillmen, P., Coutre, S., Barr, P. M., Fraser, G., Tedeschi, A., Burger, J. A., Dilhuydy, M., Hess, G., Moreno, C., Cramer, P., Liu, E., Chang, S., Vermeulen, J., Styles, L., Howes, A., James, D. F., Patel, K., Graef, T., Valentino, R. 2018; 18 (10): 648-+

  Abstract

  Multiple studies have demonstrated the efficacy and safety of ibrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). This first-in-class inhibitor of Bruton's tyrosine kinase has become a standard treatment for patients with CLL and MCL.We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with ibrutinib versus comparators. Data were pooled from 4 completed randomized controlled studies that had included 756 ibrutinib-treated and 749 comparator-treated patients with CLL/SLL or relapsed/refractory MCL. Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates.The median treatment duration was 13.3 months (maximum, 28.2 months) for ibrutinib and 5.8 months (maximum, 27.3 months) for comparators. When adjusted for exposure, diarrhea, atrial fibrillation, and hypertension were the only common grade ≥ 3 AEs more often reported with ibrutinib than with the comparators. Dose reductions (7% vs. 14%) and discontinuation (12% vs. 16%) because of AEs occurred less often with ibrutinib, and deaths due to AEs occurred at similar rates (6% vs. 7%). When adjusted for exposure, the corresponding data were all lower with ibrutinib than with the comparators (0.06 vs. 0.22, 0.11 vs. 0.22, and 0.06 vs. 0.09 patient-exposure-years, respectively). The prevalence of common grade 3/4 AEs with ibrutinib generally decreased over time, with the exception of hypertension.These results from an integrated analysis support a favorable benefit/risk profile of ibrutinib in patients with CLL/SLL and MCL.

  View details for PubMedID 30061088

• High-Dose Vincristine Sulfate Liposome Injection, for Advanced, Relapsed, or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in an Adolescent and Young Adult Subgroup of a Phase 2 Clinical Trial JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY Schiller, G. J., Damon, L. E., Coutre, S. E., Hsu, P., Bhat, G., Douer, D. 2018

  Abstract

  A study of vincristine sulfate (VCR) liposome injection (VSLI) was conducted in patients with advanced, relapsed, or refractory, Philadelphia chromosome-negative acute lymphoblastic/lymphocytic leukemia (ALL). A retrospective subgroup analysis of the results was performed to evaluate the safety and efficacy of VSLI in the adolescent and young adult (AYA) patients.Of the 65 patients treated in the pivotal Phase 2 Study HBS407 (NCT00495079), 44 patients were aged ≤39 years (median 27 [range 19-39] years) and were included in this analysis. Patients received VSLI (2.25 mg/m2 intravenously every 7 ± 3 days) without dose capping or concurrent steroid administration in continuous 28-day cycles.VSLI was well tolerated in the AYA patients over a median of 5 (range 1-15) doses administered. One-third of patients (36%) experienced treatment-related serious adverse events (AEs) with peripheral neuropathy (7%), tumor lysis syndrome (7%), and febrile neutropenia (5%) in >1 patient. Neuropathy-associated AEs occurred in 82% patients; no neuropathy-related deaths occurred. The rate of complete remission (CR) (with or without complete blood count recovery) by investigator assessment was 25% in AYA patients, and the overall response rate was 39%. Median leukemia-free survival in AYA patients attaining CR was 135 (range 32-463) days, and median overall survival was 141 (range 13-620) days.VSLI provided a meaningful clinical benefit to AYA patients with ALL, and its safety profile was comparable to that of VCR despite the delivery of higher doses (individual and cumulative).

  View details for PubMedID 30239252

• Pathological assessment of gastrointestinal biopsies from patients with idelalisib-associated diarrhea and colitis FUTURE ONCOLOGY Yeung, C. S., Hockenbery, D. M., Westerhoff, M., Coutre, S. E., Sedlak, R. H., Dubowy, R. L., Munugalavadla, V., Taylor, K., Bosch, F. 2018; 14 (22): 2265–77

  Abstract

  Idelalisib (IDELA) treatment is associated with diarrhea/colitis (incidence of ∼15% grade ≥3). We performed a retrospective analysis of gastrointestinal biopsies from 29 patients treated with IDELA across nine clinical trials.A central core laboratory performed histopathologic review, immunohistochemistry, and droplet digital PCR viral studies. These results were correlated with tissue immune profiling data and morphologic features per modified Geboes score.Out of 29 eligible patients with abdominal pain or diarrhea, 24 (82.8%) had reported adverse event terms of diarrhea and/or colitis. Infectious pathogens were detected in 9/29 samples. Most biopsies presented with mixed/inflammatory infiltrates and contained increased numbers of FOXP3+ cells versus normal controls.This study revealed evidence of T-cell dysregulation and a substantial infectious component in association with IDELA-related diarrhea/colitis.

  View details for PubMedID 29569483

• Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2 HAEMATOLOGICA Barr, P. M., Robak, T., Owen, C., Tedeschi, A., Bairey, O., Bartlett, N. L., Burger, J. A., Hillmen, P., Coutre, S., Devereux, S., Grosicki, S., McCarthy, H., Li, J., Simpson, D., Offner, F., Moreno, C., Zhou, C., Styles, L., James, D., Kipps, T. J., Ghia, P. 2018; 103 (9): 1502–10

  Abstract

  Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged ≥65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P<0.0001). The 24-month progression-free survival was 89% with ibrutinib (97% and 89% in patients with del[11q] and unmutated immunoglobulin heavy chain variable region gene, respectively). Progression-free survival rates at 24 months were also similar regardless of age (<75 years [88%], ≥75 years [89%]). Overall response rate was 92% (125/136). Rate of complete response increased substantially from 7% at 12 months to 18% with extended follow up. Greater quality of life improvements occurred with ibrutinib versus chlorambucil in Functional Assessment of Chronic Illness Therapy-Fatigue (P=0.0013). The most frequent grade ≥3 adverse events were neutropenia (12%), anemia (7%), and hypertension (5%). Rate of discontinuations due to adverse events was 12%. Results demonstrated that first-line ibrutinib for elderly patients with chronic lymphocytic leukemia provides sustained response and progression-free survival benefits over chemotherapy, with depth of response improving over time without new toxicity concerns. This trial was registered at clinicaltrials.gov identifier 01722487 and 01724346.

  View details for PubMedID 29880603

• Cost-effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia in older adults without deletion 17p BLOOD ADVANCES Barnes, J., Divi, V., Begaye, A., Wong, R., Coutre, S., Owens, D. K., Goldhaber-Fiebert, J. D. 2018; 2 (15): 1946–56

  Abstract

  Ibrutinib is a novel oral therapy that has shown significant efficacy as initial treatment of chronic lymphocytic leukemia (CLL). It is a high-cost continuous therapy differing from other regimens that are given for much shorter courses. Our objective was to evaluate the cost-effectiveness of ibrutinib for first-line treatment of CLL in patients older than age 65 years without a 17p deletion. We developed a semi-Markov model to analyze the cost-effectiveness of ibrutinib vs a comparator therapy from a US Medicare perspective. No direct comparison between ibrutinib and the best available treatment alternative, obinutuzumab plus chlorambucil (chemoimmunotherapy), exists. Therefore, we compared ibrutinib to a theoretical treatment alternative, which was modeled to confer the effectiveness of an inferior treatment (chlorambucil alone) and the costs and adverse events of chemoimmunotherapy, which would provide ibrutinib with the best chance of being cost-effective. Even so, the incremental cost-effectiveness ratio of ibrutinib vs the modeled comparator was $189 000 per quality-adjusted life-year (QALY) gained. To reach a willingness-to-pay threshold (WTP) of $150 000 per QALY, the monthly cost of ibrutinib would have to be at most $6800, $1700 less than the modeled cost of $8500 per month (a reduction of $20 400 per year). When the comparator efficacy is increased to more closely match that seen in trials evaluating chemoimmunotherapy, ibrutinib costs more than $262 000 per QALY gained, and the monthly cost of ibrutinib would need to be lowered to less than $5000 per month to be cost-effective. Ibrutinib is not cost-effective as initial therapy at a WTP threshold of $150 000 per QALY gained.

  View details for PubMedID 30097461

  View details for PubMedCentralID PMC6093732

• Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocyticleukaemia treated with ibrutinib from 3 clinical trials BRITISH JOURNAL OF HAEMATOLOGY Jones, J., Mato, A., Coutre, S., Byrd, J. C., Furman, R. R., Hillmen, P., Osterborg, A., Tam, C., Stilgenbauer, S., Wierda, W. G., Heerema, N. A., Eckert, K., Clow, F., Zhou, C., Chu, A. D., James, D. F., O'Brien, S. M. 2018; 182 (4): 504–12

  Abstract

  Patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1-12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow-up of 28 months, overall response rate was 85% and estimated 30-month progression-free and overall survival rates were 57% [95% confidence interval (CI) 50-64] and 69% (95% CI 61-75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression-free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult-to-treat CLL/SLL populations.

  View details for PubMedID 29873072

• Comparable outcomes of patients eligible vs ineligible for SWOG leukemia studies BLOOD Statler, A., Othus, M., Erba, H. P., Chauncey, T. R., Radich, J. P., Coutre, S., Advani, A., Nand, S., Ravandi, F., Mukherjee, S., Sekeres, M. A. 2018; 131 (25): 2782–88

  Abstract

  Patients may be deemed ineligible for a clinical trial for reasons that do not directly impact efficacy or safety. We identified reasons for ineligibility and compared outcomes of ineligible with eligible patients treated on Southwest Oncology Group (SWOG) Leukemia Committee protocols. Patients enrolled in SWOG phase 2, 2/3, or 3 protocols open since 2005 were analyzed for eligibility status, reasons for ineligibility, baseline characteristics, Eastern Cooperative Oncology Group (ECOG) performance status (PS), serious adverse events (SAEs), complete remission (CR) status, and overall survival. A total of 2361 patients were enrolled in the 13 included studies. Of these, 247 (10%) were deemed ineligible; 78 were excluded from analyses, and 169 were included. Of the 169 included in analyses, 60% (101/169) were excluded due to missing baseline documentation. Baseline characteristics comparing ineligible to eligible patients were similar, with the exception of ECOG PS for S0325 (P = .02) and S0530 (P = .002). In multivariable analyses, neither the proportion of patients with ECOG PS ≥ 2 (P = .12) nor the rate of grade 5 SAEs (P = .62) differed between groups. There was no difference in survival between eligible and ineligible patients (P = .25), and CR rates were similar, with the exception of S0325 (P < .001) and S0703 (P = .004). The findings of this study suggest that nonessential eligibility criteria can be less restrictive, thus expanding patient enrollment and avoiding protocol deviations. The clinical trials included in this study were registered at www.clincialtrials.gov as #NCT00085709, #NCT00066794, #NCT00070499, #NCT00109837, #NCT00093418, #NCT00492856, #NCT00337168, #NCT00352365, #NCT00658814, #NCT00792948, #NCT00945815, #NCT00840177, and #NCT01522976.

  View details for PubMedID 29618479

• Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up BLOOD Kreitman, R. J., Tallman, M. S., Robak, T., Coutre, S., Wilson, W. H., Stetler-Stevenson, M., FitzGerald, D. J., Santiago, L., Gao, G., Lanasa, M. C., Pastan, I. 2018; 131 (21): 2331–34

  Abstract

  Anti-CD22 moxetumomab pasudotox achieved 46% complete remissions (CRs) in previously reported phase 1 testing in relapsed/refractory hairy cell leukemia (HCL; n = 28). The importance of minimal residual disease (MRD) after CR in HCL is unknown. A 21-patient extension cohort received 50 µg/kg every other day for 3 doses in 4-week cycles. These patients plus 12 previously reported at this upper dose level received 143 cycles without dose-limiting toxicity. The combined 33-patient cohort achieved 64% CR and 88% overall response rates, with median CR duration of 42.4 months. Of 32 50-µg/kg patients evaluable for MRD by bone marrow aspirate flow cytometry (most stringent assessment), median CR duration was 13.5 (4.9-42.4) months in 9 MRD-positive CRs vs 42.1 (24.0-69.2) months in 11 MRD-negative CRs (P < .001). Among MRD-negative CRs, 10 patients had ongoing CR, 9 without MRD, at end of study. To our knowledge, moxetumomab pasudotox is the only nonchemotherapy regimen that can eliminate MRD in a significant percentage of HCL patients, to enhance CR duration. Repeated dosing, despite early neutralizing antibodies, increased active drug levels without detectable toxicity from immunogenicity. The activity and safety profiles of moxetumomab pasudotox support ongoing phase 3 testing in HCL. This trial was registered at www.clinicaltrials.gov as #NCT00586924.

  View details for PubMedID 29487070

• Prognostic Factors for Complete Response to Ibrutinib in Patients With Chronic Lymphocytic Leukemia A Pooled Analysis of 2 Clinical Trials JAMA ONCOLOGY O'Brien, S. M., Jaglowski, S., Byrd, J. C., Bannerji, R., Blum, K. A., Fox, C. P., Furman, R. R., Hillmen, P., Kipps, T. J., Montillo, M., Sharman, J., Suzuki, S., James, D. F., Chu, A. D., Coutre, S. E. 2018; 4 (5): 712–16

  Abstract

  Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor taken once daily, is approved in the United States for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and allows for treatment without chemotherapy. Extended treatment with ibrutinib has demonstrated increased complete response (CR) rates over time.To analyze baseline factors that predict CR in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with ibrutinib.Univariate and multivariate analyses of pooled data from 2 clinical trials were used to assess the prognostic value of baseline factors associated with CR in 327 patients from the PCYC-1102 and PCYC-1112 studies treated with single-agent ibrutinib. Participants were followed up in academic and community medical centers in the United States, the United Kingdom, Australia, France, Italy, Ireland, Poland, Spain, and Austria.Odds ratio (OR) of CR rate.The 327 patients included in this analysis had a median age of 67 years (range, 30-86 years) and 227 (69.4%) were male. At baseline, 185 patients (56.6%) had bulky disease (lymph node ≥5 cm), 184 (56.3%) had advanced-stage disease, and 182 (55.7%) had an Eastern Cooperative Oncology Group performance status of 1 or higher. Thirty-one patients (9.5%) were in the first-line setting; 38 (11.6%) had undergone 1 previous therapy, 81 (24.8%) had undergone 2, and 177 (54.1%) had undergone 3 or more; patients with relapsed/refractory disease had undergone a median of 3 (range, 0-12) previous therapies. Median time on study was 26.4 months (range, 0.3-55.6 months). Thirty-two of the 327 patients (9.8%) treated with ibrutinib had a CR (PCYC-1102: relapsed/refractory, 12 of 101 [11.9%]; treatment-naive, 8 of 31 [25.8%]; and PCYC-1112: 12 of 195 [6.2%]). The median time to CR for these patients was 14.7 months (range, 4.6-47.1 months). Univariate analysis of baseline factors showed that bulky disease, clinical stage, number of previous therapies, and β2-microglobulin concentration had a significant effect on the odds of CR. The final multivariate model showed that patients with no previous therapy vs patients with at least 1 previous therapy (OR, 2.65; 95% CI, 1.01-6.95; P = .047) and patients without bulky disease (lymph node <5 cm) vs those with bulky disease (lymph node ≥5 cm [OR, 4.97; 95% CI, 1.91-12.91; P = .001]) had an increased likelihood of CR.Patients receiving ibrutinib as a first-line therapy for chronic lymphocytic leukemia and those without bulky disease had a better likelihood of CR to treatment. The CR rate with continued longer-term ibrutinib treatment was higher than in previous reports.clinicaltrials.gov Identifiers: NCT01105247 and NCT01578707.

  View details for PubMedID 29470582

  View details for PubMedCentralID PMC5885180

• Older Patients (pts) With Treatment-Naive Chronic Lymphocytic Leukemia (CLL) Treated With Ibrutinib (ibr): Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in RESONATE-2 Owen, C., Tedeschi, A., Coutre, S., Dean, J. P., Burger, J. A., Kipps, T. J. WILEY. 2018: S127

  View details for Web of Science ID 000430468400375

• Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML BLOOD Swords, R. T., Coutre, S., Maris, M. B., Zeidner, J. F., Foran, J. M., Cruz, J., Erba, H. P., Berdeja, J. G., Tam, W., Vardhanabhuti, S., Pawlikowska-Dobler, I., Faessel, H. M., Dash, A. B., Sedarati, F., Dezube, B. J., Faller, D. V., Savona, M. R. 2018; 131 (13): 1415–24

  Abstract

  Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

  View details for PubMedID 29348128

• A phase I, open-label, dose-escalation study of amrubicin in combination with lenalidomide and weekly dexamethasone in previously treated adults with relapsed or refractory multiple myeloma. International journal of hematology Dinner, S., Dunn, T. J., Price, E., Coutré, S. E., Gotlib, J., Berube, C., Kaufman, G. P., Medeiros, B. C., Liedtke, M. 2018

  Abstract

  This phase 1 study investigated the safety of the anthracycline amrubicin combined with lenalidomide and dexamethasone in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous amrubicin 40-80 mg/m2 on day one, lenalidomide 15 mg orally on days 1-14, and dexamethasone 40 mg orally weekly on 21 day cycles. 14 patients were enrolled, and completed a median of three cycles. The maximum tolerated dose was not reached. One patient experienced dose limiting toxicity of dizziness and diarrhea. The most frequent non-hematologic toxicity was infection (79%). Serious adverse events included cord compression and sepsis. Three patients (21%) had a partial response or better, and seven (50%) had stable disease. The median duration of response was 4.4 months, and the median progression-free survival was 3 months. Amrubicin combined with lenalidomide and dexamethasone, was safe and demonstrated clinical activity in relapsed or refractory multiple myeloma.Clinicaltrials.gov identifier: NCT01355705.

  View details for PubMedID 29802551

• Phase 3 study of ibrutinib as first-line treatment in older patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): a 4-year follow-up from the RESONATE-2 study Burger, J. A., Barr, P. M., Robak, T., Owen, C., Ghia, P., Tedeschi, A., Bairey, O., Hillmen, P., Coutre, S. E., Devereux, S., Grosicki, S., McCarthy, H., Li, J., Simpson, D., Offner, F., Moreno, C., Dai, S., Dean, J. P., James, D. F., Kipps, T. P. KARGER. 2018: 29

  View details for Web of Science ID 000446816500074

• Outcomes of ibrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) with high-risk prognostic factors in an integrated analysis of 3 randomized phase 3 studies Kipps, T. J., Mahler, M., Fraser, G., Coutre, S., Brown, J., Barrientos, J., Barr, P., Byrd, J. C., O'Brien, S., Dilhuydy, M., Jaeger, U., Moreno, C., Cramer, P., Stilgenbauer, S., Chanan-Khan, A., Salman, M., Cheng, M., Londhe, A., Ninomoto, J., Howes, A., James, D., Hallek, M., Hillmen, P. TAYLOR & FRANCIS LTD. 2017: 10–12

  View details for Web of Science ID 000423431100010

• Venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL) with 17p deletion: outcome and minimal residual disease from the full population of the pivotal M13-982 trial Chyla, B., Stilgenbauer, S., Eichhorst, B., Schetelig, J., Munir, T., Hillmen, P., Seymour, J. F., Roberts, A. W., Coutre, S., Jurczak, W., Mulligan, S. P., Puvvada, S., Wendtner, C., Davids, M. S., Boettcher, S., Cerri, E., Zhou, L., Popovic, R., Poteracki, M., Arzt, J., Kim, S., Verdugo, M., Bhathena, A., Wierda, W., Hallek, M. TAYLOR & FRANCIS LTD. 2017: 234–35

  View details for Web of Science ID 000423431100209

• study in patients with previously treated CLL/SLL. Leukemia Brown, J. R., Hillmen, P., O'Brien, S., Barrientos, J. C., Reddy, N. M., Coutre, S. E., Tam, C. S., Mulligan, S. P., Jaeger, U., Barr, P. M., Furman, R. R., Kipps, T. J., Cymbalista, F., Thornton, P., Caligaris-Cappio, F., Delgado, J., Montillo, M., Devos, S., Moreno, C., Pagel, J. M., Munir, T., Burger, J. A., Chung, D., Lin, J., Gau, L., Chang, B., Cole, G., Hsu, E., James, D. F., Byrd, J. C. 2017

  Abstract

  In the phase 3 RESONATE(TM) study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%), and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs. ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared to patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs. later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.Leukemia accepted article preview online, 08 June 2017. doi:10.1038/leu.2017.175.

  View details for DOI 10.1038/leu.2017.175

  View details for PubMedID 28592889

• Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL BLOOD Barr, P. M., Brown, J. R., Hillmen, P., O'Brien, S., Barrientos, J. C., Reddy, N. M., Coutre, S., Mulligan, S. P., Jaeger, U., Furman, R. R., Cymbalista, F., Montillo, M., Dearden, C., Robak, T., Moreno, C., Pagel, J. M., Burger, J. A., Suzuki, S., Sukbuntherng, J., Cole, G., James, D. F., Byrd, J. C. 2017; 129 (19): 2612-2615

  Abstract

  Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ∼9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/or TP53 status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing ≥8 consecutive days of ibrutinib had a shorter median PFS vs those missing <8 days (10.9 months vs not reached). These results support sustained adherence to once-daily ibrutinib dosing at 420 mg as clinically feasible to achieve optimal outcomes in patients with previously treated CLL. The trial was registered at www.clinicaltrials.gov as #NCT01578707.

  View details for DOI 10.1182/blood-2016-12-737346

  View details for PubMedID 28373262

• Use of anticoagulants and antiplatelet in patients with chronic lymphocytic leukaemia treated with single-agent ibrutinib. British journal of haematology Jones, J. A., Hillmen, P., Coutre, S., Tam, C., Furman, R. R., Barr, P. M., Schuster, S. J., Kipps, T. J., Flinn, I. W., Jaeger, U., Burger, J. A., Cheng, M., Ninomoto, J., James, D. F., Byrd, J. C., O'Brien, S. M. 2017

  Abstract

  Bleeding events have been observed among a subgroup of chronic lymphocytic leukaemia (CLL) patients treated with ibrutinib. We analysed data from two studies of single-agent ibrutinib to better characterize bleeding events and pattern of anticoagulation and antiplatelet use. Among 327 ibrutinib-treated patients, concomitant anticoagulation (11%) or antiplatelet use (34%) was common, but major bleeding was infrequent (2%). Bleeding events were primarily grade 1, and infrequently (1%) led to discontinuation. Among 175 patients receiving concomitant anticoagulant or antiplatelet agents, 5 had major bleeding events (3%). These events were typically observed in conjunction with other factors, such as coexisting medical conditions and/or concurrent medications.

  View details for DOI 10.1111/bjh.14660

  View details for PubMedID 28397242

• Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial LANCET HAEMATOLOGY Jones, J. A., Robak, T., Brown, J. R., Awan, F. T., Badoux, X., Coutre, S., Loscertales, J., Taylor, K., Vandenberghe, E., Wach, M., Wagner-Johnston, N., Ysebaert, L., Dreiling, L., Dubowy, R., Xing, G., Flinn, I. W., Owen, C. 2017; 4 (3): E114-E126

  Abstract

  Idelalisib, a selective inhibitor of PI3Kδ, is approved for the treatment of patients with relapsed chronic lymphocytic leukaemia (CLL) in combination with rituximab. We aimed to assess the efficacy and safety of idelalisib in combination with a second-generation anti-CD20 antibody, ofatumumab, in a similar patient population.In this global, open-label, randomised, controlled phase 3 trial, we enrolled patients with relapsed CLL progressing less than 24 months from last therapy. Patients refractory to ofatumumab were excluded. Patients were stratified by relapsed versus refractory disease, presence or absence of del(17p) or TP53 mutation, or both, and IGHV mutated versus unmutated. We randomised patients in a 2:1 ratio using a web-based interactive system that generated a unique treatment code, and assigned patients to receive either idelalisib plus ofatumumab (oral idelalisib 150 mg twice daily continuously plus ofatumumab 300 mg intravenously in week 1, then 1000 mg intravenously weekly for 7 weeks, and every 4 weeks for 16 weeks) or ofatumumab alone (ofatumumab dosing as per the combination group, except 2000 mg was substituted for the 1000 mg dose). An independent review committee assessed response, including progressive disease, based on imaging using modified International Workshop on Chronic Lymphocytic Leukaemia 2008 criteria. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. We did a primary analysis (data cutoff Jan 15, 2015) and an updated analysis (data cutoff Sept 1, 2015). This trial is registered with Clinicaltrials.gov, number NCT01659021.Between Dec 17, 2012, and March 31, 2014, we enrolled 261 patients (median age 68 years [IQR 61-74], median previous therapies three [IQR 2-4]). At the primary analysis, median progression-free survival was 16·3 months (95% CI 13·6-17·8) in the idelalisib plus ofatumumab group and 8·0 months (5·7-8·2) in the ofatumumab group (adjusted hazard ratio [HR] 0·27, 95% CI 0·19-0·39, p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib plus ofatumumab group were neutropenia (59 [34%] patients vs 14 [16%] in the ofatumumab group), diarrhoea (34 [20%] vs one [1%]), and pneumonia (25 [14%] vs seven [8%]). The most frequent grade 3 or worse adverse events in the ofatumumab group were neutropenia (14 [16%]), pneumonia (seven [8%]), and thrombocytopenia (six [7%] vs 19 [11%] in the idelalisib plus ofatumumab group). Serious infections were more common in the idelalisib plus ofatumumab group and included pneumonia (23 [13%] patients in the idelalisib plus ofatumumab group vs nine [10%] in the ofatumumab group), sepsis (11 [6%] vs one [1%]), and Pneumocystis jirovecii pneumonia (eight [5%] vs one [1%]). 22 treatment-related deaths occurred in the idelalisib plus ofatumumab group (the most common being sepsis, septic shock, viral sepsis, and pneumonia). Six treatment-related deaths occurred in the ofatumumab group (the most common being progressive multifocal leukoencephalopathy and pneumonia).The idelalisib plus ofatumumab combination resulted in better progression-free survival compared with ofatumumab alone in patients with relapsed CLL, including in those with high-risk disease, and thus might represent a new treatment alternative for this patient population.Gilead Sciences, Inc.

  View details for Web of Science ID 000397265700009

  View details for PubMedID 28257752

• Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research Coutré, S. E., Furman, R. R., Flinn, I. W., Burger, J. A., Blum, K., Sharman, J., Jones, J., Wierda, W., Zhao, W., Heerema, N. A., Johnson, A. J., Tran, A., Zhou, C., Bilotti, E., James, D. F., Byrd, J. C., O'Brien, S. 2017; 23 (5): 1149-1155

  Abstract

  Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL.Experimental Design: We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC-1102 and the long-term extension study PCYC-1103.Results: Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1-12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade ≥3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time.Conclusions: Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib. Clin Cancer Res; 23(5); 1149-55. ©2017 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-1431

  View details for PubMedID 28073846

• Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood Mantha, S., Goldman, D. A., Devlin, S. M., Lee, J., Zannino, D., Collins, M., Douer, D., Iland, H. J., Litzow, M. R., Stein, E. M., Appelbaum, F. R., Larson, R. A., Stone, R., Powell, B. L., Geyer, S., Laumann, K., Rowe, J. M., Erba, H., Coutre, S., Othus, M., Park, J. H., Wiernik, P. H., Tallman, M. S. 2017

  Abstract

  Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all-trans retinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were ALLG APML3 (single arm of ATRA + idarubicin ± prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA + cytarabine + daunorubicin). A total of 1009 patients were included in the original trials, of which 995 had sufficient data to be included in our multivariate analysis. In this final cohort, there were 37 HD cases during the first 30 days following induction, for an estimated cumulative incidence of 3.7% (95% confidence interval [CI], 2.6% to 5.0%). Using multivariate Cox proportional hazards regression, the hazard ratio of HD in the first 30 days was 2.17 (95% CI, 0.84-5.62) for an ECOG performance status of 3-4 vs 0-2 and 5.20 (95% CI, 2.70-10.02) for a white blood cell count of ≥20 000/μL vs <20 000/μL. In this large cohort of APL patients, high white blood cell count emerged as an independent predictor of early HD.

  View details for DOI 10.1182/blood-2016-10-747170

  View details for PubMedID 28082441

• Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia. Annals of hematology Shustik, C., Bence-Bruckler, I., Delage, R., Owen, C. J., Toze, C. L., Coutre, S. 2017; 96 (7): 1185–96

  Abstract

  Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients. New options include two agents targeting B cell receptor (BCR) signaling pathways (ibrutinib and idelalisib) and a B cell lymphoma-2 (BCL-2) inhibitor (venetoclax). Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option for younger patients with a suitable donor.

  View details for PubMedID 28389687

  View details for PubMedCentralID PMC5486803

• Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia DeAngelo, D. J., George, T. I., Linder, A., Langford, C., Perkins, C., Ma, J., Westervelt, P., Merker, J. D., Berube, C., Coutre, S., Liedtke, M., Medeiros, B., Sternberg, D., Dutreix, C., Ruffie, P. A., Corless, C., Graubert, T. J., Gotlib, J. 2017

  Abstract

  Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.Leukemia advance online publication, 25 August 2017; doi:10.1038/leu.2017.234.

  View details for PubMedID 28744009

• Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica Brown, J. R., Moslehi, J., O'Brien, S., Ghia, P., Hillmen, P., Cymbalista, F., Shanafelt, T. D., Fraser, G., Rule, S., Kipps, T. J., Coutre, S., Dilhuydy, M. S., Cramer, P., Tedeschi, A., Jaeger, U., Dreyling, M., Byrd, J. C., Howes, A., Todd, M., Vermeulen, J., James, D. F., Clow, F., Styles, L., Valentino, R., Wildgust, M., Mahler, M., Burger, J. A. 2017; 102 (10): 1796–1805

  Abstract

  The first-in-class Bruton's tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6-16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months versus 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation (clinicaltrials.gov identifier: 01578707, 01722487, 01611090, 01646021).

  View details for PubMedID 28751558

• Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood Ryan, C. E., Sahaf, B., Logan, A. C., O'Brien, S., Byrd, J. C., Hillmen, P., Brown, J. R., Dyer, M. J., Mato, A. R., Keating, M. J., Jaglowski, S., Clow, F., Rezvani, A. R., Styles, L., Coutre, S. E., Miklos, D. B. 2016

  Abstract

  Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.

  View details for PubMedID 27802969

• Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study LANCET ONCOLOGY Stilgenbauer, S., Eichhorst, B., Schetelig, J., Coutre, S., Seymour, J. F., Munir, T., Puvvada, S. D., Wendtner, C., Roberts, A. W., Jurczak, W., Mulligan, S. P., Boettcher, S., Mobasher, M., Zhu, M., Desai, M., Chyla, B., Verdugo, M., Enschede, S. H., Cerri, E., Humerickhouse, R., Gordon, G., Hallek, M., Wierda, W. G. 2016; 17 (6): 768-778

  Abstract

  Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia.In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment.Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related).Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia.AbbVie and Genentech.

  View details for DOI 10.1016/S1470-2045(16)30019-5

  View details for Web of Science ID 000377066400061

  View details for PubMedID 27178240

• Discussion: Managing Risk When Using Idelalisib. Clinical advances in hematology & oncology : H&O Coutre, S. E., Burger, J. A., Pagel, J. M. 2016; 14 (5): 13-?

  View details for PubMedID 27168205

• Evolving Frontline Treatment in Chronic Lymphocytic Leukemia. Clinical advances in hematology & oncology : H&O Coutre, S. E. 2016; 14 (5): 5-6

  View details for PubMedID 27168203

• A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma. British journal of haematology Dunn, T. J., Dinner, S., Price, E., Coutré, S. E., Gotlib, J., Hao, Y., Berube, C., Medeiros, B. C., Liedtke, M. 2016; 173 (2): 253-259

  Abstract

  Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

  View details for DOI 10.1111/bjh.13946

  View details for PubMedID 27040320

• Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome LEUKEMIA & LYMPHOMA Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615

  Abstract

  The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

  View details for DOI 10.3109/10428194.2015.1091930

  View details for Web of Science ID 000372499800017

• Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leukemia & lymphoma Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615

  Abstract

  The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

  View details for DOI 10.3109/10428194.2015.1091930

  View details for PubMedID 26374199

• Telomere Length Recovery: A Strong Predictor of Overall Survival in Acute Promyelocytic Leukemia ACTA HAEMATOLOGICA Baljevic, M., Dumitriu, B., Lee, J., Paietta, E. M., Wiernik, P. H., Racevskis, J., Chen, C., Stein, E. M., Gallagher, R. E., Rowe, J. M., Appelbaum, F. R., Powell, B. L., Larson, R. A., Coutre, S. E., Lancet, J., Litzow, M. R., Luger, S. M., Young, N. S., Tallman, M. S. 2016; 136 (4): 210-218

  Abstract

  Telomeres are the capping ends of chromosomes that protect the loss of genetic material and prevent chromosomal instability. In human tissue-specific stem/progenitor cells, telomere length (TL) is maintained by the telomerase complex, which consists of a reverse transcriptase catalytic subunit (TERT) and an RNA template (TERC). Very short telomeres and loss-of-function mutations in the TERT and TERC genes have been reported in acute myeloid leukemia, but the role of telomeres in acute promyelocytic leukemia (APL) has not been well established. We report the results for a large cohort of 187 PML/RARα-positive APL patients. No germline mutations in the TERT or TERC genes were identified. Codon 279 and 1062 TERT polymorphisms were present at a frequency similar to that in the general population. TL measured in blood or marrow mononuclear cells at diagnosis was significantly shorter in the APL patients than in healthy volunteers, and shorter telomeres at diagnosis were significantly associated with high-risk disease. For patients who achieved complete remission, the median increase in TL from diagnosis to remission (delta TL) was 2.0 kilobase (kb), and we found delta TL to be the most powerful predictor of overall survival when compared with well-established risk factors for poor outcomes in APL.

  View details for DOI 10.1159/000448160

  View details for Web of Science ID 000388158200003

  View details for PubMedID 27632567

  View details for PubMedCentralID PMC5198772

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

  View details for PubMedID 27539794

• Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia NEW ENGLAND JOURNAL OF MEDICINE Burger, J. A., Tedeschi, A., Barr, P. M., Robak, T., Owen, C., Ghia, P., Bairey, O., Hillmen, P., Bartlett, N. L., Li, J., Simpson, D., Grosicki, S., Devereux, S., McCarthy, H., Coutre, S., Quach, H., GAIDANO, G., MASLYAK, Z., Stevens, D. A., Janssens, A., Offner, F., Mayer, J., O'Dwyer, M., Hellmann, A., Schuh, A., Siddiqi, T., Polliack, A., Tam, C. S., Suri, D., Cheng, M., Clow, F., Styles, L., James, D. F., Kipps, T. J. 2015; 373 (25): 2425-2437

  Abstract

  Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

  View details for DOI 10.1056/NEJMoa1509388

  View details for Web of Science ID 000366461400009

  View details for PubMedID 26639149

  View details for PubMedCentralID PMC4722809

• Idelalisib-associated Enterocolitis: Clinicopathologic Features and Distinction From Other Enterocolitides. American journal of surgical pathology Louie, C. Y., DiMaio, M. A., Matsukuma, K. E., Coutre, S. E., Berry, G. J., Longacre, T. A. 2015; 39 (12): 1653-1660

  Abstract

  Idelalisib is a highly specific small-molecule phosphoinositide-3-kinase δ inhibitor that was recently approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. The known side effects of idelalisib include severe diarrhea and colitis. Here we report the histologic findings in idelalisib-associated enterocolitis in 11 patients with chronic lymphocytic leukemia or follicular lymphoma receiving idelalisib over a 5-year period (2011 to 2015) at our institution. All 11 patients were receiving idelalisib and underwent colonoscopy for the evaluation of diarrhea. None of the patients had previously received a stem cell transplant. Histologically, the colon biopsies in all 11 cases showed some degree of apoptosis within crypts, with 5 cases showing moderate to severe apoptosis involving the majority of the crypts with loss of goblet cells. No viral inclusions were seen in any case and immunohistochemical stains for cytomegalovirus performed in 9/11 cases were negative. All cases showed at least focal acute cryptitis, and 8 of these cases showed mild architectural distortion. Increased inflammation within the lamina propria was seen in 7 cases, and increased intraepithelial lymphocytes within crypts was seen in 8 cases; the lymphocytes were mostly T cells with a predominance of CD8 T cells, with the majority expressing the α/β T-cell receptor. Diagnoses of graft-versus-host disease, autoimmune enteropathy, infectious enterocolitis, and although thought to be less likely, inflammatory bowel disease were considered in each case. The presence of numerous intraepithelial lymphocytes in addition to severe villous blunting and apoptosis in the small intestinal biopsies from a subset of these patients additionally raised the possibility of autoimmune enteropathy, common variable immunodeficiency, or less likely, celiac disease. Awareness of the histologic features of idelalisib-associated enterocolitis is important to distinguish it from potential mimics, particularly graft-versus-host disease, autoimmune enteropathy, and cytomegalovirus/infectious enterocolitis.

  View details for DOI 10.1097/PAS.0000000000000525

  View details for PubMedID 26426383

• Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide BRITISH JOURNAL OF HAEMATOLOGY Sanford, D., Lo-Coco, F., Sanz, M. A., Di Bona, E., Coutre, S., Altman, J. K., Wetzler, M., Allen, S. L., Ravandi, F., Kantarjian, H., Cortes, J. E. 2015; 171 (4): 471-477

  View details for DOI 10.1111/bjh.13607

  View details for PubMedID 26205361

• Management of adverse events associated with idelalisib treatment: expert panel opinion LEUKEMIA & LYMPHOMA Coutre, S. E., Barrientos, J. C., Brown, J. R., de Vos, S., Furman, R. R., Keating, M. J., Li, D., O'Brien, S. M., Pagel, J. M., Poleski, M. H., Sharman, J. P., Yao, N., Zelenetz, A. D. 2015; 56 (10): 2779-2786

  View details for DOI 10.3109/10428194.2015.1022770

  View details for PubMedID 25726955

• Acute Lymphoblastic Leukemia, Version 2.2015 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Alvarnas, J. C., Brown, P. A., Aoun, P., Ballen, K. K., Barta, S. K., Borate, U., Boyer, M. W., Burke, P. W., Cassaday, R., Castro, J. E., Coccia, P. F., Coutre, S. E., Damon, L. E., DeAngelo, D. J., Douer, D., Frankfurt, O., Greer, J. P., Johnson, R. A., Kantarjian, H. M., Klisovic, R. B., Kupfer, G., Litzow, M., Liu, A., Rao, A. V., Shah, B., Uy, G. L., Wang, E. S., Zelenetz, A. D., Gregory, K., Smith, C. 2015; 13 (10): 1240-1279

  Abstract

  Treatment of acute lymphoblastic leukemia (ALL) continues to advance, as evidenced by the improved risk stratification of patients and development of newer treatment options. Identification of ALL subtypes based on immunophenotyping and cytogenetic and molecular markers has resulted in the inclusion of Philadelphia-like ALL and early T-cell precursor ALL as subtypes that affect prognosis. Identification of Ikaros mutations has also emerged as a prognostic factor. In addition to improved prognostication, treatment options for patients with ALL have expanded, particularly with regard to relapsed/refractory ALL. Continued development of second-generation tyrosine kinase inhibitors and the emergence of immunotherapy, including blinatumomab and chimeric antigen receptor T-cell therapy, have improved survival. Furthermore, incorporation of minimal residual disease (MRD) monitoring has shown insight into patient outcomes and may lead to treatment modification or alternative treatment strategies in select populations. This excerpt focuses on the sections of the ALL guidelines specific to clinical presentation and diagnosis, treatment of relapsed/refractory ALL, and incorporation of MRD monitoring. To view the most recent complete version of these guidelines, visit NCCN.org.

  View details for Web of Science ID 000363434000010

  View details for PubMedID 26483064

• A Pediatric Case of T-Cell Prolymphocytic Leukemia PEDIATRIC BLOOD & CANCER Mitton, B., Coutre, S., Willert, J., Schlis, K., Porteus, M., Kharbanda, S., Agarwal-Hashmi, R. 2015; 62 (6): 1061-1062

  Abstract

  T-cell Prolymphocytic Leukemia (T-PLL) is a rare entity, and to date has never been reported in children. Here, we describe the first pediatric case of T-PLL in a 16-year old male and review his clinical course through treatment. He underwent therapy with alemtuzumab and pentostatin, which was successful in inducing initial remission. He then underwent an allogeneic matched sibling stem cell transplant following a myeloablative conditioning regimen and remains disease-free 1.5 years after diagnosis. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/pbc.25336

  View details for PubMedID 25417638

• Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib BLOOD Byrd, J. C., Furman, R. R., Coutre, S. E., Burger, J. A., Blum, K. A., Coleman, M., Wierda, W. G., Jones, J. A., Zhao, W., Heerema, N. A., Johnson, A. J., Shaw, Y., Bilotti, E., Zhou, C., James, D. F., O'Brien, S. 2015; 125 (16): 2497-2506

  Abstract

  Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early-phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naïve and relapsed/refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment-related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse.

  View details for DOI 10.1182/blood-2014-10-606038

  View details for Web of Science ID 000354751700011

  View details for PubMedID 25700432

  View details for PubMedCentralID PMC4400288

• A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood O'Brien, S. M., Lamanna, N., Kipps, T. J., Flinn, I., Zelenetz, A. D., Burger, J. A., Keating, M., Mitra, S., Holes, L., Yu, A. S., Johnson, D. M., Miller, L. L., Kim, Y., Dansey, R. D., Dubowy, R. L., Coutre, S. E. 2015; 126 (25): 2686–94

  Abstract

  Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930.

  View details for PubMedID 26472751

• Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia LEUKEMIA RESEARCH Liedtke, M., Dunn, T., Dinner, S., Coutre, S. E., Berubea, C., Gotlib, J., Patel, S., Medeiros, B. 2014; 38 (12): 1441-1445

  Abstract

  The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to ≥second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.

  View details for DOI 10.1016/j.leukres.2014.09.018

  View details for Web of Science ID 000345614400011

• Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia. Leukemia research Liedtke, M., Dunn, T., Dinner, S., Coutré, S. E., Berube, C., Gotlib, J., Patel, S., Medeiros, B. 2014; 38 (12): 1441-1445

  Abstract

  The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to ≥second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.

  View details for DOI 10.1016/j.leukres.2014.09.018

  View details for PubMedID 25449689

• Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma BLOOD Flinn, I. W., Kahl, B. S., Leonard, J. P., Furman, R. R., Brown, J. R., Byrd, J. C., Wagner-Johnston, N. D., Coutre, S. E., Benson, D. M., Peterman, S., Cho, Y., Webb, H. K., Johnson, D. M., Yu, A. S., Ulrich, R. G., Godfrey, W. R., Miller, L. L., Spurgeon, S. E. 2014; 123 (22): 3406-3413

  Abstract

  Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension study. Adverse events (AEs) occurring in 20% or more patients (total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), and chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These trials were registered at clinicaltrials.gov as NCT00710528 and NCT01090414.

  View details for DOI 10.1182/blood-2013-11-538546

  View details for PubMedID 24615776

• A phase 1 study of the PI3K delta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL) BLOOD Kahl, B. S., Spurgeon, S. E., Furman, R. R., Flinn, I. W., Coutre, S. E., Brown, J. R., Benson, D. M., Byrd, J. C., Peterman, S., Cho, Y., Yu, A., Godfrey, W. R., Wagner-Johnston, N. D. 2014; 123 (22): 3398-3405

  Abstract

  Idelalisib, an oral inhibitor of phosphatidylinositol-3-kinase δ (PI3Kδ), was evaluated in a 48-week phase 1 study (50-350 mg daily or twice daily) enrolling 40 patients with relapsed or refractory mantle cell lymphoma (MCL). Primary outcome was safety and dose-limiting toxicity (DLT). Secondary outcomes were pharmacokinetic parameters, pharmacodynamic effects, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Patients without DLT and no evidence of disease progression after 48 weeks enrolled in the extension study. Patients had median age of 69 years (range, 52-83) and received median of 4 prior therapies (1-14); 17 of 40 patients (43%) were refractory to their most recent treatment. Median duration of idelalisib treatment was 3.5 months (range, 0.7-30.7), with 6 (15%) continuing extension treatment. Common grade ≥3 adverse events (AEs) included (total%/grade ≥3%) diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (23/3), decreased appetite (20/15), upper respiratory infection (20/0), pneumonia (13/10), and alanine transaminase or aspartate transaminase elevations (60/20). ORR was 16 of 40 patients (40%), with CR in 2 of 40 patients (5%). Median DOR was 2.7 months, median PFS was 3.7 months, and 1-year PFS was 22%. These data provide proof of concept that targeting PI3Kδ is a viable strategy and worthy of additional study in MCL. This trial was registered at www.clinicaltrials.gov as #NCT00710528.

  View details for DOI 10.1182/blood-2013-11-537555

  View details for PubMedID 24615778

• Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110 delta, for relapsed/refractory chronic lymphocytic leukemia BLOOD Brown, J. R., Byrd, J. C., Coutre, S. E., Benson, D. M., Flinn, I. W., Wagner-Johnston, N. D., Spurgeon, S. E., Kahl, B. S., Bello, C., Webb, H. K., Johnson, D. M., Peterman, S., Li, D., Jahn, T. M., Lannutti, B. J., Ulrich, R. G., Yu, A. S., Miller, L. L., Furman, R. R. 2014; 123 (22): 3390-3397

  Abstract

  In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.

  View details for DOI 10.1182/blood-2013-11-535047

  View details for PubMedID 24615777

• Arsenic trioxide during consolidation for patients with previously untreated low/intermediate risk acute promyelocytic leukaemia may eliminate the need for maintenance therapy BRITISH JOURNAL OF HAEMATOLOGY Coutre, S. E., Othus, M., Powell, B., Willman, C. L., Stock, W., Paietta, E., Levitan, D., Wetzler, M., Attar, E. C., Altman, J. K., Gore, S. D., Maher, T., Kopecky, K. J., Tallman, M. S., Larson, R. A., Appelbaum, F. R. 2014; 165 (4): 497-503

  View details for DOI 10.1111/bjh.12775

  View details for Web of Science ID 000334686500007

• SWOG S0910: a phase 2 trial of clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukaemia. British journal of haematology Advani, A. S., McDonough, S., Coutre, S., Wood, B., Radich, J., Mims, M., O'Donnell, M., Elkins, S., Becker, M., Othus, M., Appelbaum, F. R. 2014; 165 (4): 504-509

  Abstract

  Precursor B-acute lymphoblastic leukaemias (pre-B ALLs) comprise the majority of ALLs and virtually all blasts express CD22 in the cytoplasm and on the cell surface. In the present study (Southwestern Oncology Group S0910), we evaluated the addition of epratuzumab, a humanized monoclonal antibody against CD22, to the combination of clofarabine and cytarabine in adults with relapsed/refractory pre-B ALL. The response rate [complete remission and complete remission with incomplete count recovery] was 52%, significantly higher than our previous trial with clofarabine/cytarabine alone, where the response rate was 17%. This result is encouraging and suggests a potential benefit to adding epratuzumab to chemotherapy for ALL; however, a randomized trial will be needed to answer this question.

  View details for DOI 10.1111/bjh.12778

  View details for PubMedID 24579885

• Arsenic trioxide during consolidation for patients with previously untreated low/intermediate risk acute promyelocytic leukaemia may eliminate the need for maintenance therapy. British journal of haematology Coutre, S. E., Othus, M., Powell, B., Willman, C. L., Stock, W., Paietta, E., Levitan, D., Wetzler, M., Attar, E. C., Altman, J. K., Gore, S. D., Maher, T., Kopecky, K. J., Tallman, M. S., Larson, R. A., Appelbaum, F. R. 2014; 165 (4): 497-503

  Abstract

  Aa total of 105 patients (age ≥18 years) with newly diagnosed low or intermediate risk acute promyelocytic leukaemia (APL) were treated with a standard induction and consolidation regimen including arsenic trioxide (ATO). Sixty-eight patients who were polymerase chain reaction (PCR) negative for PML-RARA post-consolidation were randomized to either 1 year of maintenance with tretinoin, mercaptopurine and methotrexate, or observation. Enrollment in this non-inferiority trial was stopped prematurely due to slow accrual. With a median follow up of 36·1 months, the overall survival of the 105 patients was 93%, and there have been no relapses in the patients randomized to maintenance or observation. These results demonstrate that cures can be expected in >90% of patients with low and intermediate risk APL and suggest that maintenance therapy may not be needed if patients are treated with an intensive post-remission regimen including ATO. This trial was registered at clinicaltrials.gov as #NCT00492856.

  View details for DOI 10.1111/bjh.12775

  View details for PubMedID 24528179

  View details for PubMedCentralID PMC4064464

• SWOG S0910: a phase 2 trial of clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukaemia BRITISH JOURNAL OF HAEMATOLOGY Advani, A. S., McDonough, S., Coutre, S., Wood, B., Radich, J., Mims, M., O'Donnell, M., Elkins, S., Becker, M., Othus, M., Appelbaum, F. R. 2014; 165 (4): 504-509

  View details for DOI 10.1111/bjh.12778

  View details for Web of Science ID 000334686500008

• Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia NEW ENGLAND JOURNAL OF MEDICINE Furman, R. R., Sharman, J. P., Coutre, S. E., Cheson, B. D., Pagel, J. M., Hillmen, P., Barrientos, J. C., Zelenetz, A. D., Kipps, T. J., Flinn, I., Ghia, P., Eradat, H., Ervin, T., Lamanna, N., Coiffier, B., Pettitt, A. R., Ma, S., Stilgenbauer, S., Cramer, P., Aiello, M., Johnson, D. M., Miller, L. L., Li, D., Jahn, T. M., Dansey, R. D., Hallek, M., O'Brien, S. M. 2014; 370 (11): 997-1007

  View details for DOI 10.1056/NEJMoa1315226

  View details for Web of Science ID 000332689100007

• A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia BLOOD Nand, S., Othus, M., Godwin, J. E., Willman, C. L., Norwood, T. H., Howard, D. S., Coutre, S. E., Erba, H. P., Appelbaum, F. R. 2013; 122 (20): 3432-3439

  View details for DOI 10.1182/blood-2013-06-506592

  View details for Web of Science ID 000327666500013

• A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood Nand, S., Othus, M., Godwin, J. E., Willman, C. L., Norwood, T. H., Howard, D. S., Coutre, S. E., Erba, H. P., Appelbaum, F. R. 2013; 122 (20): 3432-3439

  Abstract

  This trial tested the safety and efficacy of a regimen consisting of hydroxyurea followed by azacitidine, 75 mg/m(2) for 7 days, and gemtuzumab ozogamicin, 3 mg/m(2) on day 8, in older patients with newly diagnosed acute myeloid leukemia. Those achieving a complete remission received 1 consolidation treatment followed by 4 cycles of azacitidine. The patients were stratified into good-risk (age 60-69 years or performance status 0-1) and poor-risk (age ≥70 years and performance status 2 or 3) groups. Specific efficacy and safety goals were defined as being supportive of further study of the regimen. Eighty-three patients were registered in the good-risk cohort and 59 in poor-risk cohort, with median age of 71 and 75 years, respectively. In the good-risk group, 35 patients (44%) achieved a complete remission. Median relapse-free and overall survivals were 8 and 11 months, respectively. Six patients (8%) died within 30 days of registration. In the poor-risk group, 19 (35%) achieved a complete remission. Median relapse-free and overall survivals were 7 and 11 months, respectively. Seven patients (14%) died early. The results of this trial met predefined goals for efficacy and safety for the poor-risk cohort but not the good-risk group. .

  View details for DOI 10.1182/blood-2013-06-506592

  View details for PubMedID 24092933

• PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma BLOOD Richardson, P. G., Schlossman, R. L., Alsina, M., Weber, D. M., Coutre, S. E., Gasparetto, C., Mukhopadhyay, S., Ondovik, M. S., Khan, M., Paley, C. S., Lonial, S. 2013; 122 (14): 2331-2337

  Abstract

  Panobinostat is an oral pan-deacetylase inhibitor that synergizes with bortezomib to inhibit both the aggresome and proteasome pathways in preclinical studies. PANORAMA 2 is a phase 2 trial of panobinostat in combination with bortezomib and dexamethasone to treat patients with relapsed and bortezomib-refractory multiple myeloma (with ≥2 prior lines of therapy, including an immunomodulatory drug, and patients who had progressed on or within 60 days of the last bortezomib-based therapy). Fifty-five heavily pretreated patients were enrolled (median, 4 prior regimens, including a median of 2 prior bortezomib-containing regimens). The overall response rate was 34.5% (1 near-complete response and 18 partial responses). An additional 10 patients achieved minimal response, for a clinical benefit rate of 52.7%. Median exposure and progression-free survival were 4.6 and 5.4 months, respectively. In patients who achieved a response, median time to response was 1.4 months, and median duration of response was 6.0 months. Common grade 3/4 adverse events, regardless of study drug relationship, included thrombocytopenia (63.6%), fatigue (20.0%), and diarrhea (20.0%). Only 1 patient had grade 3 peripheral neuropathy. Panobinostat, when combined with bortezomib and dexamethasone, can recapture responses in heavily pretreated, bortezomib-refractory multiple myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01083602.

  View details for DOI 10.1182/blood-2013-01-481325

  View details for Web of Science ID 000326078200016

  View details for PubMedID 23950178

• Acute myeloid leukemia, version 2.2013. Journal of the National Comprehensive Cancer Network O'Donnell, M. R., Tallman, M. S., Abboud, C. N., Altman, J. K., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Lancet, J., Maness, L. J., Marcucci, G., Martin, M. G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Wang, E. S., Gregory, K. M., Naganuma, M. 2013; 11 (9): 1047-1055

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Acute Myeloid Leukemia and discuss the clinical evidence that support the recommendations. The updates described in this article focus on the acute promyelocytic leukemia (APL) section, featuring recommendations for additional induction/consolidation regimens in patients with low- or intermediate-risk APL, and providing guidance on maintenance strategies for APL.

  View details for PubMedID 24029121

• Acute Myeloid Leukemia, Version 2.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Donnell, M. R., Tallman, M. S., Abboud, C. N., Altman, J. K., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Lancet, J., Maness, L. J., Marcucci, G., Martin, M. G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Wang, E. S., Gregory, K. M., Naganuma, M. 2013; 11 (9): 1047-1055

  Abstract

  These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Acute Myeloid Leukemia and discuss the clinical evidence that support the recommendations. The updates described in this article focus on the acute promyelocytic leukemia (APL) section, featuring recommendations for additional induction/consolidation regimens in patients with low- or intermediate-risk APL, and providing guidance on maintenance strategies for APL.

  View details for Web of Science ID 000324310800003

• Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia. Haematologica Pollyea, D. A., Zehnder, J., Coutre, S., Gotlib, J. R., Gallegos, L., Abdel-Wahab, O., Greenberg, P., Zhang, B., Liedtke, M., Berube, C., Levine, R., Mitchell, B. S., Medeiros, B. C. 2013; 98 (4): 591-596

  Abstract

  There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ≥ 60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ≥ 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway.

  View details for DOI 10.3324/haematol.2012.076414

  View details for PubMedID 23242596

• Treatment of adults with acute lymphoblastic leukemia: Do the specifics of the regimen matter? Results From a Prospective Randomized Trial CANCER Lamanna, N., Heffner, L. T., Kalaycio, M., Schiller, G., Coutre, S., Moore, J., Seiter, K., Maslak, P., Panageas, K., Golde, D., Weiss, M. A. 2013; 119 (6): 1186-1194

  Abstract

  Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m(2) daily for 5 days with mitoxantrone 80 mg/m(2) (the ALL-2 regimen) as a novel induction regimen. Compared with historic controls, the ALL-2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)-positive ALL.The authors conducted a multicenter, prospective, randomized trial of the ALL-2 regimen compared with a standard 4-drug induction (the L-20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004.The median follow-up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL-2 regimen versus the L-20 regimen was 83% versus 71% (P = .06). More patients on the L-20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL-2) versus 7% (L-20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL-2 arm versus 27% on the L-20.Despite superior results of induction therapy with the ALL-2 regimen, this treatment did not improve long-term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.

  View details for DOI 10.1002/cncr.27901

  View details for Web of Science ID 000315696600012

  View details for PubMedID 23280086

• High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia JOURNAL OF CLINICAL ONCOLOGY O'Brien, S., Schiller, G., Lister, J., Damon, L., Goldberg, S., Aulitzky, W., Ben-Yehuda, D., Stock, W., Coutre, S., Douer, D., Heffner, L. T., Larson, M., Seiter, K., Smith, S., Assouline, S., Kuriakose, P., Maness, L., Nagler, A., Rowe, J., Schaich, M., Shpilberg, O., Yee, K., Schmieder, G., Silverman, J. A., Thomas, D., Deitcher, S. R., Kantarjian, H. 2013; 31 (6): 676-683

  Abstract

  Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT).Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi).The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%).High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

  View details for DOI 10.1200/JCO.2012.46.2309

  View details for Web of Science ID 000315086400015

  View details for PubMedID 23169518

• A Phase I/II Study of Bortezomib (VELCADE) in Combination with Pralatrexate in Relapsed/Refractory Multiple Myeloma 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Dunn, T. J., Dinner, S. N., Berube, C., Gotlib, J., Coutre, S. E., Medeiros, B. C., Liedtke, M. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049604427

• Combinations of the Phosphatidylinositol 3-Kinase-Delta (PI3K delta) Inhibitor Gs-1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Previously Treated, Indolent Non-Hodgkin Lymphoma: Results From a Phase I Study 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Fowler, N. H., de Vos, S., Schreeder, M. T., Leonard, J. P., Flinn, I. W., Coutre, S., Wagner-Johnston, N. D., Sharman, J., Boccia, R. V., Barrientos, J. C., Boyd, T. E., Holes, L. M., Lannutti, B. J., Johnson, D., Jahn, T. M., Miller, L. L., Godfrey, W. R. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049600297

• Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838903369

• Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia AMERICAN JOURNAL OF HEMATOLOGY Sun, D., Elson, P., Liedtke, M., Medeiros, B. C., Earl, M., Alizadeh, A., Bates, J., Sekeres, M. A., Coutre, S., Kalaycio, M., Sobecks, R., Copelan, E., Advani, A. S. 2012; 87 (10): 957-960

  Abstract

  We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ≥350 cells/μL at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/μL (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC ≥350 cells/μL on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/μL (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/μL vs. ≥350 cells/μL, P ≤ .0004 for OS and EFS) along with WBC at diagnosis (≤6.0 or >30.0 K/μL vs. >6.0-30.0 K/μL, P ≤ 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL.

  View details for DOI 10.1002/ajh.23279

  View details for Web of Science ID 000309065700081

  View details for PubMedID 22729847

• Acute Myeloid Leukemia Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Donnell, M. R., Abboud, C. N., Altman, J., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Goorha, S., Lancet, J., Maness, L. J., Marcucci, G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Tallman, M. S., Wang, E. S., Naganuma, M., Gregory, K. M. 2012; 10 (8): 984-1021

  Abstract

  Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML provide recommendations on the diagnostic evaluation and workup for AML, risk assessment based on cytogenetic and molecular features, treatment options for induction and consolidation therapies for younger and older (age ≥ 65 years) adult patients, and key supportive care considerations.

  View details for Web of Science ID 000307494000010

• Acute myeloid leukemia. Journal of the National Comprehensive Cancer Network O'Donnell, M. R., Abboud, C. N., Altman, J., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Goorha, S., Lancet, J., Maness, L. J., Marcucci, G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Tallman, M. S., Wang, E. S., Naganuma, M., Gregory, K. M. 2012; 10 (8): 984-1021

  Abstract

  Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML provide recommendations on the diagnostic evaluation and workup for AML, risk assessment based on cytogenetic and molecular features, treatment options for induction and consolidation therapies for younger and older (age ≥ 65 years) adult patients, and key supportive care considerations.

  View details for PubMedID 22878824

• Acute Lymphoblastic Leukemia JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Alvarnas, J. C., Brown, P. A., Aoun, P., Ballen, K. K., Bellam, N., Blum, W., Boyer, M. W., Carraway, H. E., Coccia, P. F., Coutre, S. E., Cultrera, J., Damon, L. E., DeAngelo, D. J., Douer, D., Frangoul, H., Frankfurt, O., Goorha, S., Millenson, M. M., O'Brien, S., Petersdorf, S. H., Rao, A. V., Terezakis, S., Uy, G., Wetzler, M., Zelenetz, A. D., Naganuma, M., Gregory, K. M. 2012; 10 (7): 858-913

  Abstract

  The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL.

  View details for Web of Science ID 000306303900009

  View details for PubMedID 22773801

• Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia LEUKEMIA Pollyea, D. A., Kohrt, H. E., Gallegos, L., Figueroa, M. E., Abdel-Wahab, O., Zhang, B., Bhattacharya, S., Zehnder, J., Liedtke, M., Gotlib, J. R., Coutre, S., Berube, C., Melnick, A., Levine, R., Mitchell, B. S., Medeiros, B. C. 2012; 26 (5): 893-901

  Abstract

  Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

  View details for DOI 10.1038/leu.2011.294

  View details for Web of Science ID 000303883500005

  View details for PubMedID 22033493

• Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia LEUKEMIA & LYMPHOMA Wendtner, C., Hillmen, P., Mahadevan, D., Buehler, A., Uharek, L., Coutre, S., Frankfurt, O., Bloor, A., Bosch, F., Furman, R. R., Kimby, E., Gribben, J. G., Gobbi, M., Dreisbach, L., Hurd, D. D., Sekeres, M. A., Ferrajoli, A., Shah, S., Zhang, J., Moutouh-de Parseval, L., Hallek, M., Heerema, N. A., Stilgenbauer, S., Chanan-Khan, A. A. 2012; 53 (3): 417-423

  Abstract

  Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.

  View details for DOI 10.3109/10428194.2011.618232

  View details for Web of Science ID 000300451100012

  View details for PubMedID 21879809

• Treatment advances have not improved the early death rate in acute promyelocytic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL McClellan, J. S., Kohrt, H. E., Coutre, S., Gotlib, J. R., Majeti, R., Alizadeh, A. A., Medeiros, B. C. 2012; 97 (1): 133-136

  Abstract

  Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977-2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.

  View details for DOI 10.3324/haematol.2011.046490

  View details for Web of Science ID 000299870500022

  View details for PubMedID 21993679

  View details for PubMedCentralID PMC3248942

• Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Liedtke, M., Twist, C. J., Medeiros, B. C., Gotlib, J. R., Berube, C., Bieber, M. M., Bhat, N. M., Teng, N. N., Coutre, S. E. 2012; 97 (1): 30-37

  Abstract

  This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6-65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

  View details for DOI 10.3324/haematol.2011.045997

  View details for Web of Science ID 000299870500009

  View details for PubMedID 21993685

  View details for PubMedCentralID PMC3248928

• Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia AMERICAN JOURNAL OF HEMATOLOGY Medeiros, B. C., Kohrt, H. E., Gotlib, J., Coutre, S. E., Zhang, B., Arber, D. A., Zehnder, J. L. 2012; 87 (1): 45-50

  Abstract

  Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247.

  View details for DOI 10.1002/ajh.22191

  View details for Web of Science ID 000298257700010

  View details for PubMedID 22052619

• Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kipps, T. J., Swinnen, L. J., Wierda, W. G., Jones, J. A., Coutre, S. E., Smith, M. R., Yang, J., Cui, Y., Busman, T., Enschede, S., Humerickhouse, R. AMER SOC HEMATOLOGY. 2011: 1669–69

  View details for Web of Science ID 000299597106074

• A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3K delta) Inhibitor, CAL-101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Sharman, J., de Vos, S., Leonard, J. P., Furman, R. R., Coutre, S. E., Flinn, I. W., Schreeder, M. T., Barrientos, J. C., Wagner-Johnston, N. D., Boyd, T., Fowler, N. H., Holes, L., Lannutti, B., Johnson, D., Jahn, T. M., Miller, L. L. AMER SOC HEMATOLOGY. 2011: 779–80

  View details for Web of Science ID 000299597102382

• Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse BLOOD Levis, M., Ravandi, F., Wang, E. S., Baer, M. R., Perl, A., Coutre, S., Erba, H., Stuart, R. K., Baccarani, M., Cripe, L. D., Tallman, M. S., Meloni, G., Godley, L. A., Langston, A. A., Amadori, S., Lewis, I. D., Nagler, A., Stone, R., Yee, K., Advani, A., Douer, D., Wiktor-Jedrzejczak, W., Juliusson, G., Litzow, M. R., Petersdorf, S., Sanz, M., Kantarjian, H. M., Sato, T., Tremmel, L., Bensen-Kennedy, D. M., Small, D., Smith, B. D. 2011; 117 (12): 3294-3301

  Abstract

  In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

  View details for DOI 10.1182/blood-2010-08-301796

  View details for Web of Science ID 000288848500012

  View details for PubMedID 21270442

  View details for PubMedCentralID PMC3069671

• Acute Myeloid Leukemia JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Donnell, M. R., Abboud, C. N., Altman, J., Appelbaum, F. R., Coutre, S. E., Damon, L. E., Foran, J. M., Goorha, S., Maness, L. J., Marcucci, G., Maslak, P., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Tallman, M. S., Wang, E. S. 2011; 9 (3): 280-317

  View details for Web of Science ID 000287991200005

  View details for PubMedID 21393440

• CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies BLOOD Kohrt, H. E., Houot, R., Goldstein, M. J., Weiskopf, K., Alizadeh, A. A., Brody, J., Mueller, A., Pachynski, R., Czerwinski, D., Coutre, S., Chao, M. P., Chen, L., Tedder, T. F., Levy, R. 2011; 117 (8): 2423-2432

  Abstract

  Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells after activation, including NK cells. In the present study, we show that an anti-CD137 agonistic mAb enhances the antilymphoma activity of rituximab by enhancing ADCC. Human NK cells up-regulate CD137 after encountering rituximab-coated tumor B cells, and subsequent stimulation of these NK cells with anti-CD137 mAb enhances rituximab-dependent cytotoxicity against the lymphoma cells. In a syngeneic murine lymphoma model and in a xenotransplanted human lymphoma model, sequential administration of anti-CD20 mAb followed by anti-CD137 mAb had potent antilymphoma activity in vivo. These results support a novel, sequential antibody approach against B-cell malignancies by targeting first the tumor and then the host immune system.

  View details for DOI 10.1182/blood-2010-08-301945

  View details for PubMedID 21193697

• Yield of diagnostic procedures for invasive fungal infections in neutropenic febrile patients with chest computed tomography abnormalities MYCOSES Ho, D. Y., Lin, M., Schaenman, J., Rosso, F., Leung, A. N., Coutre, S. E., Sista, R. R., Montoya, J. G. 2011; 54 (1): 59-70

  Abstract

  Haematological patients with neutropenic fever are frequently evaluated with chest computed tomography (CT) to rule out invasive fungal infections (IFI). We retrospectively analysed data from 100 consecutive patients with neutropenic fever and abnormal chest CT from 1998 to 2005 to evaluate their chest CT findings and the yield of diagnostic approaches employed. For their initial CTs, 79% had nodular opacities, with 24.1% associated with the halo sign. Other common CT abnormalities included pleural effusions (48%), ground glass opacities (37%) and consolidation (31%). The CT findings led to a change in antifungal therapy in 54% of the patients. Fifty-six patients received diagnostic procedures, including 46 bronchoscopies, 25 lung biopsies and seven sinus biopsies, with a diagnostic yield for IFI of 12.8%, 35.0% and 83.3%, respectively. In conclusion, chest CT plays an important role in the evaluation of haematological patients with febrile neutropenia and often leads to a change in antimicrobial therapy. Pulmonary nodules are the most common radiological abnormality. Sinus or lung biopsies have a high-diagnostic yield for IFI as compared to bronchoscopy. Patients with IFI may not have sinus/chest symptoms, and thus, clinicians should have a low threshold for performing sinus/chest imaging, and if indicated and safe, a biopsy of the abnormal areas.

  View details for DOI 10.1111/j.1439-0507.2009.01760.x

  View details for PubMedID 19793207

• Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia BRITISH JOURNAL OF HAEMATOLOGY Advani, A. S., Gundacker, H. M., Sala-Torra, O., Radich, J. P., Lai, R., Slovak, M. L., Lancet, J. E., Coutre, S. E., Stuart, R. K., Mims, M. P., Stiff, P. J., Appelbaum, F. R. 2010; 151 (5): 430-434

  Abstract

  Clofarabine and cytarabine target different steps in DNA synthesis and replication, are synergistic in vivo, and have non-overlapping toxicities, making this combination a potentially promising treatment for acute lymphocytic leukaemia. Thirty-seven patients were treated. The median age was 41 years, 44% of patients were either in ≥2nd relapse or had refractory disease and 59% of patients had poor risk cytogenetics. Six out of 36 patients (17%) achieved a complete remission with or without complete count recovery; median overall survival was 3 months. Nucleoside transporter expression did not predict outcome. This regimen lacked sufficient activity to warrant further testing.

  View details for DOI 10.1111/j.1365-2141.2010.08387.x

  View details for Web of Science ID 000284169700003

  View details for PubMedID 21113977

• Temozolomide In Acute Myeloid Leukemia: A MGMT Promoter Methylation Status-Based Treatment Stratification 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Medeiros, B. C., Kohrt, H. E., Rajwanshi, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Zhang, M., Arber, D. A., Zehnder, J. L. AMER SOC HEMATOLOGY. 2010: 1357–58

  View details for Web of Science ID 000289662203644

• Final Results of the Phase I Study of Lenalidomide In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL-001 Study) 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Wendtner, C., Hillmen, P., Mahadevan, D., Stilgenbauer, S., Uharek, L., Coutre, S., Frankfurt, O., Bloor, A., Bosch, F., Furman, R. R., Kimby, E., Gribben, J. G., Gobbi, M., Dreisbach, L., Hurd, D. D., Sekeres, M. A., Ferrajoli, A., Shah, S., Zhang, J., de Parseval, L. M., Chanan-Khan, A. A. AMER SOC HEMATOLOGY. 2010: 591–92

  View details for Web of Science ID 000289662201479

• A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML) 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Pollyea, D. A., Kohrt, H. E., Gallegos, L., Berube, C., Coutre, S., Gotlib, J., Liedtke, M., Mitchell, B. S., Medeiros, B. C. AMER SOC HEMATOLOGY. 2010: 1347–47

  View details for Web of Science ID 000289662203619

• Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single-center experience AMERICAN JOURNAL OF HEMATOLOGY Kohrt, H. E., Patel, S., Ho, M., Owen, T., Pollyea, D. A., Majeti, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Alizadeh, A. A., Medeiros, B. C. 2010; 85 (11): 877-881

  Abstract

  The majority of patients with acute myeloid leukemia (AML) will require second-line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second-line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m(2)/day), etoposide (100 mg/m(2)/day), and cytarabine (1,000 mg/m(2)/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow-up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia-free state. Fifty-seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort.

  View details for DOI 10.1002/ajh.21857

  View details for Web of Science ID 000283568200010

  View details for PubMedID 20872554

• Classification and Risk Stratification for Acute Promyelocytic Leukemia CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Coutre, S. 2010; 10: S127-S129

  Abstract

  Acute promyelocytic leukemia (APL) as a distinct clinical entity was first described only 50 years ago. The last twenty years are notable for rapid advances in understanding the molecular basis of the disease as well as dramatic improvements in treating APL. A new classification system that stratifies patients by risk has also lead to dramatic improvement in managing the disease. Molecular monitoring for minimal residual disease holds great promise for continued improvement in decreasing relapse risk. We are now able to tailor our therapy based on risk of relapse, and ongoing clinical trials use this risk-adapted framework in an attempt to further improve outcomes.

  View details for DOI 10.3816/CLML.2010.s.024

  View details for Web of Science ID 000284236600002

  View details for PubMedID 21115430

• Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma JOURNAL OF CLINICAL ONCOLOGY Tong, W., Chen, R., Plunkett, W., Siegel, D., Sinha, R., Harvey, R. D., Badros, A. Z., Popplewell, L., Coutre, S., Fox, J. A., Mahadocon, K., Chen, T., Kegley, P., Hoch, U., Wierda, W. G. 2010; 28 (18): 3015-3022

  Abstract

  SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy.Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course.There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m(2), and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m(2), owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis.SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

  View details for DOI 10.1200/JCO.2009.26.1347

  View details for Web of Science ID 000278883200015

  View details for PubMedID 20479412

• Early Mortality in Acute Promyelocytic Leukemia May Be Higher Than Previously Reported. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Alizadeh, A. A., McClellan, J. S., Gotlib, J. R., Coutre, S., Majeti, R., Kohrt, H. E., Medeiros, B. C. AMER SOC HEMATOLOGY. 2009: 420–21

  View details for Web of Science ID 000272725801195

• Is Time of the Essence in Adult Acute Myeloid Leukemia (AML)? Time to Blast Clearance and Time to Induction Therapy Fail to Predict Overall Survival (OS). 51st Annual Meeting and Exposition of the American-Society-of-Hematology Kohrt, H. E., Patel, S., Ho, M., Owen, T., Majeti, R., Gotlib, J. R., Coutre, S., Medeiros, B. C., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2009: 646–47

  View details for Web of Science ID 000272725801797

• Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma 48th Annual Meeting of the American-Society-of-Hematology Chen, C., Reece, D. E., Siegel, D., Niesvizky, R., Boccia, R. V., Stadtmauer, E. A., Abonour, R., Richardson, P., Matous, J., Kumar, S., Bahlis, N. J., Alsina, M., Vescio, R., Coutre, S. E., Pietronigro, D., Knight, R. D., Zeldis, J. B., Rajkumar, V. WILEY-BLACKWELL PUBLISHING, INC. 2009: 164–70

  Abstract

  Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1-21) and dexamethasone 40 mg/d (days 1-4, 9-12, and 17-20 of cycles 1-4; days 1-4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, approximately 60% were male, median age was 64 years, and 61.7% had Durie-Salmon stage III disease. Median time on study was 15.4 weeks (range: 0.1-49.1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade > or =3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM.

  View details for DOI 10.1111/j.1365-2141.2009.07728.x

  View details for Web of Science ID 000267657300005

  View details for PubMedID 19545290

  View details for PubMedCentralID PMC2728892

• A randomized phase II study of sapacitabine, an oral nucleoside analogue, in elderly patients with AML previously untreated or in first relapse or previously treated MDS 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Garcia-Manero, G., Luger, S., Venugopal, P., Maness, L., Wetzler, M., Coutre, S., Stock, W., Borthakur, G., Chiao, J., Kantarjian, H. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605012

• Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Medeiros, B. C., Gotlib, J. R., Coutre, S. E., Jones, C., Khan, S. A., Rajwanshi, R., Rajwanshi, R., Zehnder, J., Zehnder, J. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605042

• Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase 48th Annual Meeting of the American-Society-of-Hematology Cortes, J., Kim, D., Raffoux, E., Martinelli, G., Ritchie, E., Roy, L., Coutre, S., Corm, S., Hamerschlak, N., Tang, J., Hochhaus, A., Khoury, H. J., Bruemmendorf, T. H., Michallet, M., Rege-Cambrin, G., Gambacorti-Passerini, C., Radich, J. P., Ernst, T., Zhu, C., Van Tornout, J. M., Talpaz, M. NATURE PUBLISHING GROUP. 2008: 2176–83

  Abstract

  Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03-20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in

  View details for DOI 10.1038/leu.2008.221

  View details for Web of Science ID 000261862200006

  View details for PubMedID 18754032

• A Phase 1 Trial of SNS-032, a Potent and Specific CDK 2, 7 and 9 Inhibitor in Chronic Lymphocytic Leukemia and Multiple Myeloma. 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Wierda, W. G., Chen, R., Plunkett, W., Coutre, S., Badros, A. Z., Popplewell, L., Siegel, D., Sinha, R., Harvey, D., Fox, J., Mahadocon, K., Kegley, P., Bolton, M. G. AMER SOC HEMATOLOGY. 2008: 1090–90

  View details for Web of Science ID 000262104703615

• Acute myeloid leukemia. Journal of the National Comprehensive Cancer Network O'Donnell, M. R., Appelbaum, F. R., Coutre, S. E., Damon, L. E., Erba, H. P., Foran, J., Lancet, J., Maness, L. J., Marcucci, G., Maslak, P. G., Millenson, M., Moore, J. O., Ravandi, F., Schuening, F., Shami, P., Smith, B. D., Stone, R. M., Tallman, M. S., Wang, E., White, F. L. 2008; 6 (10): 962-993

  View details for PubMedID 19176196

• Arsenic Trioxide Consolidation Improves Event-free and Overall Survival among Patients with Newly Diagnosed Acute Promyelocytic Leukemia: North American Intergroup Protocol C9710. ANNALS OF HEMATOLOGY Powell, B. L., Moser, B., Stock, W., Gallagher, R. E., Willman, C. L., Stone, R. M., Rowe, J. M., Coutre, S., Feusner, J. H., Gregory, J., Couban, S., Appelbaum, F. R., Tallman, M. S., Larson, R. A. 2008; 87: S77-S78

  View details for Web of Science ID 000209024100027

• Acute postoperative thrombotic thrombocytopenic purpura following hysterectomy and lymphadenectomy for endometrial cancer GYNECOLOGIC ONCOLOGY Hamilton, C. A., Kao, J. M., Coutre, S. E., Teng, N. N. 2007; 106 (2): 423-426

  Abstract

  Thrombotic thrombocytopenic purpura (TTP) in the acute postoperative setting is a recently recognized syndrome that, similar to classic or idiopathic TTP, presents variably with microangiopathic hemolytic anemia, thrombocytopenia, fever, renal failure, and mental status changes. Though most reports of postoperative TTP are in conjunction with cardiac or vascular surgery, it has also been reported following orthopedic and abdominal surgeries.We present a case of a 53 year-old female diagnosed with metastatic poorly differentiated endometrial cancer who developed TTP the day following her cytoreductive cancer surgery.To our knowledge, this represents the first reported case of postoperative TTP following gynecologic cancer surgery. Because the presentation can be confused with other early postoperative complications, awareness of this syndrome is essential as initiation of plasmapheresis can be life-saving.

  View details for DOI 10.1016/j.ygyno.2007.04.005

  View details for Web of Science ID 000248585700023

  View details for PubMedID 17499845

• International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia LEUKEMIA Rawstron, A. C., Villamor, N., Ritgen, M., Boettcher, S., Ghia, P., Zehnder, J. L., Lozanski, G., Colomer, D., Moreno, C., Geuna, M., Evans, P. A., Natkunam, Y., Coutre, S. E., Avery, E. D., Rassenti, L. Z., Kipps, T. J., Caligaris-Cappio, F., Kneba, M., Byrd, J. C., Hallek, M. J., Montserrat, E., Hillmen, P. 2007; 21 (5): 956-964

  Abstract

  The eradication of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) predicts for improved outcome. However, the wide variety of MRD techniques makes it difficult to interpret and compare different clinical trials. Our aim was to develop a standardized flow cytometric CLL-MRD assay and compare it to real-time quantitative allele-specific oligonucleotide (RQ-ASO) Immunoglobulin heavy chain gene (IgH) polymerase chain reaction (PCR). Analysis of 728 paired blood and marrow samples demonstrated high concordance (87%) for patients off-therapy. Blood analysis was equally or more sensitive than marrow in 92% of samples but marrow analysis was necessary to detect MRD within 3 months of alemtuzumab therapy. Assessment of 50 CLL-specific antibody combinations identified three (CD5/CD19 with CD20/CD38, CD81/CD22 and CD79b/CD43) with low inter-laboratory variation and false-detection rates. Experienced operators demonstrated an accuracy of 95.7% (specificity 98.8%, sensitivity 91.1%) in 141 samples with 0.01-0.1% CLL. There was close correlation and 95% concordance with RQ-ASO IgH-PCR for detection of CLL above 0.01%. The proposed flow cytometry approach is applicable to all sample types and therapeutic regimes, and sufficiently rapid and sensitive to guide therapy to an MRD-negativity in real time. These techniques may be used as a tool for assessing response and comparing the efficacy of different therapeutic approaches.

  View details for DOI 10.1038/sj.leu.2404584

  View details for Web of Science ID 000245999900014

  View details for PubMedID 17361231

• Von Willebrand disease presenting as recurrent hemorrhage after transvaginal oocyte retrieval AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Moayeri, S. E., Coutre, S. E., Ramirez, E. J., Westphal, L. M. 2007; 196 (4)

  Abstract

  A 34-year-old nulligravid woman experienced hemorrhage after each of 2 oocyte retrievals. Initial coagulopathy screening was negative. Treatments used during in vitro fertilization likely interfered with assay performance. Reevaluation remote from medications confirmed the diagnosis of von Willebrand disease. Treatments used during in vitro fertilization may increase bleeding risk and confound coagulopathy evaluation.

  View details for DOI 10.1016/j.ajog.2007.01.025

  View details for Web of Science ID 000245747600063

  View details for PubMedID 17403383

• Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime? BRITISH JOURNAL OF HAEMATOLOGY Nabhan, C., Coutre, S., Hillmen, P. 2007; 136 (3): 379-392

  Abstract

  New therapeutic modalities have substantially improved response rates and outcomes in chronic lymphocytic leukaemia (CLL), yet the mindset remains that palliation is the only goal of therapy because the disease is considered incurable. Ultimately, all patients relapse despite achieving an initial response, as minimal residual disease (MRD) persisting after therapy eventually evolves into morphological and clinical recurrence. The emergence of immune-based combination therapies capable of inducing molecular remissions, the availability of highly sensitive assays that detect MRD, and emerging data showing a longer duration of response or longer survival in patients with no detectable disease, suggest that eradicating MRD may be a reasonable option for some patients. Moreover, novel biological prognostic markers have divided CLL into favourable and unfavourable subtypes, arguing in favour of defining different goals of therapy for different patients. Clinicians are increasingly challenged with the task of how best to incorporate MRD assessment into clinical practice, especially in an era when these novel prognostic factors exist. This review summarises the current understanding of MRD from a clinical standpoint, suggests that MRD eradication maybe a reasonable option for some patients, and argues in favour of designing large randomised studies to determine whether MRD-negative remission improves outcome.

  View details for DOI 10.1111/j.1365-2141.2006.06428.x

  View details for Web of Science ID 000244038800003

  View details for PubMedID 17129223

• Refractory hematuria from amyloidosis successfully treated by splenectomy UROLOGY Ma, J. F., Coutre, S. E., Curet, M. J., Brooks, J. D. 2006; 67 (5)

  Abstract

  Systemic amyloidosis can result in a coagulopathy that is associated with low levels of factor X. We present a case of intractable, life-threatening hematuria that was successfully managed with activated recombinant human factor VII and splenectomy.

  View details for DOI 10.1016/j.urology.2005.11.048

  View details for Web of Science ID 000238390800059

  View details for PubMedID 16698382

• Acute myeloid leukemia clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network O'Donnell, M. R., Appelbaum, F. R., Baer, M. R., Byrd, J. C., Coutre, S. E., Damon, L. E., Erba, H. P., Estey, E., Foran, J., Lancet, J., Maness, L. J., Maslak, P. G., Millenson, M., Moore, J. O., Przepiorka, D., Shami, P., Smith, B. D., Stone, R. M., Tallman, M. S. 2006; 4 (1): 16-36

  View details for PubMedID 16403402

• The evolving role of alemtuzumab in management of patients with CLL LEUKEMIA Faderl, S., Coutre, S., Byrd, J. C., Dearden, C., Denes, A., Dyer, M. J., Gregory, S. A., Gribben, J. G., Hillmen, P., Keating, M., Rosen, S., Venugopal, P., Rai, K. 2005; 19 (12): 2147-2152

  Abstract

  New insights into prognostic markers and the pathophysiology of chronic lymphocytic leukemia (CLL) are beginning to change the concept of CLL treatment. Alemtuzumab has evolved as a potent and effective therapeutic option for patients with CLL. Specifically, alemtuzumab has demonstrated substantial efficacy in fludarabine-refractory patients and has shown impressive responses when administered subcutaneously in first-line therapy. A group of experts gathered to discuss new data related to the use of alemtuzumab in CLL and to assess its place in the rapidly changing approach to treating patients with this disease. The main goals of this program were to update the management guidelines that were previously developed for alemtuzumab-treated patients and to provide community oncologists with guidance on the most effective way to integrate alemtuzumab into a CLL treatment plan.

  View details for DOI 10.1038/sj.leu.2403984

  View details for Web of Science ID 000233462300015

  View details for PubMedID 16239912

• Molecular progenitor profiling in human myeloproliferative disorders. 47th Annual Meeting of the American-Society-of-Hematology Jamieson, C. H., Gotlib, J., Chao, M., Mariappan, M. R., LayRaj, M., Jones, C., Zehnder, J., Durocher, J., Lilleberg, S., Coutre, S., Weissman, I. L. AMER SOC HEMATOLOGY. 2005: 38A–39A

  View details for Web of Science ID 000233426000119

• Prognostic progenitor profiling in chronic myelomonocytic leukemia Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-International-Blood-and-Marrow-Transplant-Research Jamieson, C. H., Li, K., Gotlib, J., Coutre, S. E., Lagasse, E., Weissman, I. L. ELSEVIER SCIENCE INC. 2005: 59–59

  View details for Web of Science ID 000227329000175

• Predictive progenitor profiling in chronic myelomonocytic leukemia. 46th Annual Meeting of the American-Society-of-Hematology Jamieson, C., Gotlib, J., Coutre, S., Li, K., Weissman, I. AMER SOC HEMATOLOGY. 2004: 268B–268B

  View details for Web of Science ID 000225127701065

• Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial BLOOD McCullough, J., Vesole, D. H., Benjamin, R. J., Slichter, S. J., Pineda, A., Snyder, E., Stadtmauer, E. A., Lopez-Plaza, I., Coutre, S., Strauss, R. G., GOODNOUGH, L. T., Fridey, J. L., Raife, T., Cable, R., Murphy, S., Howard, F., Davis, K., Lin, J. S., Metzel, P., Corash, L., Koutsoukos, A., Lin, L., Buchholz, D. H., Conlan, M. G. 2004; 104 (5): 1534-1541

  Abstract

  We report a transfusion trial of platelets photochemically treated for pathogen inactivation using the synthetic psoralen amotosalen HCl. Patients with thrombocytopenia were randomly assigned to receive either photochemically treated (PCT) or conventional (control) platelets for up to 28 days. The primary end point was the proportion of patients with World Health Organization (WHO) grade 2 bleeding during the period of platelet support. A total of 645 patients (318 PCT and 327 control) were evaluated. The primary end point, the incidence of grade 2 bleeding (58.5% PCT versus 57.5% control), and the secondary end point, the incidence of grade 3 or 4 bleeding (4.1% PCT versus 6.1% control), were equivalent between the 2 groups (P =.001 by noninferiority). The mean 1-hour posttransfusion platelet corrected count increment (CCI) (11.1 x 10(3) PCT versus 16.0 x 10(3) control), average number of days to next platelet transfusion (1.9 PCT versus 2.4 control), and number of platelet transfusions (8.4 PCT versus 6.2 control) were different (P <.001). Transfusion reactions were fewer following PCT platelets (3.0% PCT versus 4.4% control; P =.02). The incidence of grade 2 bleeding was equivalent for PCT and conventional platelets, although posttransfusion platelet count increments and days to next transfusion were decreased for PCT compared with conventional platelets.

  View details for Web of Science ID 000223544000052

  View details for PubMedID 15138160

• Management guidelines for use of alemtuzumab in B-Cell chronic lymphocytic leukemia CLINICAL LYMPHOMA Keating, M., Coutre, S., Rai, K., Osterborg, A., Faderl, S., Kennedy, B., Kipps, T., Bodey, G., Byrd, J. C., Rosen, S., Dearden, C., Dyer, M. J., Hillmen, P. 2004; 4 (4): 220-227

  Abstract

  An expert opinion roundtable held August 8-9, 2002, brought together clinicians with the most extensive experience with the use of alemtuzumab to pool knowledge and develop treatment goals and guidelines for optimal therapy. By sharing our collective experience, we have been able to formulate recommendations for current clinical practice, which are included in this report, and have emphasized results that have implications for future practice. Guidelines for the management of acute "first-dose" events, prophylaxis for infection, detection and treatment of cytomegalovirus reactivation, and hematologic support are presented, with emphasis on allowing patients to proceed smoothly through therapy while maximizing therapeutic benefit. Management of adverse events is facilitated by the predictable timing of their appearance. In general, hematologic adverse events are transient, manageable, and reversible. Clinicians should be cautious of prematurely terminating treatment at 4-6 weeks in patients whose disease responds to treatment. Although resolution of peripheral blood lymphocytosis occurs early in most patients, bone marrow is unlikely to be clear of disease. In particular, grade 4 neutropenia at this time is common and, because it is manageable, it is not an indication to discontinue treatment. The eradication of minimal residual disease from blood and bone marrow observed with alemtuzumab therapy is a major step forward in the treatment of B-cell chronic lymphocytic leukemia. Combination therapies such as alemtuzumab/fludarabine with the potential to maximize eradication at all disease sites should be systematically investigated. Because high response rates and few complications are observed in previously untreated patients, the use of alemtuzumab earlier in therapy may provide optimum benefit to patients.

  View details for Web of Science ID 000220780700005

  View details for PubMedID 15072613

• Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate SEMINARS IN CANCER BIOLOGY Coutre, S., Gotlib, J. 2004; 14 (1): 23-31

  Abstract

  Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.

  View details for DOI 10.1016/j.semcancer.2003.11.004

  View details for Web of Science ID 000189081200004

  View details for PubMedID 14757533

• PKC412, inhibitor of the KIT tyrosine kinase, demonstrates efficacy in mast cell leukemia with the D816V KIT mutation. 45th Annual Meeting and Exhibition of the American-Society-of-Hematology Gotlib, J., Berube, C., Ruan, J., Growney, J., Dugan, K., Falkow, R., Rosamilia, M., Resta, D., Cohen, P., Fabbro, D., Heinrich, M., Gilliland, D. G., Coutre, S. AMER SOC HEMATOLOGY. 2003: 919A–919A

  View details for Web of Science ID 000186536703420

• PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFR alpha-induced myeloproliferative disease CANCER CELL Cools, J., Stover, E. H., Boulton, C. L., Gotlib, J., Legare, R. D., Amaral, S. M., Curley, D. P., Duclos, N., Rowan, R., Kutok, J. L., Lee, B. H., Williams, I. R., Coutre, S. E., Stone, R. M., DeAngelo, D. J., Marynen, P., Manley, P. W., Meyer, T., Fabbro, D., Neuberg, D., Weisberg, E., GRIFFIN, J. D., Gilliland, D. G. 2003; 3 (5): 459-469

  Abstract

  FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.

  View details for Web of Science ID 000183104800009

  View details for PubMedID 12781364

• T-cell prolymphocytic leukemia: update and focus on alemtuzumab (Campath-1H). Hematology Cao, T. M., Coutre, S. E. 2003; 8 (1): 1-6

  Abstract

  T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell lymphoproliferative disorder. While the etiology of T-PLL is unknown, recent progress in unraveling the molecular basis of leukemogenesis has been substantial and may yield novel therapeutic targets. T-PLL is a distinct disease entity and the diagnosis can be readily made based on characteristic clinical features and laboratory findings. Prior to the appearance of pentostatin and alemtuzumab in clinical protocols, outcome for T-PLL patients was exceedingly poor with median survival measured in months. While the use of alemtuzumab in particular has improved remissions, the disease remains incurable. Future collaborative efforts investigating novel treatment approaches will be crucial to improving survival for patients with this disease.

  View details for PubMedID 12623420

• Management of advanced chronic lymphocytic leukemia. Current hematology reports Cao, T. M., Coutre, S. E. 2003; 2 (1): 65-72

  Abstract

  Chronic lymphocytic leukemia (CLL) is generally considered to be incurable. It is the most common of the adult leukemias, and many patients are asymptomatic when diagnosed. Most patients survive for several years, and some never require treatment for their disease, leading to the belief that it is an indolent disease. However, this view is changing with the introduction of more effective therapies. Purine nucleoside analogs have become standard in the therapy of most patients. Monoclonal antibodies including alemtuzumab (Campath-IH; Berlex Laboratories, Richmond, CA) and rituximab are playing an increasingly important role in the treatment of patients with advanced disease. Clinical trials will be crucial in defining how and when to treat patients with CLL and will help establish the role of newer prognostic markers and more sensitive methodologies to detect minimal residual disease.

  View details for PubMedID 12901156

• Cytomegalovirus viremia during Campath-1H therapy for relapsed and refractory chronic lymphocytic leukemia and prolymphocytic leukemia CLINICAL LYMPHOMA Nguyen, D. D., Cao, T. M., Dugan, K., Starcher, S. A., Fechter, R. L., Coutre, S. E. 2002; 3 (2): 105-110

  Abstract

  Campath-1H is effective therapy for patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (PLL), but it is associated with profound lymphopenia and deficiencies in cell-mediated immunity. We report the incidence of cytomegalovirus (CMV) viremia in 34 patients treated with Campath-1H for relapsed or refractory CLL and PLL. All patients received infection prophylaxis during therapy and continuing for at least 2 months following Campath-1H. Five patients (15%) developed CMV viremia at a median of 28 days (range, 20-30 days) after the first dose of Campath-1H. The median CMV viral load was 860/mL (range, 420-2100/mL), as determined by quantitative plasma polymerase chain reaction (PCR). All 5 patients had a temperature > 38.5 degrees C, normal chest radiographs, normal liver function tests, and negative bacterial blood cultures with no clinical evidence of CMV disease at the time of presentation with CMV viremia. The median absolute neutrophil count (ANC) was 740/ microL (range, 340-1600/ microL), and the median absolute lymphocyte count (ALC) was 16/microL (range, 11-169/ microL) for the 5 patients at the time of CMV viremia. All 5 patients received ganciclovir therapy followed by prompt fever resolution and clearance of CMV viremia by plasma PCR. By univariate regression analysis, the following were not risk factors for CMV viremia: age, number of prior regimens, prior rituximab therapy, prior splenectomy, modified Rai stage at Campath-1H therapy (low/intermediate vs. high), ANC, and ALC; although, there was a trend towards significance for prior rituximab therapy (P = 0.07). Cytomegalovirus viremia may be a significant infectious complication during Campath-1H therapy and should be investigated further in future studies.

  View details for Web of Science ID 000178917700006

  View details for PubMedID 12435283

• Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study 43rd Annual Meeting of the American-Society-of-Hematology Sawyers, C. L., Hochhaus, A., Feldman, E., Goldman, J. M., Miller, C. B., Ottmann, O. G., Schiffer, C. A., Talpaz, M., Guilhot, F., Deininger, M. W., Fischer, T., O'Brien, S. G., Stone, R. M., Gambacorti-Passerini, C. B., Russell, N. H., Reiffers, J. J., Shea, T. C., Chapuis, B., Coutre, S., TURA, S., Morra, E., Larson, R. A., Saven, A., Peschel, C., Gratwohl, A., MANDELLI, F., Ben-Am, M., Gathmann, I., Capdeville, R., Paquette, R. L., Druker, B. J. AMER SOC HEMATOLOGY. 2002: 3530–39

  Abstract

  Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.

  View details for Web of Science ID 000175496300010

  View details for PubMedID 11986204

• Pilot study of I-131-tositumomab in advanced, previously treated, refractory chronic lymphocytic leukemia. Palestro, C. J., Gupta, N. K., Cao, T. M., French, J. N., Goris, M. L., Capizi, R., Califano, J., Rai, K. R., Coutre, S. E. SOC NUCLEAR MEDICINE INC. 2002: 312P–312P

  View details for Web of Science ID 000175560801166

• Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed JOURNAL OF CLINICAL ONCOLOGY Keating, M. J., Cazin, B., Coutre, S., Birhiray, R., Kovacsovics, T., Langer, W., Leber, B., Maughan, T., Rai, K., Tjonnfjord, G., Bekradda, M., Itzhaki, M., Herait, P. 2002; 20 (1): 205-213

  Abstract

  We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program.Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks.Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H-related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred.Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.

  View details for Web of Science ID 000173231900027

  View details for PubMedID 11773171

• Real-time PCR assay for quantitation of BCR-ABL mRNA in patients with chronic phase CML treated with the tyrosine kinase inhibitor GLEEVEC (TM) (STI-571). Gotlib, J., Jones, C. D., Zheng, K. H., Yeung, C., Dugan, K., Fechter, L., Falkow, R., Zehnder, J. L., Coutre, S. AMER SOC HEMATOLOGY. 2001: 258B–259B

  View details for Web of Science ID 000172134201177

• Pilot study of Bexxar in advanced previously heavily treated refractory chronic lymphocytic leukemia (CLL). Gupta, N. K., Cao, T. M., French, J. N., Goris, M. L., Capizi, R., Califano, J., Palestro, C. J., Rai, K. R., Coutre, S. E. AMER SOC HEMATOLOGY. 2001: 290B–290B

  View details for Web of Science ID 000172134201315

• Campth-1H for relapsed/refractory chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (PLL): The Stanford University experience. Nguyen, D. D., Cao, T. M., Dugan, K., Starcher, S. A., Fechter, R. L., Coutre, S. E. AMER SOC HEMATOLOGY. 2001: 291B–291B

  View details for Web of Science ID 000172134201319

• Incidence of cytomegalovirus (CMV) viremia during Campath-1H therapy for relapsed/refractory chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (PLL). Cao, T. M., Nguyen, D. D., Dugan, K., Starcher, S. A., Fechter, R. L., Coutre, S. E. AMER SOC HEMATOLOGY. 2001: 366A–366A

  View details for Web of Science ID 000172134101544

• United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia 42nd Annual Meeting of the American-Society-of-Hematology Soignet, S. L., Frankel, S. R., Douer, D., Tallman, M. S., Kantarjian, H., Calleja, E., Stone, R. M., Kalaycio, M., Scheinberg, D. A., Steinherz, P., Sievers, E. L., Coutre, S., DAHLBERG, S., Ellison, R., Warrell, R. P. AMER SOC CLINICAL ONCOLOGY. 2001: 3852–60

  Abstract

  To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL).Forty patients experiencing first (n = 21) or > or = second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study.Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/microL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes.This study establishes ATO as a highly effective therapy for patients with relapsed APL.

  View details for Web of Science ID 000171043400009

  View details for PubMedID 11559723

• NCCN Practice Guidelines for acute myelogenous leukemia ONCOLOGY-NEW YORK O'Donnell, M. R., Appelbaum, F. R., Baer, M. R., Carabasi, M. H., Coutre, S. E., Erba, H. P., Estey, E., Glenn, M. J., Kraut, E. H., Maslak, P., Millenson, M., Miller, C. B., Saba, H. I., Stone, R., Tallman, M. S. 2000; 14 (11A): 53-61

  View details for Web of Science ID 000166713700004

  View details for PubMedID 11195419

• Chronic myelomonocytic leukemia: Demonstration of failed monocyte apoptosis as a pathogenic event in mouse and man Lagasse, E., Coutre, S. E., Weissman, I. L. ELSEVIER SCIENCE INC. 1998: 787–87

  View details for Web of Science ID 000075830600387

• CONVERSION OF THROMBIN INTO AN ANTICOAGULANT BY PROTEIN ENGINEERING NATURE Gibbs, C. S., Coutre, S. E., Tsiang, M., Li, W. X., Jain, A. K., Dunn, K. E., Law, V. S., Mao, C. T., MATSUMURA, S. Y., MEJZA, S. J., Paborsky, L. R., Leung, L. L. 1995; 378 (6555): 413-416

  Abstract

  At sites of vascular injury, thrombin interacts with multiple procoagulant substrates, to mediate both fibrin clotting and platelet aggregation. But upon binding to thrombomodulin on the vascular endothelium, thrombin instead activates protein C, thereby functioning as an anticoagulant and attenuating clot formation. Upon infusion in vivo, both the procoagulant and anticoagulant effects of thrombin were observed. Preliminary studies indicating that thrombin's protein C activating and fibrinogen clotting activities could be dissociated by mutagenesis suggested to us that a thrombin variant that lacked procoagulant activity while retaining anticoagulant function might be an attractive antithrombotic agent. Using protein engineering, we introduced a single substitution, E229A, that substantially shifted thrombin's specificity in favour of the anticoagulant substrate, protein C. In monkeys, this modified thrombin functioned as an endogenous protein C activator demonstrating dose-dependent, reversible anticoagulation without any indication of procoagulant activity. Notably, template bleeding times were not prolonged, suggesting a reduced potential for bleeding complications.

  View details for Web of Science ID A1995TF89300066

  View details for PubMedID 7477382

• Engineering thrombin to function as a selective anticoagulant by identification of a Glu to Lys mutation that converts thrombin into an exclusive protein C activator. Tsiang, M., Li, W. X., Jain, A. K., Mao, C. T., Dunn, K. E., MATSUMURA, S. Y., Coutre, S., Leung, L. L., Paborsky, L. R., Gibbs, C. S. AMER SOC HEMATOLOGY. 1995: 1779–79

  View details for Web of Science ID A1995TH91001781

• THROMBIN APTAMER AS AN ANTICOAGULANT FOR CANINE CARDIOPULMONARY BYPASS Coutre, S. E., Griffin, L. C., Moon, M. R., DeAnda, A., Law, V. S., Leung, L. L., Miller, D. C. SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN. 1993: 540–40

  View details for Web of Science ID A1993LT57700004