Peter Greenberg

All Publications

• Distinct Transcriptomic and Exomic Abnormalities Within Myelodysplastic Syndrome Marrow Cells Leukemia & Lymphoma Im, H., Rao, V., Sridhar, K., Bentley, J., Mishra, T., Chen, R., Hall, J., Graber, A., Zhang, Y., Xiao, L., Mias, G., Snyder, M. P., Greenberg, P. L. 2018: 1-11

  View details for DOI 10.1080/10428194.2018.1452210

• The Classical Nature of Distinctive CMML Monocytes Blood Greenberg, P. L. 2017; 129: 1745-1746
• Myelodysplastic Syndromes, Version 2.2017 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Greenberg, P. L., Stone, R. M., Al-Kali, A., Barta, S. K., Bejar, R., Bennett, J. M., Carraway, H., De Castro, C. M., Deeg, H. J., DeZern, A. E., Fathi, A. T., Frankfurt, O., Gaensler, K., Garcia-Manero, G., Griffiths, E. A., Head, D., Horsfall, R., Johnson, R. A., Juckett, M., Klimek, V. M., Komrokji, R., Kujawski, L. A., Maness, L. J., O'Donnell, M. R., Pollyea, D. A., Shami, P. J., Stein, B. L., Walker, A. R., Westervelt, P., Zeidan, A., Shead, D. A., Smith, C. 2017; 15 (1): 60-87

  Abstract

  The myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid disorders with a highly variable disease course. Diagnostic criteria to better stratify patients with MDS continue to evolve, based on morphology, cytogenetics, and the presence of cytopenias. More accurate classification of patients will allow for better treatment guidance. Treatment encompasses supportive care, treatment of anemia, low-intensity therapy, and high-intensity therapy. This portion of the guidelines focuses on diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches.

  View details for Web of Science ID 000392045900007

  View details for PubMedID 28040720

• The Impact of Somatic and Germline Mutations in MDS and Related Disorders J Nat Comp Canc Network Bejar, R., Greenberg, P. L. 2017; 15: 137-141
• Myelodysplastic Syndromes, Practice Guidelines, Version 2.2017 J Nat Compr Canc Netw Greenberg, P. L., Stone, R., Al Kali, A., et al 2017; 15: 60-87
• KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study. Leukemia research Swords, R. T., Greenberg, P. L., Wei, A. H., Durrant, S., Advani, A. S., Hertzberg, M. S., Lewis, I. D., Rivera, G., Gratzinger, D., Fan, A. C., Felsher, D. W., Cortes, J. E., Watts, J. M., Yarranton, G. T., Walling, J. M., Lancet, J. E. 2016; 50: 123-131

  Abstract

  EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.

  View details for DOI 10.1016/j.leukres.2016.09.012

  View details for PubMedID 27736729

• Efficacy and safety of darbepoetin alpha in patients with myelodysplastic syndromes: a systematic review and meta-analysis BRITISH JOURNAL OF HAEMATOLOGY Park, S., Fenaux, P., Greenberg, P., Mehta, B., Callaghan, F., Kim, C., Tomita, D., Xu, H. 2016; 174 (5): 730-747

  Abstract

  We conducted a systematic review and meta-analysis to estimate the efficacy of darbepoetin alpha (DA) for treatment of myelodysplastic syndrome (MDS)-related anaemia. Eligible studies were prospective, interventional, and reported World Health Organization, French-American-British, or International Prognostic Scoring System (IPSS) criteria. Outcomes included erythroid response rate (primary); haemoglobin response; change in haemoglobin, transfusion status, and quality-of-life (QoL); and safety. Ten studies (N = 647) were analysed. Erythroid response rate range was 38-72%; median response duration range was 12-51+ months. Patients with erythropoietin (EPO) <100 iu/l had 35% [95% confidence interval (CI): 22-48%; P < 0·001) better response than patients with EPO >100 iu/l. Erythropoesis-stimulating agent (ESA)-naïve patients had 17% (95% CI: 3-32%; P = 0·022) greater response rate than those previously treated with ESA. Nonetheless, previously treated patients had response rates of 25-75%. Higher baseline haemoglobin levels, higher dose, transfusion-independence and low-risk IPSS status were reported by several studies to be associated with better response. QoL, transfusion rates and haemoglobin levels improved with treatment. Hypertension, thromboembolism and progression to acute myeloid leukaemia were reported in 2%, 1% and 1% of patients, respectively. This meta-analysis suggests that DA treatment can be useful for improving erythroid response in MDS patients with anaemia, even among patients previously treated with ESA.

  View details for DOI 10.1111/bjh.14116

  View details for Web of Science ID 000383775200010

  View details for PubMedID 27214305

• Time-dependent changes in mortality and transformation risk in MDS. Blood Pfeilstöcker, M., Tuechler, H., Sanz, G., Schanz, J., Garcia-Manero, G., Solé, F., Bennett, J. M., Bowen, D., Fenaux, P., Dreyfus, F., Kantarjian, H., Kuendgen, A., Malcovati, L., Cazzola, M., Cermak, J., Fonatsch, C., Le Beau, M. M., Slovak, M. L., Levis, A., Luebbert, M., Maciejewski, J., Machherndl-Spandl, S., Magalhaes, S. M., Miyazaki, Y., Sekeres, M. A., Sperr, W. R., Stauder, R., Tauro, S., Valent, P., Vallespi, T., van de Loosdrecht, A. A., Germing, U., Haase, D., Greenberg, P. L. 2016; 128 (7): 902-910

  Abstract

  In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. Hazards regarding mortality and acute myeloid leukemia transformation diminished over time from diagnosis in higher-risk MDS patients, whereas they remained stable in lower-risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and were essentially equivalent after 5 years. This fact led to loss of prognostic power of different scoring systems considered, which was more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management, the differing development of risks suggested a reasonable division into lower- and higher-risk MDS based on the IPSS-R at a cutoff of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower-risk patients at diagnosis remain lower risk whereas initially high-risk patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making.

  View details for DOI 10.1182/blood-2016-02-700054

  View details for PubMedID 27335276

• Cytopenia levels for aiding establishment of the diagnosis of myelodysplastic syndromes. Blood Greenberg, P. L., Tuechler, H., Schanz, J., Sanz, G., Garcia-Manero, G., Solé, F., Bennett, J. M., Bowen, D., Fenaux, P., Dreyfus, F., Kantarjian, H., Kuendgen, A., Levis, A., Malcovati, L., Cazzola, M., Cermak, J., Fonatsch, C., Le Beau, M. M., Slovak, M. L., Krieger, O., Luebbert, M., Maciejewski, J., Magalhaes, S. M., Miyazaki, Y., Pfeilstöcker, M., Sekeres, M., Sperr, W. R., Stauder, R., Tauro, S., Valent, P., Vallespi, T., van de Loosdrecht, A. A., Germing, U., Haase, D. 2016

  View details for PubMedID 27535995

• Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial LANCET ONCOLOGY Garcia-Manero, G., Fenaux, P., Al-Kali, A., Baer, M. R., Sekeres, M. A., Roboz, G. J., Gaidano, G., Scott, B. L., Greenberg, P., Platzbecker, U., Steensma, D. P., Kambhampati, S., Kreuzer, K., Godley, L. A., Atallah, E., Collins, R., Kantarjian, H., Jabbour, E., Wilhelm, F. E., Azarnia, N., Silverman, L. R. 2016; 17 (4): 496-508

  Abstract

  Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment.We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500.From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9-27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1-10·1) in the rigosertib group and 5·9 months (4·1-9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67-1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment.Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria.Onconova Therapeutics, Leukemia & Lymphoma Society.

  View details for DOI 10.1016/S1470-2045(16)00009-7

  View details for Web of Science ID 000373497600050

  View details for PubMedID 26968357

• 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

  View details for DOI 10.3109/10428194.2015.1091930

  View details for Web of Science ID 000372499800017

• The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I. Clinical cancer research Maxson, J. E., Luty, S. B., Macmaniman, J. D., Paik, J. C., Gotlib, J., Greenberg, P., Bahamadi, S., Savage, S. L., Abel, M. L., Eide, C. A., Loriaux, M. M., Stevens, E. A., Tyner, J. W. 2016; 22 (3): 757-764

  Abstract

  Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in the majority of chronic neutrophilic leukemia (CNL) and a smaller percentage of atypical chronic myeloid leukemia (aCML) cases. Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. In this study, we assess the importance of the CSF3R T640N mutation as a marker of CNL/aCML and potential therapeutic target.Sanger sequencing of leukemia samples was performed to identify CSF3R mutations in CNL and aCML. The oncogenicity of the CSF3R T640N mutation relative to the T618I mutation was assessed by cytokine independent growth assays and by mouse bone marrow transplant. Receptor dimerization and O-glycosylation of the mutants was assessed by Western blot, and JAK inhibitor sensitivity was assessed by colony assay.Here, we identify a CSF3R T640N mutation in two patients with CNL/aCML, one of whom was originally diagnosed with MDS and acquired the T640N mutation upon evolution of disease to aCML. The T640N mutation is oncogenic in cellular transformation assays and an in vivo mouse bone marrow transplantation model. It exhibits many similar phenotypic features to T618I, including ligand independence and altered patterns of O-glycosylation-despite the transmembrane location of T640 preventing access by GalNAc transferase enzymes. Cells transformed by the T640N mutation are sensitive to JAK kinase inhibition to a similar degree as cells transformed by CSF3R T618I.Because of its similarities to CSF3R T618I, the T640N mutation likely has diagnostic and therapeutic relevance in CNL/aCML. Clin Cancer Res; 1-8. ©2015 AACR.

  View details for DOI 10.1158/1078-0432.CCR-14-3100

  View details for PubMedID 26475333

• Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study. British journal of haematology Prebet, T., Sun, Z., Ketterling, R. P., Zeidan, A., Greenberg, P., Herman, J., Juckett, M., Smith, M. R., Malick, L., Paietta, E., Czader, M., Figueroa, M., Gabrilove, J., Erba, H. P., Tallman, M. S., Litzow, M., Gore, S. D. 2016; 172 (3): 384-391

  Abstract

  Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4 mg/m(2) /d PO day-3 and day-10). A total of 47 patients [29 therapy-related myelosyspastic syndrome (t-MDS) and 18 therapy-related acute myeloid leukaemia (t-AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0·008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.

  View details for DOI 10.1111/bjh.13832

  View details for PubMedID 26577691

• KB004, a First-in-Class Monoclonal Antibody Targeting the Receptor Tyrosine Kinase EphA3 in Patients with Advanced Hematologic Malignancies: Results from a Phase 1 study. Leukemia Research Swords, R. T., Greenberg, P. L., et al 2016; 50: 123-131
• Cytopenia Levels for Aiding Establishment of the Diagnosis of Myelodysplastic Syndromes Blood Greenberg, P. L., Tuechler, H., et al 2016; 128 (16): 2096
• Immune checkpoint pathways: perspectives on myeloid malignancies LEUKEMIA & LYMPHOMA Rivera, G. A., Behbahan, I. S., Greenberg, P. L. 2016; 57 (5): 995-1001

  Abstract

  Immunologic tolerance to cancer has recently been shown to have major implications for the ability of tumors to survive despite a variety of therapeutic approaches. A critical mechanism underlying this microenvironment dysfunction relates to the ability of tumor cells to block immune check points through expression of specific proteins that interfere with immune cell effector function. Recent advances based on this model have led translational work showing therapeutic efficacy in a variety of solid and lymphoid tumors. Myeloid malignancies, in particular myelodysplastic syndromes (MDS), have significant immune dysregulation of variable degree based on their clinical stages which makes feasible extending such therapeutic approaches to this group of diseases. This review will discuss recent advances in the field of immune checkpoint biology including recent clinical trials with checkpoint inhibitors in patients with a variety of clinical conditions, with focus on such potential therapy in patients with myeloid malignancies.

  View details for DOI 10.3109/10428194.2015.1107554

  View details for Web of Science ID 000375027000006

  View details for PubMedID 26916355

• Frequency of del(12p) is Commonly Underestimated in Myelodysplastic Syndromes: Results from a German Diagnostic Study in Comparison with an International Control Group GENES CHROMOSOMES & CANCER Braulke, F., Mueller-Thomas, C., Goetze, K., Platzbecker, U., Germing, U., Hofmann, W., Giagounidis, A. A., Luebbert, M., Greenberg, P. L., Bennett, J. M., Sole, F., Slovak, M. L., Ohyashiki, K., Le Beau, M. M., Tuechler, H., Pfeilstoecker, M., Hildebrandt, B., Aul, C., Stauder, R., Valent, P., Fonatsch, C., Bacher, U., Truemper, L., Haase, D., Schanz, J. 2015; 54 (12): 809-817

  View details for DOI 10.1002/gcc.22292

  View details for Web of Science ID 000365405700010

  View details for PubMedID 26355708

• Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial LANCET HAEMATOLOGY Platzbecker, U., Wong, R. S., Verma, A., Abboud, C., Araujo, S., Chiou, T., Feigert, J., Yeh, S., Goetze, K., Gorin, N., Greenberg, P., Kambhampati, S., Kim, Y., Lee, J., Lyons, R., Ruggeri, M., Santini, V., Cheng, G., Jang, J. H., Chen, C., Johnson, B., Bennett, J., Mannino, F., Kamel, Y. M., Stone, N., Dougherty, S., Chan, G., Giagounidis, A. 2015; 2 (10): E417-E426

  View details for Web of Science ID 000362075400012

• Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM). Leukemia Della Porta, M. G., Tuechler, H., Malcovati, L., Schanz, J., Sanz, G., Garcia-Manero, G., Solé, F., Bennett, J. M., Bowen, D., Fenaux, P., Dreyfus, F., Kantarjian, H., Kuendgen, A., Levis, A., Cermak, J., Fonatsch, C., Le Beau, M. M., Slovak, M. L., Krieger, O., Luebbert, M., Maciejewski, J., Magalhaes, S. M., Miyazaki, Y., Pfeilstöcker, M., Sekeres, M. A., Sperr, W. R., Stauder, R., Tauro, S., Valent, P., Vallespi, T., van de Loosdrecht, A. A., Germing, U., Haase, D., Greenberg, P. L., Cazzola, M. 2015; 29 (7): 1502-1513

  Abstract

  A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the World Health Organization (WHO)-classification-based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features, and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that the WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS with the IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS versus IPSS-R model. Overall, both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant in formation for the implementation of risk-adapted strategies in MDS.

  View details for DOI 10.1038/leu.2015.55

  View details for PubMedID 25721895

• Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy HEMATOLOGICAL ONCOLOGY Silverman, L. R., Greenberg, P., Raza, A., Olnes, M. J., Holland, J. F., Reddy, P., Maniar, M., Wilhelm, F. 2015; 33 (2): 57-66

  Abstract

  Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System. Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts. One patient with a complete bone marrow response also achieved a complete cytogenetic response. A second patient with stable bone marrow blasts achieved a partial cytogenetic response. Two of the responding patients and three patients with stable disease had hematological improvements. Rigosertib-induced bone marrow blast decreases and stability appeared to be predictive of prolonged survival. IV rigosertib had a favorable safety profile without significant myelosuppression. Most common drug-related toxicities included fatigue, diarrhea, nausea, dysuria, and hematuria. In summary, IV rigosertib is well tolerated and has clinical activity in patients with higher risk MDS following DNMT inhibitor treatment. A multinational pivotal phase 3 randomized clinical trial of rigosertib versus best supportive care for patients with MDS with excess blasts following prior treatment with DNMT inhibitors (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE) has recently completed enrollment. © 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

  View details for DOI 10.1002/hon.2137

  View details for Web of Science ID 000356335700001

  View details for PubMedID 24777753

• MDS prognostic scoring systems - Past, present, and future BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY Jonas, B. A., Greenberg, P. L. 2015; 28 (1): 3-13

  Abstract

  The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid haemopathies characterized by defective differentiation of haematopoietic cells and expansion of the abnormal clone. This leads to bone marrow failure with the resulting peripheral blood cytopenias and evolution to or toward acute myeloid leukaemia that characterize MDS clinically. The clinical heterogeneity of MDS has led several groups to analyze patient and clinical characteristics to develop prognostic scoring systems yielding estimates of overall and leukaemia-free survival to guide clinical decision-making. These models have evolved over time as our understanding of the pathogenesis, natural history, and treatment of MDS has improved. Rapid advances in flow cytometric analysis, adjuncts to standard metaphase cytogenetics, and gene mutation analysis are revolutionizing our understanding of MDS pathogenesis and prognosis. Despite the existence of multiple well-validated prognostic scoring systems, further refinements of current models with these new sources of prognostic data are needed and are described herein.

  View details for DOI 10.1016/j.beha.2014.11.001

  View details for Web of Science ID 000350186600002

  View details for PubMedID 25659725

• Myelodysplastic Syndromes, Version 2.2015 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Greenberg, P. L., Stone, R. M., Bejar, R., Bennett, J. M., Bloomfield, C. D., Borate, U., De Castro, C. M., Deeg, H. J., DeZern, A. E., Fathi, A. T., Frankfurt, O., Gaensler, K., Garcia-Manero, G., Griffiths, E. A., Head, D., Klimek, V., Komrokji, R., Kujawski, L. A., Maness, L. J., O'Donnell, M. R., Pollyea, D. A., Scott, B., Shami, P. J., Stein, B. L., Westervelt, P., Wheeler, B., Shead, D. A., Smith, C. 2015; 13 (3): 261-272

  Abstract

  The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care.

  View details for Web of Science ID 000350781700004

  View details for PubMedID 25736003

• Validation of cytogenetic risk groups according to International Prognostic Scoring Systems by peripheral blood CD34(+)FISH:results from a German diagnostic study in comparison with an international control group HAEMATOLOGICA Braulke, F., Platzbecker, U., Mueller-Thomas, C., Goetze, K., Germing, U., Bruemmendorf, T. H., Nolte, F., Hofmann, W., Giagounidis, A. A., Luebbert, M., Greenberg, P. L., Bennett, J. M., Sole, F., Mallo, M., Slovak, M. L., Ohyashiki, K., Le Beau, M. M., Tuechler, H., Pfeilstoecker, M., Noesslinger, T., Hildebrandt, B., Shirneshan, K., Aul, C., Stauder, R., Sperr, W. R., Valent, P., Fonatsch, C., Truemper, L., Haase, D., Schanz, J. 2015; 100 (2): 205-213

  Abstract

  International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%-20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34(+)) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34(+) peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34(+) blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913).

  View details for Web of Science ID 000351278900018

  View details for PubMedID 25344522

• Synergistic Interactions of Molecular and Clinical Advances for Characterizing the Myelodysplastic Syndromes J Nat Compr Canc Network Greenberg, P. L. 2015; 13 (7): 829-832
• Mesenchymal stromal cell density is increased in higher grade myelodysplastic syndromes and independently predicts survival. American journal of clinical pathology Johnson, R. C., Kurzer, J. H., Greenberg, P. L., Gratzinger, D. 2014; 142 (6): 795-802

  Abstract

  We retrospectively tested the prognostic and diagnostic significance of CD271+ mesenchymal stromal cell (MSC) density in cytopenic patients who underwent bone marrow biopsy to evaluate for myelodysplastic syndromes (MDS).CD271+ MSC density was quantitated by automated image analysis of tissue microarray cores in 125 cytopenic patients: 40 lower grade MDS (<5% marrow blasts), 24 higher grade MDS, and 61 benign.CD271+ MSC density was increased in higher grade MDS compared with benign (P = .006) and lower grade MDS (P = .02). CD271+ MSC density was predictive of survival among patients with MDS independent of Revised International Prognostic Scoring System (IPSS-R), history of transfusion, therapy-related MDS, and fibrosis (hazard ratio, 3.4; P < .001). Among low or intermediate IPSS-R patients, median survival was significantly shorter in the high CD271+ MSC density group (47 vs 18 months, P < .02).High CD271+ MSC density is characteristic of higher grade MDS and is associated with poor risk independent of known prognostic factors.

  View details for DOI 10.1309/AJCP71OPHKOTLSUG

  View details for PubMedID 25389333

• Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS BRITISH JOURNAL OF HAEMATOLOGY Zeidan, A. M., Lee, J., Prebet, T., Greenberg, P., Sun, Z., Juckett, M., Smith, M. R., Paietta, E., Gabrilove, J., Erba, H. P., Katterling, R. P., Tallman, M. S., Gore, S. D. 2014; 167 (1): 62-68

  View details for DOI 10.1111/bjh.13008

  View details for Web of Science ID 000342685300007

• Comparison of the prognostic utility of the revised International Prognostic Scoring System and the French Prognostic Scoring System in azacitidine-treated patients with myelodysplastic syndromes BRITISH JOURNAL OF HAEMATOLOGY Zeidan, A. M., Lee, J., Prebet, T., Greenberg, P., Sun, Z., Juckett, M., Smith, M. R., Paietta, E., Gabrilove, J., Erba, H. P., Tallman, M. S., Gore, S. D. 2014; 166 (3): 352-359

  Abstract

  The revised International Prognostic Scoring System (IPSS-R) was developed in a cohort of untreated myelodysplastic syndromes (MDS) patients. A French Prognostic Scoring System (FPSS) was recently reported to identify differential survival among azacitidine-treated patients with high-risk MDS. We applied the FPSS and IPSS-R to 150 patients previously randomized to azacitidine monotherapy or a combination of azacitidine with entinostat (a histone deacetylase inhibitor). Neither score predicted response but both discriminated patients with different overall survival (OS; median OS, FPSS: 9·7, 14·7, and 25·3 months, P = 0·018; IPSS-R: 12·5, 11·3, 20·8, and 36 months, P = 0·005). Statistical analysis suggested no improvement in OS prediction for the FPSS over the IPSS-R in azacitidine-treated patients.

  View details for DOI 10.1111/bjh.12884

  View details for Web of Science ID 000339478800006

  View details for PubMedID 24712482

  View details for PubMedCentralID PMC4299460

• Prolonged Administration of Azacitidine With or Without Entinostat for Myelodysplastic Syndrome and Acute Myeloid Leukemia With Myelodysplasia-Related Changes: Results of the US Leukemia Intergroup Trial E1905 JOURNAL OF CLINICAL ONCOLOGY Prebet, T., Sun, Z., Figueroa, M. E., Ketterling, R., Melnick, A., Greenberg, P. L., Herman, J., Juckett, M., Smith, M. R., Malick, L., Paietta, E., Czader, M., Litzow, M., Gabrilove, J., Erba, H. P., Gore, S. D., Tallman, M. S. 2014; 32 (12): 1242-?

  Abstract

  Although azacitidine (AZA) improves survival in patients with high-risk myelodysplastic syndrome, the overall response remains approximately 50%. Entinostat is a histone deacetylase inhibitor that has been combined with AZA with significant clinical activity in a previous phase I dose finding study.Open label phase II randomized trial comparing AZA 50 mg/m(2)/d given for 10 days ± entinostat 4 mg/m(2)/d day 3 and day 10. All subtypes of myelodysplasia, chronic myelomonocytic leukemia, and acute myeloid leukemia with myelodysplasia-related changes were eligible for the study. The primary objective was the rate of hematologic normalization (HN; complete remission + partial remission + trilineage hematological improvement).One hundred forty-nine patients were analyzed, including 97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia. In the AZA group, 32% (95% CI, 22% to 44%) experienced HN and 27% (95% CI, 17% to 39%) in the AZA + entinostat group. Both arms exceeded the HN rate of historical control (Cancer and Leukemia Group B 9221 trial), but only the AZA group fulfilled the primary objective of the study. Rates of overall hematologic response were 46% and 44%, respectively. Median overall survivals were 18 months for the AZA group and 13 months for the AZA + entinostat group. The combination arm led to less demethylation compared with the monotherapy arm, suggesting pharmacodynamic antagonism.Addition of entinostat to AZA did not increase clinical response as defined by the protocol and was associated with pharmacodynamic antagonism. However, the prolonged administration of AZA by itself seems to increase HN rate compared with standard dosing and warrants additional investigation.

  View details for DOI 10.1200/JCO.2013.50.3102

  View details for Web of Science ID 000335139000014

  View details for PubMedID 24663049

• Mesenchymal Stromal Cell Density is Increased in Higher Grade Myelodysplastic Syndromes and Independently Predicts Survival. J Clin Path Johnson, R., Kurzer, J., Greenberg, P., Gratzinger, D. 2014; 142: 795-802
• Update on Myelodysplastic Syndromes Classification and Prognosis. Surgical pathology clinics Gratzinger, D., Greenberg, P. L. 2013; 6 (4): 693-728

  Abstract

  Myelodysplastic syndromes (MDS) are a collection of cytogenetically heterogeneous clonal bone marrow (BM) failure disorders derived from aberrant hematopoietic stem cells in the setting of an aberrant hematopoietic stem cell niche. Patients suffer from variably progressive and symptomatic bone marrow failure with a risk of leukemic transformation. Diagnosis of MDS has long been based on morphologic assessment and blast percentage as in the original French-American-British classification. The recently developed Revised International Prognostic Scoring System provides improved prognostication using more refined cytogenetic, marrow blast, and cytopenia parameters. With the advent of deep sequencing technologies, dozens of molecular abnormalities have been identified in MDS.

  View details for DOI 10.1016/j.path.2013.08.005

  View details for PubMedID 26839194

• Monosomal karyotype in MDS: explaining the poor prognosis? LEUKEMIA Schanz, J., Tuechler, H., Sole, F., Mallo, M., Luno, E., Cervera, J., Grau, J., Hildebrandt, B., Slovak, M. L., Ohyashiki, K., Steidl, C., Fonatsch, C., Pfeilstoecker, M., Noesslinger, T., Valent, P., Giagounidis, A., Aul, C., Luebbert, M., Stauder, R., Krieger, O., Le Beau, M. M., Bennett, J. M., Greenberg, P., Germing, U., Haase, D. 2013; 27 (10): 1988-1995

  Abstract

  Monosomal karyotype (MK) is associated with an adverse prognosis in patients in acute myeloid leukemia (AML). This study analyzes the prognostic impact of MK in a cohort of primary, untreated patients with myelodysplastic syndromes (MDS). A total of 431 patients were extracted from an international database. To analyze whether MK is an independent prognostic marker in MDS, cytogenetic and clinical data were explored in uni- and multivariate models regarding overall survival (OS) as well as AML-free survival. In all, 204/431 (47.3%) patients with MK were identified. Regarding OS, MK was prognostically significant in patients with ≤ 4 abnormalities only. In highly complex karyotypes (≥ 5 abnormalities), MK did not separate prognostic subgroups (median OS 4.9 months in MK+ vs 5.6 months in patients without MK, P=0.832). Based on the number of abnormalities, MK-positive karyotypes (MK+) split into different prognostic subgroups (MK+ and 2 abnormalities: OS 13.4 months, MK+ and 3 abnormalities: 8.0 months, MK+ and 4 abnormalities: 7.9 months and MK+ and ≥ 5 abnormalities: 4.9 months; P<0.01). In multivariate analyses, MK was not an independent prognostic factor. Our data support the hypothesis that a high number of complex abnormalities, associated with an instable clone, define the subgroup with the worst prognosis in MDS, independent of MK.

  View details for DOI 10.1038/leu.2013.187

  View details for Web of Science ID 000325642600005

  View details for PubMedID 23787396

• Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. Journal of clinical oncology Koreth, J., Pidala, J., Perez, W. S., Deeg, H. J., Garcia-Manero, G., Malcovati, L., Cazzola, M., Park, S., Itzykson, R., AdeS, L., Fenaux, P., Jadersten, M., Hellstrom-Lindberg, E., Gale, R. P., Beach, C. L., Lee, S. J., Horowitz, M. M., Greenberg, P. L., Tallman, M. S., DiPersio, J. F., Bunjes, D., Weisdorf, D. J., Cutler, C. 2013; 31 (21): 2662-2670

  Abstract

  Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk.A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165).For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates.For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.

  View details for DOI 10.1200/JCO.2012.46.8652

  View details for PubMedID 23797000

  View details for PubMedCentralID PMC3825320

• The Multifaceted Nature of Myelodysplastic Syndromes: Clinical, Molecular, and Biological Prognostic Features JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Greenberg, P. L. 2013; 11 (7): 877-885

  Abstract

  The myelodysplastic syndromes (MDS) consist of a heterogeneous spectrum of myeloid clonal hemopathies. The Revised International Prognostic Scoring System (IPSS-R) provides a recently refined method for clinically evaluating the prognosis of patients with MDS. Molecular profiling has recently generated extensive data describing critical hematopoietic molecular and biologic derangements contributing to clinical phenotypes. Current molecular insights have demonstrated roles of specific somatic gene mutations in the development and clinical outcomes of MDS, including their propensity to progress to more aggressive stages, such as acute myeloid leukemia. This article focuses on these recently reported clinical and underlying pathogenetic findings. The discussion provides a synthesis of the prognostic clinical, molecular, and biologic abnormalities intrinsic to the aberrant marrow hematopoietic and microenvironmental influences in MDS.

  View details for Web of Science ID 000321614400010

  View details for PubMedID 23847221

• Myelodysplastic syndromes: clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Greenberg, P. L., Attar, E., Bennett, J. M., Bloomfield, C. D., Borate, U., De Castro, C. M., Deeg, H. J., Frankfurt, O., Gaensler, K., Garcia-Manero, G., Gore, S. D., Head, D., Komrokji, R., Maness, L. J., Millenson, M., O'Donnell, M. R., Shami, P. J., Stein, B. L., Stone, R. M., Thompson, J. E., Westervelt, P., Wheeler, B., Shead, D. A., Naganuma, M. 2013; 11 (7): 838-874

  Abstract

  The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid leukemia. These disorders primarily affect older adults. The NCCN Clinical Practice Guidelines in Oncology for MDS provide recommendations on the diagnostic evaluation and classification of MDS, risk evaluation according to established prognostic assessment tools (including the new revised International Prognostic Scoring System), treatment options according to risk categories, and management of related anemia.

  View details for PubMedID 23847220

• Myelodysplastic Syndromes JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Greenberg, P. L., Attar, E., Bennett, J. M., Bloomfield, C. D., Borate, U., De Castro, C. M., Deeg, H. J., Frankfurt, O., Gaensler, K., Garcia-Manero, G., Gore, S. D., Head, D., Komrokji, R., Maness, L. J., Millenson, M., O'Donnell, M. R., Shami, P. J., Stein, B. L., Stone, R. M., Thompson, J. E., Westervelt, P., Wheeler, B., Shead, D. A., Naganuma, M. 2013; 11 (7): 838-874

  View details for Web of Science ID 000321614400009

• 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

• Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Pang, W. W., Pluvinage, J. V., Price, E. A., Sridhar, K., Arber, D. A., Greenberg, P. L., Schrier, S. L., Park, C. Y., Weissman, I. L. 2013; 110 (8): 3011-3016

  Abstract

  Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.

  View details for DOI 10.1073/pnas.1222861110

  View details for Web of Science ID 000315954400082

  View details for PubMedID 23388639

  View details for PubMedCentralID PMC3581956

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

  Abstract

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

  View details for DOI 10.1200/JCO.2012.44.5791

  View details for Web of Science ID 000314820400017

  View details for PubMedID 23295809

• A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine LEUKEMIA & LYMPHOMA Greenberg, P. L., Garcia-Manero, G., Moore, M., Damon, L., Roboz, G., Hu, K., Yang, A. S., Franklin, J. 2013; 54 (2): 321-328

  Abstract

  Patients with myelodysplastic syndrome (MDS) receiving hypomethylating agents commonly develop thrombocytopenia. This double-blind study evaluated the efficacy and safety of romiplostim, a peptibody protein that increases platelets, in patients with MDS receiving decitabine. Patients received romiplostim 750 μg (n = 15) or placebo (n = 14) and decitabine. Median platelet counts at the beginning of each decitabine cycle trended lower in placebo-treated than in romiplostim-treated patients. Bleeding events occurred in 43% of placebo-treated and 27% of romiplostim-treated patients, and platelet transfusions were administered to 57% of placebo-treated and 47% of romiplostim-treated patients. Overall clinical therapeutic response was achieved by 21% of placebo-treated and 33% of romiplostim-treated patients. Treatment was generally well tolerated. Progression to acute myeloid leukemia (AML) occurred in one patient per group. Adding romiplostim to decitabine treatment is well tolerated and may be beneficial, as indicated by trends toward higher platelet counts at the beginning of each treatment cycle and lower platelet transfusion rates and percentages of patients with bleeding events.

  View details for DOI 10.3109/10428194.2012.713477

  View details for Web of Science ID 000313285400021

  View details for PubMedID 22906162

• Specific plasma autoantibody reactivity in myelodysplastic syndromes Scientific Reports Mias, G. I., Chen, R., Zhang, Y., Sridhar, K., Sharon, D., Xiao, L., Im, H., Snyder, M. P., Greenberg, P. L. 2013; 3: 3311-3319

  View details for DOI 10.1038/srep03311

• Reduced rRNA expression and increased rDNA promoter methylation in CD34(+) cells of patients with myelodysplastic syndromes BLOOD Raval, A., Sridhar, K. J., Patel, S., Turnbull, B. B., Greenberg, P. L., Mitchell, B. S. 2012; 120 (24): 4812-4818

  Abstract

  Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis. The DNA-hypomethylating agents 5-azacytidine and 5-aza-2'-deoxycytidine are effective treatments for patients with MDS, increasing the time to progression to acute myelogenous leukemia and improving overall response rates. Although genome-wide increases in DNA methylation have been documented in BM cells from MDS patients, the methylation signatures of specific gene promoters have not been correlated with the clinical response to these therapies. Recently, attention has been drawn to the potential etiologic role of decreased expression of specific ribosomal proteins in MDS and in other BM failure states. Therefore, we investigated whether rRNA expression is dysregulated in MDS. We found significantly decreased rRNA expression and increased rDNA promoter methylation in CD34(+) hematopoietic progenitor cells from the majority of MDS patients compared with normal controls. Treatment of myeloid cell lines with 5-aza-2'-deoxycytidine resulted in a significant decrease in the methylation of the rDNA promoter and an increase in rRNA levels. These observations suggest that an increase in rDNA promoter methylation can result in decreased rRNA synthesis that may contribute to defective hematopoiesis and BM failure in some patients with MDS.

  View details for DOI 10.1182/blood-2012-04-423111

  View details for Web of Science ID 000313115300023

  View details for PubMedID 23071274

• Revised International Prognostic Scoring System for Myelodysplastic Syndromes BLOOD Greenberg, P. L., Tuechler, H., Schanz, J., Sanz, G., Garcia-Manero, G., Sole, F., Bennett, J. M., Bowen, D., Fenaux, P., Dreyfus, F., Kantarjian, H., Kuendgen, A., Levis, A., Malcovati, L., Cazzola, M., Cermak, J., Fonatsch, C., Le Beau, M. M., Slovak, M. L., Krieger, O., Luebbert, M., Maciejewski, J., Magalhaes, S. M., Miyazaki, Y., Pfeilstoecker, M., Sekeres, M., Sperr, W. R., Stauder, R., Tauro, S., Valent, P., Vallespi, T., van de Loosdrecht, A. A., Germing, U., Haase, D. 2012; 120 (12): 2454-2465

  Abstract

  The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.

  View details for DOI 10.1182/blood-2012-03-420489

  View details for Web of Science ID 000309044600019

  View details for PubMedID 22740453

• Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow LABORATORY INVESTIGATION Flores-Figueroa, E., Varma, S., Montgomery, K., Greenberg, P. L., Gratzinger, D. 2012; 92 (9): 1330-1341

  Abstract

  Mesenchymal stromal cells (MSCs) support hematopoiesis and are cytogenetically and functionally abnormal in myelodysplastic syndrome (MDS), implying a possible pathophysiologic role in MDS and potential utility as a diagnostic or risk-stratifying tool. We have analyzed putative MSC markers and their relationship to CD34+ hematopoietic stem/progenitor cells (HSPCs) within intact human bone marrow in paraffin-embedded bone marrow core biopsies of benign, MDS and leukemic (AML) marrows using tissue microarrays to facilitate scanning, image analysis and quantitation. We found that CD271+, ALP+ MSCs formed an extensive branching perivascular, periosteal and parenchymal network. Nestin was brightly positive in capillary/arteriolar endothelium and occasional subendothelial cells, whereas CD146 was most brightly expressed in SMA+ vascular smooth muscle/pericytes. CD271+ MSCs were distinct by double immunofluorescence from CD163+ macrophages and were in close contact with but distinct from brightly nestin+ and from brightly CD146+ vascular elements. Double immunofluorescence revealed an intimate spatial relationship between CD34+ HSPCs and CD271+ MSCs; remarkably, 86% of CD34+ HSPCs were in direct contact with CD271+ MSCs across benign, MDS and AML marrows, predominantly in a perivascular distribution. Expression of the intercrine chemokine CXCL12 was strong in the vasculature in both benign and neoplastic marrow, but was also present in extravascular parenchymal cells, particularly in MDS specimens. We identified these parenchymal cells as MSCs by ALP/CXCL12 and CD271/CXCL12 double immunofluorescence. The area covered by CXCL12+ ALP+ MSCs was significantly greater in MDS compared with benign and AML marrow (P=0.021, Kruskal-Wallis test). The preservation of direct CD271+ MSC/CD34+ HSPC contact across benign and neoplastic marrow suggests a physiologically important role for the CD271+ MSC/CD34+ HSPC relationship and possible abnormal exposure of CD34+ HSPCs to increased MSC CXCL12 expression in MDS.

  View details for DOI 10.1038/labinvest.2012.93

  View details for Web of Science ID 000308274600008

  View details for PubMedID 22710983

• Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS BLOOD Barreyro, L., Will, B., Bartholdy, B., Zhou, L., Todorova, T. I., Stanley, R. F., Ben-Neriah, S., Montagna, C., Parekh, S., Pellagatti, A., Boultwood, J., Paietta, E., Ketterling, R. P., Cripe, L., Fernandez, H. F., Greenberg, P. L., Tallman, M. S., Steidl, C., Mitsiades, C. S., Verma, A., Steidl, U. 2012; 120 (6): 1290-1298

  Abstract

  Cellular and interpatient heterogeneity and the involvement of different stem and progenitor compartments in leukemogenesis are challenges for the identification of common pathways contributing to the initiation and maintenance of acute myeloid leukemia (AML). Here we used a strategy of parallel transcriptional analysis of phenotypic long-term hematopoietic stem cells (HSCs), short-term HSCs, and granulocyte-monocyte progenitors from individuals with high-risk (-7/7q-) AML and compared them with the corresponding cell populations from healthy controls. This analysis revealed dysregulated expression of 11 genes, including IL-1 receptor accessory protein (IL1RAP), in all leukemic stem and progenitor cell compartments. IL1RAP protein was found to be overexpressed on the surface of HSCs of AML patients, and marked cells with the -7/7q- anomaly. IL1RAP was also overexpressed on HSCs of patients with normal karyotype AML and high-risk myelodysplastic syndrome, suggesting a pervasive role in different disease subtypes. High IL1RAP expression was independently associated with poor overall survival in 3 independent cohorts of AML patients (P = 2.2 × 10(-7)). Knockdown of IL1RAP decreased clonogenicity and increased cell death of AML cells. Our study identified genes dysregulated in stem and progenitor cells in -7/7q- AML, and suggests that IL1RAP may be a promising therapeutic and prognostic target in AML and high-risk myelodysplastic syndrome.

  View details for DOI 10.1182/blood-2012-01-404699

  View details for Web of Science ID 000307449300020

  View details for PubMedID 22723552

  View details for PubMedCentralID PMC3418722

• Molecular and genetic features of myelodysplastic syndromes INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Greenberg, P. L. 2012; 34 (3): 215-222

  Abstract

  Multifactorial pathogenetic features underlying myelodysplastic syndromes (MDS) relate to inherent abnormalities within the hematopoietic precursor cell population. The predominant final common pathogenetic pathway causing ineffective hematopoiesis in MDS has been the varying degrees of apoptosis of the hematopoietic precursors and their progeny. A variety of molecular abnormalities have been demonstrated in MDS. These lesions are attributable to nonrandom cytogenetic and oncogenic mutations, indicative of chromosomal and genetic instability, transcriptional RNA splicing abnormalities, and epigenetic changes. Evolutionary cytogenetic changes may occur during the course of the disorder, which are associated with disease progression. These genetic derangements reflect a multistep process believed to underlie the transformation of MDS to acute myeloid leukemia. Recent findings provide molecular insights into specific gene mutations playing major roles for the development and clinical outcome of MDS and their propensity to progress to a more aggressive stage. Use of more comprehensive and sensitive methods for molecular profiling using 'next-generation' sequencing techniques for MDS marrow cells will likely further define critical biologic lesions underlying this spectrum of diseases.

  View details for DOI 10.1111/j.1751-553X.2011.01390.x

  View details for Web of Science ID 000305694300001

  View details for PubMedID 22212119

• Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes CELL Chen, R., Mias, G. I., Li-Pook-Than, J., Jiang, L., Lam, H. Y., Chen, R., Miriami, E., Karczewski, K. J., Hariharan, M., Dewey, F. E., Cheng, Y., Clark, M. J., Im, H., Habegger, L., Balasubramanian, S., O'Huallachain, M., Dudley, J. T., Hillenmeyer, S., Haraksingh, R., Sharon, D., Euskirchen, G., Lacroute, P., Bettinger, K., Boyle, A. P., Kasowski, M., Grubert, F., Seki, S., Garcia, M., Whirl-Carrillo, M., Gallardo, M., Blasco, M. A., Greenberg, P. L., Snyder, P., Klein, T. E., Altman, R. B., Butte, A. J., Ashley, E. A., Gerstein, M., Nadeau, K. C., Tang, H., Snyder, M. 2012; 148 (6): 1293-1307

  Abstract

  Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.

  View details for DOI 10.1016/j.cell.2012.02.009

  View details for Web of Science ID 000301889500023

  View details for PubMedID 22424236

  View details for PubMedCentralID PMC3341616

• New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge JOURNAL OF CLINICAL ONCOLOGY Schanz, J., Tuechler, H., Sole, F., Mallo, M., Luno, E., Cervera, J., Granada, I., Hildebrandt, B., Slovak, M. L., Ohyashiki, K., Steidl, C., Fonatsch, C., Pfeilstoecker, M., Noesslinger, T., Valent, P., Giagounidis, A., Aul, C., Luebbert, M., Stauder, R., Krieger, O., Garcia-Manero, G., Faderl, S., Pierce, S., Le Beau, M. M., Bennett, J. M., Greenberg, P., Germing, U., Haase, D. 2012; 30 (8): 820-829

  Abstract

  The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients.Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results.In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score.In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories.

  View details for DOI 10.1200/JCO.2011.35.6394

  View details for Web of Science ID 000302626600017

  View details for PubMedID 22331955

• Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow Lab Investigation Flores-Figueroa E, Varma S, Montgomery K, Greenberg P, Gratzinger D 2012; 92: 1330-1341
• Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na LEUKEMIA RESEARCH Seetharam, M., Fan, A. C., Tran, M., Xu, L., Renschler, J. P., Felsher, D. W., Sridhar, K., Wilhelm, F., Greenberg, P. L. 2012; 36 (1): 98-103

  Abstract

  In a Phase I/II clinical trial, 13 higher risk red blood cell-dependent myelodysplastic syndrome (MDS) patients unresponsive to hypomethylating therapy were treated with the multikinase inhibitor ON 01910.Na. Responses occurred in all morphologic, prognostic risk and cytogenetic subgroups, including four patients with marrow complete responses among eight with stable disease, associated with good drug tolerance. In a subset of patients, a novel nanoscale immunoassay showed substantially decreased AKT2 phosphorylation in CD34+ marrow cells from patients responding to therapy but not those who progressed on therapy. These data demonstrate encouraging efficacy and drug tolerance with ON 01910.Na treatment of higher risk MDS patients.

  View details for DOI 10.1016/j.leukres.2011.08.022

  View details for Web of Science ID 000298149100035

  View details for PubMedID 21924492

• A Novel Nano-Immunoassay (NIA) Reveals Inhibition of PI3K and MAPK Pathways in CD34+Bone Marrow Cells of Patients with Myelodysplastic Syndrome (MDS) Treated with the Multi-Kinase Inhibitor On 01910.Na (Rigosertib) 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Fan, A. C., Xu, L., Sridhar, K. J., Tran, M., Banerjee, P., Renschler, J. P., Tripuraneni, R., Wilhelm, F., Greenberg, P. L., Felsher, D. W. AMER SOC HEMATOLOGY. 2011: 1626–26

  View details for Web of Science ID 000299597105536

• Myelodysplastic Syndromes: Dissecting the Heterogeneity JOURNAL OF CLINICAL ONCOLOGY Greenberg, P. L. 2011; 29 (15): 1937-1938

  View details for DOI 10.1200/JCO.2011.35.2211

  View details for Web of Science ID 000290716900016

  View details for PubMedID 21519018

• NCCN Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. Journal of the National Comprehensive Cancer Network Greenberg, P. L., Attar, E., Bennett, J. M., Bloomfield, C. D., De Castro, C. M., Deeg, H. J., Foran, J. M., Gaensler, K., Garcia-Manero, G., Gore, S. D., Head, D., Komrokji, R., Maness, L. J., Millenson, M., Nimer, S. D., O'Donnell, M. R., Schroeder, M. A., Shami, P. J., Stone, R. M., Thompson, J. E., Westervelt, P. 2011; 9 (1): 30-56

  Abstract

  These suggested practice guidelines are based on extensive evaluation of the reviewed risk-based data and indicate useful current approaches for managing patients with MDS. Four drugs have recently been approved by the FDA for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic abnormalities; azacytidine and decitabine for treating patients with higher-risk or nonresponsive MDS; and deferasirox for iron chelation of iron overloaded patients with MDS. However, because a substantial proportion of patient subsets with MDS lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, further determination of the effects of these therapeutic interventions on the patient's quality of life is important.(116,119,120,128,129) Progress toward improving management of MDS has occurred over the past few years, and more advances are anticipated using these guidelines as a framework for coordination of comparative clinical trials.

  View details for PubMedID 21233243

• Myelodysplastic Syndromes JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Greenberg, P. L., Attar, E., Bennett, J. M., Bloomfield, C. D., De Castro, C. M., Deeg, H. J., Foran, J. M., Gaensler, K., Garcia-Manero, G., Gore, S. D., Head, D., Komrokji, R., Maness, L. J., Millenson, M., Nimer, S. D., O'Donnell, M. R., Schroeder, M. A., Shami, P. J., Stone, R. M., Thompson, J. E., Westervelt, P. 2011; 9 (1): 30-56

  View details for Web of Science ID 000287217200005

• Prospective assessment of effects on iron-overload parameters of deferasirox therapy in patients with myelodysplastic syndromes LEUKEMIA RESEARCH Greenberg, P. L., Koller, C. A., Cabantchik, Z. I., Warsi, G., Glynos, T., Paley, C., Schiffer, C. 2010; 34 (12): 1560-1565

  Abstract

  We report the first prospective study evaluating the effects of deferasirox on liver iron concentration (LIC), labile plasma iron (LPI) and pharmacokinetics (PK) along with serum ferritin values in patients with IPSS Low- and Intermediate-1 risk myelodysplastic syndromes (MDS) and evidence of iron overload. Twenty-four heavily transfused MDS patients were enrolled in a planned 52 weeks of therapy. PK studies showed dose-proportional total drug exposure. Data demonstrated that deferasirox was well tolerated and effectively reduced LIC, LPI and serum ferritin in the iron-overloaded patients with MDS who completed 24 and 52 weeks of therapy despite ongoing receipt of red blood cell transfusions.

  View details for DOI 10.1016/j.leukres.2010.06.013

  View details for Web of Science ID 000283845900018

  View details for PubMedID 20615548

• Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy BLOOD Kantarjian, H. M., Giles, F. J., Greenberg, P. L., Paquette, R. L., Wang, E. S., Gabrilove, J. L., Garcia-Manero, G., Hu, K., Franklin, J. L., Berger, D. P. 2010; 116 (17): 3163-3170

  Abstract

  We evaluated the efficacy and safety of romiplostim, a thrombopoietin mimetic, in patients with low- or intermediate-risk myelodysplastic syndromes (MDS) receiving azacitidine therapy. Forty patients with low- or intermediate-risk MDS were stratified by baseline platelet counts (< 50 vs ≥ 50 × 10(9)/L) and randomized to romiplostim 500 μg or 750 μg or placebo subcutaneously once weekly during 4 cycles of azacitidine. The primary endpoint was the incidence of clinically significant thrombocytopenic events, defined by grade 3 or 4 thrombocytopenia starting on day 15 of the first cycle or platelet transfusion at any time during the 4-cycle treatment period. No formal hypothesis testing was planned. The incidence of clinically significant thrombocytopenic events in patients receiving romiplostim 500 μg, romiplostim 750 μg, or placebo was 62%, 71%, and 85%, respectively. The incidence of platelet transfusions was 46%, 36%, and 69%, respectively. These differences were not statistically significant with the small numbers in each group. Romiplostim 750 μg significantly raised median platelet counts during cycle 3 on day 1 (P = .0373) and at the nadir (P = .0035) compared with placebo. Grade 3 rash and arthralgia each were reported in 1 romiplostim-treated patient (4%). This study suggests romiplostim may provide clinical benefits in MDS patients during azacitidine therapy.

  View details for DOI 10.1182/blood-2010-03-274753

  View details for Web of Science ID 000283583700011

  View details for PubMedID 20631375

• Current therapeutic approaches for patients with myelodysplastic syndromes BRITISH JOURNAL OF HAEMATOLOGY Greenberg, P. L. 2010; 150 (2): 131-143

  Abstract

  The myelodysplastic syndromes (MDS) are a heterogeneous spectrum of disorders requiring selective therapy based on patients' specific clinical features, predominantly their prognostic subgroups, age and performance status. Guidelines for management of patients with MDS have been generated by a number of national panels. This review focuses on evidence-based data supporting therapeutic approaches, which have also been recommended by the US National Comprehensive Cancer Network MDS Panel, with discussion of accessibility of recommended drugs in the US and in other countries. For lower risk disease (International Prognostic Scoring System Low and Intermediate-1) therapy is aimed at haematological improvement whereas for higher risk disease (Intermediate-2 and High) treatment focuses on altering disease natural history. Recent information regarding additional clinical and biological features has provided useful parameters for assessing disease prognosis that aid risk-based management decisions. The rationale for use of low versus high intensity therapies with these agents, including allogeneic haematopoietic stem cell transplantation, is discussed in detail.

  View details for DOI 10.1111/j.1365-2141.2010.08226.x

  View details for Web of Science ID 000279438600001

  View details for PubMedID 20507314

• NCCN Task Force: Transfusion and iron overload in patients with myelodysplastic syndromes. Journal of the National Comprehensive Cancer Network Greenberg, P. L., Rigsby, C. K., Stone, R. M., Deeg, H. J., Gore, S. D., Millenson, M. M., Nimer, S. D., O'Donnell, M. R., Shami, P. J., Kumar, R. 2009; 7: S1-16

  Abstract

  The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force to critically review the evidence for iron chelation and the rationale for treatment of transfusional iron overload in patients with myelodysplastic syndromes (MDS). The task force was charged with addressing issues related to tissue iron toxicity; the role of MRI in assessing iron overload; the rationale and role of treating transfusional iron overload in patients with MDS; and the impact of iron overload on bone marrow transplantation. This report summarizes the background data and ensuing discussion from the NCCN Task Force meeting on transfusional iron overload in MDS.

  View details for PubMedID 20064286

• Relationship of differential gene expression profiles in CD34(+) myelodysplastic syndrome marrow cells to disease subtype and progression BLOOD Sridhar, K., Ross, D. T., Tibshirani, R., Butte, A. J., Greenberg, P. L. 2009; 114 (23): 4847-4858

  Abstract

  Microarray analysis with 40 000 cDNA gene chip arrays determined differential gene expression profiles (GEPs) in CD34(+) marrow cells from myelodysplastic syndrome (MDS) patients compared with healthy persons. Using focused bioinformatics analyses, we found 1175 genes significantly differentially expressed by MDS versus normal, requiring a minimum of 39 genes to separately classify these patients. Major GEP differences were demonstrated between healthy and MDS patients and between several MDS subgroups: (1) those whose disease remained stable and those who subsequently transformed (tMDS) to acute myeloid leukemia; (2) between del(5q) and other MDS patients. A 6-gene "poor risk" signature was defined, which was associated with acute myeloid leukemia transformation and provided additive prognostic information for International Prognostic Scoring System Intermediate-1 patients. Overexpression of genes generating ribosomal proteins and for other signaling pathways was demonstrated in the tMDS patients. Comparison of del(5q) with the remaining MDS patients showed 1924 differentially expressed genes, with underexpression of 1014 genes, 11 of which were within the 5q31-32 commonly deleted region. These data demonstrated (1) GEPs distinguishing MDS patients from healthy and between those with differing clinical outcomes (tMDS vs those whose disease remained stable) and cytogenetics [eg, del(5q)]; and (2) molecular criteria refining prognostic categorization and associated biologic processes in MDS.

  View details for DOI 10.1182/blood-2009-08-236422

  View details for Web of Science ID 000272190700014

  View details for PubMedID 19801443

• Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996) BLOOD Greenberg, P. L., Sun, Z., Miller, K. B., Bennett, J. M., Tallman, M. S., Dewald, G., Paietta, E., van der Jagt, R., Houston, J., Thomas, M. L., Cella, D., Rowe, J. M. 2009; 114 (12): 2393-2400

  Abstract

  This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels < 200 mU/mL vs > or = 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein(+) CD34(+) marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

  View details for DOI 10.1182/blood-2009-03-211797

  View details for Web of Science ID 000269925000007

  View details for PubMedID 19564636

• A phase II intra-patient dose-escalation trial of weight-based darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J., Lavori, P., Quesada, S., Stein, R. S., Shahnia, S., Greenberg, P. L. 2009; 84 (1): 15-20

  Abstract

  This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate-1 risk myelodysplastic syndrome (MDS). Intra-patient dose escalation of DA was undertaken in three 6-week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte-colony stimulating factor (G-CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight-based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G-CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low-level non-neutralizing anti-DA antibodies. Our data indicate that weekly weight-based dosing of DA, with the addition of G-CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower-risk MDS patients.

  View details for DOI 10.1002/ajh.21316

  View details for Web of Science ID 000262219900004

  View details for PubMedID 19006226

• NCCN Task Force Report: Transfusion and Iron Overload in Patients with Myelodysplastic Syndromes J Nat Comp Cancer Network Greenberg, P., Rigsby C, Stone RM, Deeg J, Gore S, Millenson M, Nimer S, O'Donnell M, Shami P, Kumar R 2009; 7 ((Suppl 9): S1-16
• Myelodysplastic syndromes. Journal of the National Comprehensive Cancer Network Greenberg, P. L., Attar, E., Battiwalla, M., Bennett, J. M., Bloomfield, C. D., DeCastro, C. M., Deeg, H. J., Erba, H. P., Foran, J. M., Garcia-Manero, G., Gore, S. D., Head, D., Maness, L. J., Millenson, M., Nimer, S. D., O'Donnell, M. R., Saba, H. I., Shami, P. J., Spiers, K., Stone, R. M., Tallman, M. S., Westervelt, P. 2008; 6 (9): 902-926

  View details for PubMedID 18926100

• The costs of drugs used to treat myelodysplastic syndromes following National Comprehensive Cancer Network Guidelines. Journal of the National Comprehensive Cancer Network Greenberg, P. L., Cosler, L. E., Ferro, S. A., Lyman, G. H. 2008; 6 (9): 942-953

  Abstract

  Guidelines for management of patients with myelodysplastic syndromes (MDS) have been generated by the National Comprehensive Cancer Network (NCCN) Myelodysplastic Syndromes Panel. Because MDS is a heterogeneous spectrum of disorders, these patients have been categorized into prognostic subgroups, predominantly using the International Prognostic Scoring System (IPSS). Several drugs have been used to treat these patients, and their selection and sequential recommended use by the panel depend on disease characteristics and responses to treatment. Recombinant erythropoietin alfa and darbepoetin alfa have been the mainstay of therapy for treating anemia associated with MDS. The FDA has recently approved several other drugs for treating MDS, including azacytidine and decitabine for all stages of disease, lenalidomide for low-risk anemic patients with del(5q) chromosomal abnormality, and deferasirox for treating iron overload. For iron chelation, deferoxamine is also used occasionally. Treatment with immunosuppressive therapy (antithymocyte globulin and cyclosporin) has been therapeutically beneficial for a subset of younger patients with MDS. Because the financial cost of these therapies are substantial and have received only limited attention, this article evaluates the costs of specific drugs and their sequential use in the lower-risk IPSS (low and intermediate-1) subgroups based on the NCCN guidelines. Results estimate an average annual cost for potentially anemia-altering drugs of $63,577 per patient, ranging from $26,000 to $95,000, depending on the specific therapies. In patients for whom the therapies fail, annual costs for iron chelation plus red blood cell transfusions are estimated to average $41,412. The economic impact of drug therapy should be weighed against the patient's potential for improvement in clinical outcomes, quality of life, and transfusion requirements.

  View details for PubMedID 18926103

• Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy JOURNAL OF CLINICAL ONCOLOGY Sloand, E. M., Wu, C. O., Greenberg, P., Young, N., Barrett, J. 2008; 26 (15): 2505-2511

  Abstract

  Marrow failure in some patients with myelodysplastic syndrome (MDS) responds to immunosuppressive treatment (IST), but long-term outcome after IST has not been described. We evaluated patients with MDS treated with IST at our institution to determine their clinical course compared with a comparable supportive care only group.One hundred twenty-nine patients with MDS received IST with a median follow-up of 3.0 years (range, 0.03 to 11.3 years), using antithymocyte globulin (ATG) or cyclosporine (CsA) in combination or singly. Variables affecting response and survival were studied and outcomes were compared with those of 816 patients with MDS reported to the International Myelodysplasia Risk Analysis Workshop (IMRAW) who received only supportive care.Thirty-nine (30%) of 129 patients receiving IST responded either completely or partially: 18 (24%) of 74 patients responded to ATG, 20 (48%) of 42 patients responded to ATG plus CsA, and one (8%) of 13 patients responded to CsA. Thirty-one percent (12 of 39) of the responses were complete, resulting in transfusion independence and near-normal blood counts. In multivariate analysis, younger age was the most significant factor favoring response to therapy. Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus CsA treatment (P = .001 and P = .048, respectively). In multivariate analysis of the combined IMRAW and IST cohorts, younger age, treatment with IST, and intermediate or low International Prognostic Scoring System score significantly favored survival.IST produced significant improvement in the pancytopenia of a substantial proportion of patients with MDS and was associated with improved overall and progression-free survival, especially in younger individuals with lower-risk disease.

  View details for DOI 10.1200/JCO.2007.11.9214

  View details for Web of Science ID 000255970300018

  View details for PubMedID 18413642

• A 2-gene classifier for predicting response to the famesyltransferase inhibitor tipifarnib in acute myeloid leukemia BLOOD Raponi, M., Lancet, J. E., Fan, H., Dossey, L., Lee, G., Gojo, I., Feldman, E. J., Gotlib, J., Morris, L. E., Greenberg, P. L., Wright, J. J., Harousseau, J., Loewenberg, B., Stone, R. M., De Porre, P., Wang, Y., Karp, J. E. 2008; 111 (5): 2589-2596

  Abstract

  At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.

  View details for DOI 10.1182/blood-2007-09-112730

  View details for Web of Science ID 000253671600023

  View details for PubMedID 18160667

• Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study EUROPEAN JOURNAL OF HAEMATOLOGY Porter, J., Galanello, R., Saglio, G., Neufeld, E. J., Vichinsky, E., Cappellini, M. D., Olivieri, N., Piga, A., Cunningham, M. J., Soulieres, D., Gattermann, N., Tchernia, G., Maertens, J., Giardina, P., Kwiatkowski, J., Quarta, G., Jeng, M., Forni, G. L., Stadler, M., Cario, H., Debusscher, L., Della Porta, M., Cazzola, M., Greenberg, P., Alimena, G., Rabault, B., Gathmann, I., Ford, J. M., Alberti, D., Rose, C. 2008; 80 (2): 168-176

  Abstract

  This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3-81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond-Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or beta-thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC).In patients with baseline LIC > or = 7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC (P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 +/- 0.14 mg/kg/d; greatest in DBA: 0.4 +/- 0.11 mg/kg/d). Overall, LIC changes were dependent on dose (P < 0.001) and transfusional iron intake (P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group (r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases.Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups.

  View details for DOI 10.1111/j.1600-0609.2007.00985.x

  View details for Web of Science ID 000252320600010

  View details for PubMedID 18028431

  View details for PubMedCentralID PMC2268958

• Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience BLOOD Park, S., Grabar, S., Kelaidi, C., Beyne-Rauzy, O., Picard, F., Bardet, V., Coiteux, V., Leroux, G., Lepelley, P., Daniel, M., Cheze, S., Mahe, B., Ferrant, A., Ravoet, C., Escoffre-Barbe, M., AdeS, L., Vey, N., Aljassern, L., Stamatoullas, A., Mannone, L., Dombret, H., Bourgeois, K., Greenberg, P., Fenaux, P., Dreyfus, F. 2008; 111 (2): 574-582

  Abstract

  We analyzed prognostic factors of response, response duration, and possible impact on survival of epoetin alpha, epoetin beta, or darbepoetin alpha (DAR) with or without granulocyte colony-stimulating factor in 403 myelodysplastic syndrome (MDS) patients. Sixty-two percent (40% major and 22% minor) and 50% erythroid responses were seen, and median response duration was 20 and 24 months according to IWG 2000 and 2006 criteria, respectively. Significantly higher response rates were observed with less than 10% blasts, low and int-1 International Prognostic Scoring System (IPSS), red blood cell transfusion independence, serum EPO level less than 200 IU/L, and, with IWG 2006 criteria only, shorter interval between diagnosis and treatment. Significantly longer response duration was associated with major response (IWG 2000 criteria), IPSS low to INT-1, blasts less than 5%, and absence of multilineage dysplasia. Minor responses according to IWG 2000 were reclassified as "nonresponders" or "responders" according to IWG 2006 criteria. However, among those IWG 2000 minor responders, response duration did not differ between IWG 2006 responders and nonresponders. Multivariate adjusted comparisons of survival between our cohort and the untreated MDS cohort used to design IPSS showed similar rate of progression to acute myeloid leukemia in both cohorts, but significantly better overall survival in our cohort, suggesting that epoetin or DAR treatment may have a favorable survival impact in MDS.

  View details for DOI 10.1182/blood-2007-06-096370

  View details for Web of Science ID 000252458700027

  View details for PubMedID 17940203

• International MDS Risk Analysis Workshop (IMRAW)/IPSS Re-analyzed: Impact of cytopenias on clinical outcomes in Myelodysplastic Syndrome Am J Hematology Kao, J. M., McMillan, A., Greenberg, P. L. 2008; 83: 765-770
• Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q 48th Annual Meeting of the American-Society-of-Hematology Raza, A., Reeves, J. A., Feldman, E. J., Dewald, G. W., Bennett, J. M., Deeg, J., Dreisbach, L., Schiffer, C. A., Stone, R. M., Greenberg, P. L., Curtin, P. T., Klimek, V. M., Shammo, J. M., Thomas, D., Knight, R. D., Schmidt, M., Wride, K., Zeldis, J. B., List, A. F. AMER SOC HEMATOLOGY. 2008: 86–93

  Abstract

  Lenalidomide is approved for red blood cell (RBC) transfusion-dependent anemia due to low or intermediate-1 (int-1) risk myelodysplastic syndromes (MDSs) associated with a chromosome 5q deletion with or without additional cytogenetic abnormalities. We report results of a multicenter, phase 2 trial evaluating lenalidomide therapy for transfusion-dependent patients with low- or int-1-risk MDS without deletion 5q. Eligible patients had 50,000/mm(3) or more platelets and required 2 U or more RBCs within the previous 8 weeks; 214 patients received 10 mg oral lenalidomide daily or 10 mg on days 1 to 21 of a 28-day cycle. The most common grade 3/4 adverse events were neutropenia (30%) and thrombocytopenia (25%). Using an intention-to-treat analysis, 56 (26%) patients achieved transfusion independence (TI) after a median of 4.8 weeks of treatment with a median duration of TI of 41.0 weeks. In patients who achieved TI, the median rise in hemoglobin was 32 g/L (3.2 g/dL; range, 10-98 g/L [1.0-9.8 g/dL]) from baseline. A 50% or greater reduction in transfusion requirement occurred in 37 additional patients, yielding a 43% overall rate of hematologic improvement (TI response + ||>or= 50% reduction in transfusion requirement). Lenalidomide has clinically meaningful activity in transfusion-dependent patients with low- or int-1-risk MDS who lack the deletion 5q karyotypic abnormality.

  View details for DOI 10.1182/blood-2007-01-068833

  View details for Web of Science ID 000252002000017

  View details for PubMedID 17893227

• Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF Blood Park S, Grabar S, Kelaidi C, Greenberg P, et al. 2008; 111: 574-582
• Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): A 1-year prospective study. Eur J Haematol Porter J, Galanello R, Saglio S, Greenberg P, et al 2008; 80: 168-176
• Phase II Study of Lenalidomide in Transfusion-Dependent, Low and Intermediate-1-Risk Myelodysplastic Syndromes with Normal and Abnormal Karyotypes Other than Deletion 5q. Blood Raza A, Reeves JE, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, Dreisbach L, Schiffer CA, Stone RM, Greenberg PL, et al 2008; 111: 86-93
• Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference LEUKEMIA RESEARCH Valent, P., Horny, H., Bennett, J. M., Fonatsch, C., Germing, U., Greenberg, P., Haferlach, T., Haase, D., Kolb, H., Krieger, O., Loken, M., van de Loosdrecht, A., Ogata, K., Orfao, A., Pfeilstocker, M., Ruter, B., Sperr, W. R., Stauder, R., Wells, D. A. 2007; 31 (6): 727-736

  Abstract

  The classification, scoring systems, and response criteria for myelodysplastic syndromes (MDS) have recently been updated and have become widely accepted. In addition, several new effective targeted drugs for patients with MDS have been developed. The current article provides a summary of updated and newly proposed markers, criteria, and standards in MDS, with special reference to the diagnostic interface and refinements in evaluations and scoring. Concerning the diagnostic interface, minimal diagnostic criteria for MDS are proposed, and for patients with unexplained cytopenia who do not fulfill these criteria, the term 'idiopathic cytopenia of uncertain significance' (ICUS) is suggested. In addition, new diagnostic and prognostic parameters, histopathologic and immunologic determinants, proposed refinements in scoring systems, and new therapeutic approaches are discussed. Respective algorithms and recommendations should facilitate diagnostic and prognostic evaluations in MDS, selection of patients for therapies, and the conduct of clinical trials.

  View details for DOI 10.1016/j.leukres.2006.11.009

  View details for Web of Science ID 000247764200001

  View details for PubMedID 17257673

• Chronic myelogenous leukemia. Journal of the National Comprehensive Cancer Network O'Brien, S., Berman, E., Bhalla, K., Copelan, E. A., Devetten, M. P., Emanuel, P. D., Erba, H. P., Greenberg, P. L., Moore, J. O., Przepiorka, D., Radich, J. P., Schilder, R. J., Shami, P., Smith, B. D., Snyder, D. S., Soiffer, R. J., Tallman, M. S., Talpaz, M., Wetzler, M. 2007; 5 (5): 474-496

  View details for PubMedID 17509252

• A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia BLOOD Lancet, J. E., Gojo, I., Gotlib, J., Feldman, E. J., Greer, J., Liesveld, J. L., Bruzek, L. M., Morris, L., Park, Y., Adjei, A. A., Kaufmann, S. H., Garrett-Mayer, E., Greenberg, P. L., Wright, J. J., Karp, J. E. 2007; 109 (4): 1387-1394

  Abstract

  Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.

  View details for DOI 10.1182/blood-2006-04-014357

  View details for Web of Science ID 000244219400013

  View details for PubMedID 17082323

• Myelodysplastic Syndromes: Impact of recently analyzed variables for modifying current classification methods Clinical Leukemia Kao JM, Greenberg PL 2007; 1: 172-182
• Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus Statements and Report from a Working Conference Leukemia Research Valent P, Horny HP, Bennett JM, Fonatsch C, Germing U, Greenberg P, et al 2007; 31: 727-736
• Phase I/II, randomized, MultiCenter, dose-ascension study of the p38MAPK inhibitor scio469 in patients with myelodysplastic syndrome (MDS). 48th Annual Meeting of the American-Society-of-Hematology Sokol, L., Cripe, L., Kantarjian, H., Sekeres, M. A., Parmar, S., Greenberg, P., Goldberg, S., Bhushan, V., Shammo, J., Hohl, R., Li, Y., Lowe, A., Zhu, J., List, A. AMER SOC HEMATOLOGY. 2006: 751A–751A

  View details for Web of Science ID 000242440003447

• Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion NEW ENGLAND JOURNAL OF MEDICINE List, A., Dewald, G., Bennett, J., Giagounidis, A., Raza, A., Feldman, E., Powell, B., Greenberg, P., Thomas, D., Stone, R., Reeder, C., Wride, K., Patin, J., Schmidt, M., Zeldis, J., Knight, R. 2006; 355 (14): 1456-1465

  Abstract

  Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal 5q31- clone in patients with this disorder.One hundred forty-eight patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Hematologic, bone marrow, and cytogenetic changes were assessed after 24 weeks of treatment by an intention-to-treat analysis.Among the 148 patients, 112 had a reduced need for transfusions (76%; 95% confidence interval [CI], 68 to 82) and 99 patients (67%; 95% CI, 59 to 74) no longer required transfusions, regardless of the karyotype complexity. The response to lenalidomide was rapid (median time to response, 4.6 weeks; range, 1 to 49) and sustained; the median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. The maximum hemoglobin concentration reached a median of 13.4 g per deciliter (range, 9.2 to 18.6), with a corresponding median rise of 5.4 g per deciliter (range, 1.1 to 11.4), as compared with the baseline nadir value before transfusion. Among 85 patients who could be evaluated, 62 had cytogenetic improvement, and 38 of the 62 had a complete cytogenetic remission. There was complete resolution of cytologic abnormalities in 38 of 106 patients whose serial bone marrow samples could be evaluated. Moderate-to-severe neutropenia (in 55% of patients) and thrombocytopenia (in 44%) were the most common reasons for interrupting treatment or adjusting the dose of lenalidomide.Lenalidomide can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients who have the myelodysplastic syndrome with the 5q31 deletion. (ClinicalTrials.gov number, NCT00065156 [ClinicalTrials.gov].).

  View details for Web of Science ID 000240976200007

  View details for PubMedID 17021321

• Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia BLOOD Cheson, B. D., Greenberg, P. L., Bennett, J. M., Lowenberg, B., Wijermans, P. W., Nimer, S. D., Pinto, A., Beran, M., de Witte, T. M., Stone, R. M., Mittelman, M., Sanz, G. F., Gore, S. D., Schiffer, C. A., Kantarjian, H. 2006; 108 (2): 419-425

  Abstract

  The myelodysplastic syndromes (MDSs) are heterogeneous with respect to clinical characteristics, pathologic features, and cytogenetic abnormalities. This heterogeneity is a challenge for evaluating response to treatment. Therapeutic trials in MDS have used various criteria to assess results, making cross-study comparisons problematic. In 2000, an International Working Group (IWG) proposed standardized response criteria for evaluating clinically significant responses in MDS. These criteria included measures of alteration in the natural history of disease, hematologic improvement, cytogenetic response, and improvement in health-related quality of life. The relevance of the response criteria has now been validated prospectively in MDS clinical trials, and they have gained acceptance in research studies and in clinical practice. Because limitations of the IWG criteria have surfaced, based on practical and reported experience, some modifications were warranted. In this report, we present recommendations for revisions of some of the initial criteria.

  View details for DOI 10.1182/blood-2005-10-4149

  View details for Web of Science ID 000239129500012

  View details for PubMedID 16609072

• Myelodysplastic Syndromes: Clinical and Biological Advances Cambridge University Press, Cambridge, England Greenberg, P. L. 2006
• A phase II study of the farnesyltransferase inhibitor tipifarnib in elderly patients with previously untreated poor-risk acute myeloid leukemia Blood Lancet J, Gojo I, Gotlib J, Greenberg PL, et al 2006; 108: 1387-1394
• Myelodysplastic syndromes: iron overload consequences and current chelating therapies. Journal of the National Comprehensive Cancer Network Greenberg, P. L. 2006; 4 (1): 91-96

  Abstract

  Chronic red blood cell transfusion support in patients with myelodysplastic syndromes (MDS) is often necessary but may cause hemosiderosis and its consequences. The pathophysiologic effects of iron overload relate to increased non-transferrin bound iron generating toxic oxygen free radicals. Studies in patients with MDS and thalassemia major have shown adverse clinical effects of chronic iron overload on cardiac function in patients who underwent polytransfusion. Iron chelation therapy in patients with thalassemia who were effectively chelated has prevented or partially reversed some of these consequences. A small group of patients with MDS who had undergone effective subcutaneous desferrioxamine (DFO) chelation for 1 to 4 years showed substantial hematologic improvements, including transfusion independence. However, because chronic lengthy subcutaneous infusions of DFO in elderly patients have logistic difficulties, this chelation therapy is generally instituted late in the clinical course. Two oral iron chelators, deferiprone (L1) and deferasirox (ICL670), provide potentially useful treatment for iron overload. This article reviews data indicating that both agents are relatively well tolerated, were at least as effective as DFO for decreasing iron burdens in comparative thalassemia trials, and (for deferiprone) were associated with improved cardiac outcomes. These outcomes could potentially alter the tissue siderosis-associated morbidity of patients with MDS, particularly those with pre-existing cardiac disease.

  View details for PubMedID 16403408

• Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood Cheson BD, Greenberg PL, Bennett JM, et al 2006; 108: 419-425
• Hematologic and cytogenetic response to lenalidomide in myelodysplastic syndrome with chromosome 5q deletion. New Eng J Med List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, et al 2006; 355: 1456-1465
• Myelodysplastic syndromes clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Greenberg, P. L., Baer, M. R., Bennett, J. M., Bloomfield, C. D., De Castro, C. M., Deeg, H. J., Devetten, M. P., Emanuel, P. D., Erba, H. P., Estey, E., Foran, J., Gore, S. D., Millenson, M., Navarro, W. H., Nimer, S. D., O'Donnell, M. R., Saba, H. I., Spiers, K., Stone, R. M., Tallman, M. S. 2006; 4 (1): 58-77

  View details for PubMedID 16403405

• Management of patients with higher risk myelodysplastic syndromes CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY Fukumoto, J. S., Greenberg, P. L. 2005; 56 (2): 179-192

  Abstract

  Higher risk myelodysplastic syndromes (MDS) include patients in the Intermediate-2 and high-risk categories of the International Prognostic Scoring System, as well as patients with MDS secondary to radiation or chemical exposure. Ideally, the goal of therapy is to alter the natural history of disease in these patients to achieve cure or durable remission. High-intensity chemotherapy can achieve moderate rates of complete remission, however, durability of remission and overall survival tend to be short. Hematopoietic stem cell transplantation (HSCT) offers the possibility of cure, with long-term disease-free survival inversely related to age. Patients who are elderly or have poor functional status are candidates for reduced intensity HSCT, although this is still an experimental modality. Azacitidine is a hypomethylating agent that is a reasonable option for many patients ineligible for high-intensity therapies. Other therapies, such as immunomodulatory agents, arsenic trioxide, and farnesyl transferase inhibitors have thus far shown limited usefulness in higher risk MDS. This paper reviews the various therapeutic options for higher risk MDS, providing rationale for specific management approaches for these patients.

  View details for DOI 10.1016/j.critrevonc.2005.04.006

  View details for Web of Science ID 000233455300001

  View details for PubMedID 15979321

• Chronic myelogenous leukemia. Journal of the National Comprehensive Cancer Network O'Brien, S., Berman, E., Bhalla, K., Copelan, E. A., Devetten, M. P., Emanuel, P. D., Erba, H. P., Greenberg, P. L., Moore, J. O., Przepiorka, D., Radich, J. P., Schilder, R. J., Shami, P., Smith, B. D., Snyder, D. S., Soiffer, R. J., Tallman, M. S., Talpaz, M., Wetzler, M. 2005; 3 (6): 732-755

  View details for PubMedID 16316611

• A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome BLOOD Cutler, C. S., Lee, S. J., Greenberg, P., Deeg, H. J., Perez, W. S., Anasetti, C., Bolwell, B. J., Cairo, M. S., Gale, R. P., Klein, J. P., Lazarus, H. M., Liesveld, J. L., McCarthy, P. L., Milone, G. A., Rizzo, J. D., Schultz, K. R., Trigg, M. E., Keating, A., Weisdorf, D. J., Antin, J. H., Horowitz, M. M. 2004; 104 (2): 579-585

  Abstract

  Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.

  View details for DOI 10.1182/blood-2004-01-0338

  View details for Web of Science ID 000222571400047

  View details for PubMedID 15039286

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

  Abstract

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

  View details for DOI 10.1200/JCO.2004.07.048

  View details for Web of Science ID 000220287900017

  View details for PubMedID 15020609

• A Decision Analysis of Allogeneic Bone Marrow Transplantation for the Myelodysplastic Syndromes: Delayed Transplantation for Low Risk Myelodysplasia is Associated with Improved Outcome Blood Cutler C, Lee SJ, Greenberg P, et al 2004; 104: 579-585
• Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic syndrome: an Eastern Cooperative Oncology Group (ECOG) study LEUKEMIA RESEARCH Cherry, A. M., Brockman, S. R., Paternoster, S. F., Hicks, G. A., Neuberg, D., Higgins, R. R., Bennett, J. M., Greenberg, P. L., Miller, K., Tallman, M. S., Rowe, J., DeWald, G. W. 2003; 27 (12): 1085-1090

  Abstract

  Cytogenetic analysis can be important in determining the prognosis and diagnosis of a number of hematological disorders, including myelodysplastic syndromes (MDS). Here, we compared metaphase chromosomal analyses on bone marrow aspirates from MDS patients with interphase fluorescence in situ hybridization (FISH) using probes specific for chromosomes nos. 5, 7, 8, 11, 13 and 20. Forty-three patients enrolled in ECOG protocol E1996 for low risk MDS and five patients enrolled in ECOG protocol E3996 for high risk MDS were studied by both metaphase chromosomal analysis and interphase FISH. Excluding those with a clonal loss of the Y chromosome, an abnormal clone was detected by cytogenetic analysis in 18 of 48 samples (37.5%). In comparison, our FISH panel detected an abnormal clone in 17 of 48 samples (35.4%). Twenty-nine of 30 samples with apparently normal karyotypes, including those with a missing Y chromosome, were also normal by our FISH panel. One patient had an occult deletion of chromosome 11 that was detected by FISH. These results indicate that around 60% of patients with MDS do not have abnormalities that are detectable by either chromosomal or FISH studies. In addition, it appears that interphase FISH studies are nearly as sensitive as cytogenetic analyses and can be a useful tool in studying bone marrow aspirates where cytogenetic analysis is not possible.

  View details for DOI 10.1016/S0145-2126(03)00104-8

  View details for Web of Science ID 000185431400004

  View details for PubMedID 12921944

• Phase it study of Bevacizumab (anti-VEGF humanized monoclonal antibody) in patients with myelodysplastic syndrome (MDS): Preliminary results 45th Annual Meeting and Exhibition of the American-Society-of-Hematology Gotlib, J., Jamieson, C. H., List, A., Cortes, J., Albitar, M., Sridhar, K., Dugan, K., Quesada, S., Diaz, G., Pate, O., Novotny, W., Chen, H., Greenberg, P. L. AMER SOC HEMATOLOGY. 2003: 425A–425A

  View details for Web of Science ID 000186536701545

• Novel biospecific agents for the treatment of myelodysplastic syndromes. J Nat Comprehensive Cancer Network Gotlib J, Greenberg P 2003; 1: 473-480
• Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: A pilot study LEUKEMIA Deeg, H. J., Gotlib, J., Beckham, C., Dugan, K., Holmberg, L., Schubert, M., Appelbaum, F., Greenberg, P. 2002; 16 (2): 162-164

  Abstract

  Blockade of tumor necrosis factor (TNF)alpha by a soluble TNF receptor fusion protein (etanercept; Enbrel) improved in vitro hemopoiesis from the marrow of patients with myelodysplastic syndrome (MDS). Therefore, we enrolled 14 MDS patients (4 RA, 2 RARS, 6 RAEB, 2 CMML), 44-80 (median 60) years old, in a pilot trial. Etanercept, 25 mg, was given twice a week s.c. for 16 weeks (increased to three times a week if no response at 8 weeks). Among 12 evaluable patients, four had rises in hemoglobin by 1-1.5 gm/dl (three) or decreased transfusion requirements (one). Two patients had increased platelet counts (54% and 73%), and two increased neutrophils (63% and 120%). Baseline TNFalpha levels, determined in all patients, did not correlate with responses. Among eight marrows available for sequential in vitro assays, four showed increases in CFU-GM of 1.5- to 5-fold at 8 weeks, whereas three showed 3- to 10-fold decrements relative to baseline. Thus, etanercept treatment resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others. Additional trials are needed to evaluate its clinical efficacy in MDS.

  View details for Web of Science ID 000173710800003

  View details for PubMedID 11840280

• Myelodysplastic syndromes. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program Greenberg, P. L., Young, N. S., Gattermann, N. 2002: 136-161

  Abstract

  The myelodysplastic syndromes (MDS) are characterized by hemopoietic insufficiency associated with cytopenias leading to serious morbidity plus the additional risk of leukemic transformation. Therapeutic dilemmas exist in MDS because of the disease's multifactorial pathogenetic features, heterogeneous stages, and the patients' generally elderly ages. Underlying the cytopenias and evolutionary potential in MDS are innate stem cell lesions, cellular/cytokine-mediated stromal defects, and immunologic derangements. This article reviews the developing understanding of biologic and molecular lesions in MDS and recently available biospecific drugs that are potentially capable of abrogating these abnormalities. Dr. Peter Greenberg's discussion centers on decision-making approaches for these therapeutic options, considering the patient's clinical factors and risk-based prognostic category. One mechanism underlying the marrow failure present in a portion of MDS patients is immunologic attack on the hemopoietic stem cells. Considerable overlap exists between aplastic anemia, paroxysmal nocturnal hemoglobinuria, and subsets of MDS. Common or intersecting pathophysiologic mechanisms appear to underlie hemopoietic cell destruction and genetic instability, which are characteristic of these diseases. Treatment results and new therapeutic strategies using immune modulation, as well as the role of the immune system in possible mechanisms responsible for genetic instability in MDS, will be the subject of discussion by Dr. Neal Young. A common morphological change found within MDS marrow cells, most sensitively demonstrated by electron microscopy, is the presence of ringed sideroblasts. Such assessment shows that this abnormal mitochondrial iron accumulation is not confined to the refractory anemia with ring sideroblast (RARS) subtype of MDS and may also contribute to numerous underlying MDS pathophysiological processes. Generation of abnormal sideroblast formation appears to be due to malfunction of the mitochondrial respiratory chain, attributable to mutations of mitochondrial DNA, to which aged individuals are most vulnerable. Such dysfunction leads to accumulation of toxic ferric iron in the mitochondrial matrix. Understanding the broad biologic consequences of these derangements is the focus of the discussion by Dr. Norbert Gattermann.

  View details for PubMedID 12446422

• Treatment of myelodysplastic syndrome with agents interfering with inhibitory cytokines ANNALS OF THE RHEUMATIC DISEASES Greenberg, P. 2001; 60: III41-III42

  Abstract

  Results of these trials provide evidence for biological activity and some clinical efficacy of agents potentially blocking inhibitory cytokines in patients with MDS. However, given the limited responses, it appears that factors additional to TNFalpha inhibitory activity contribute to the development of cytopenias in these patients. Further studies are warranted using anti-TNFalpha/anti-inhibitory cytokine approaches, either alone or in combination with other agents, capable of abrogating the effects of additional inhibitory mechanisms in MDS.

  View details for Web of Science ID 000171874400009

  View details for PubMedID 11890651

• Implications of pathogenetic and prognostic features for management of myelodysplastic syndromes LANCET Greenberg, P. 2001; 357 (9262): 1059-1060

  View details for Web of Science ID 000167996200004

  View details for PubMedID 11297953

• NCCN Practice Guidelines for chronic myelogenous leukemia ONCOLOGY-NEW YORK Talpaz, M., Berman, E., Clift, R. A., Copelan, E. A., Emanuel, P. D., Erba, H. P., Glenn, M. J., Greenberg, P. L., Jones, R. J., O'Brien, S., Saba, H. I., Schilder, R., Snyder, D. S., Soiffer, R. J., Tallman, M. S., Wetzler, M., Ravandi-Kashani, F., Kantarjian, H., Talpaz, M. 2000; 14 (11A): 229-240

  View details for Web of Science ID 000166713700023

  View details for PubMedID 11195415

• The Myelodysplastic Syndromes . HEMATOLOGY:BASIC PRINCIPLES AND PRACTICE 3rd Ed., Hoffman R, Benz E, Shattil S, Furie B, Cohen H, Silberstein L, McGlave P, Eds. Churchill Livingstone, NY, Greenberg, P. 2000: 1106-1129
• Prognostic scoring systems for risk assessment in myelodysplastic syndromes. Forum (Genoa, Italy) Greenberg, P. L., Sanz, G. F., Sanz, M. A. 1999; 9 (1): 17-31

  Abstract

  Clinical heterogeneity complicates therapy planning and makes it difficult to evaluate clinical trials in myelodysplastic syndromes (MDS). Thus, the development of a prognostic classification of MDS is of major clinical relevance, especially when considering the advanced age of most patients and the aggressiveness of the treatment modalities available. This review summarises the results of different studies focusing on prognostic factors in MDS and describes the relative advantages of the prognostic scoring systems that have been recently developed. This paper also discusses the prognostic factors of particular subtypes of patients. The percentage of marrow blasts, cytogenetic pattern and number and degree of cytopenias are the most powerful prognostic indicators in MDS. Although some limitations are evident, the recently developed scoring systems, and particularly the International Prognostic Scoring System, are extremely useful for predicting survival and acute leukaemic risk in individuals with MDS and should be incorporated into the design and analysis of therapeutic trials in these disorders. A risk-adapted treatment strategy is now possible and highly recommended for MDS patients.

  View details for PubMedID 10101208

• Apoptosis and its role in the myelodysplastic syndromes: implications for disease natural history and treatment LEUKEMIA RESEARCH Greenberg, P. L. 1998; 22 (12): 1123-1136

  Abstract

  Apoptosis (programmed cell death) is an active cellular process which regulates cell population size by decreasing cell survival. In this review the underlying cellular and molecular mechanisms of apoptosis in hemopoietic and non-hemopoietic cells are described, with specific focus on these issues in the myelodysplastic syndrome (MDS), a myeloid clonal hemopathy. Apoptosis-regulating genes exist as families whose protein products are either anti-apoptotic or pro-apoptotic. Numerous stimuli can serve as initiators of the cell death pathway, including essentially all chemotherapeutic drugs, irradiation, certain inhibitory cytokines and deprivation of relevant growth factors. Morphological evidence of increased apoptosis in marrow hemopoietic cells has been demonstrated in patients with MDS. The reviewed data provide support for the hypothesis that early in MDS, increased apoptosis is associated with ineffective progenitor and maturing hemopoietic cell survival, and occurs concomitant with cytopenias/ineffective hemopoiesis; conversely, the progression of MDS toward AML occurs in concert with decreased apoptosis and an increased degree of neoplastic cell survival, leading to subsequent expansion of the abnormal precursor cells. These processes are associated with alterations in the balance between pro- and anti-apoptotic oncoprotein expression within the hemopoietic precursors, which may be modified by cytokine treatment. Investigations evaluating apoptotic events in MDS have improved our understanding of the biology of hemopoietic cell survival as related to pathogenetic features of this disease. By modifying levels of apoptosis, such studies provide a framework for future potentially beneficial therapeutic approaches to treat patients with MDS.

  View details for Web of Science ID 000077758000006

  View details for PubMedID 9922076

• Bcl-2 expression by myeloid precursors in myelodysplastic syndromes: relation to disease progression 36th Annual Meeting of the American-Society-of-Hematology Davis, R. E., Greenberg, P. L. PERGAMON-ELSEVIER SCIENCE LTD. 1998: 767–77

  Abstract

  the bcl-2 oncogene blocks apoptosis in various cell types and is expressed by normal myeloid precursors, declining with maturation. To investigate whether bcl-2 plays a role in the increase of myeloblasts in myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML), we studied bcl-2 expression in initial (pre-therapy) bone marrow biopsies from MDS at early (refractory anemia, RA, with or without ring sideroblasts) and advanced stages (RA with excess blasts, and in transformation). Sequential biopsies were also studied to evaluate the effect of time or disease progression, including evolution to AML, or therapy with granulocyte colony stimulating factor (G-CSF). Early myeloid precursors (EMPs), predominantly myeloblasts, were identified in paraffin sections after immunostaining; bcl-2-positive EMPs were enumerated as a percentage of all EMPs (Bcl-2%), and by their absolute frequency per x 900 microscopic field (Bcl-2 index).in initial biopsies, the Bcl-2% and Bcl-2 index in early MDS (9.9+/-2.6 and 1.4+/-0.6, respectively; mean+/-S.E.) were significantly lower than in advanced MDS (26.4+/-3.6, 4.6+/-1.4), but similar to controls (8.1+/-0.3 and 0.8+/-0.1). The Bcl-2% and Bcl-2 index in three patients with AML evolved from MDS (57.4+/-17.9 and 85.1+/-62.4) were similar to values for seven patients with de novo AML (63.0+/-10.0, 98.4+/-29.8) and significantly higher than values for other groups. Bcl-2% showed relative increments with time or disease progression (range, 21-273%; 11 of 18 sequential biopsies from six of ten MDS patients), which was not clearly altered by G-CSF therapy (four of six patients with, two of four patients without treatment).bcl-2 expression by EMPs (in both proportion and absolute number) correlated with initial MDS stage, progressed over time independent of G-CSF therapy, and was associated with evolution to AML. These data provide support for the hypothesis that MDS progression is related to accumulation of immature myeloid cells with increased bcl-2 expression and decreased apoptosis.

  View details for Web of Science ID 000075292300001

  View details for PubMedID 9716007

• Risk factors and their relationship to prognosis in myelodysplastic syndromes LEUKEMIA RESEARCH Greenberg, P. L. 1998; 22: S3-S6

  Abstract

  Recent efforts have been directed at improving the methodology for predicting clinical outcomes in patients with myelodysplastic syndromes (MDS). This review focuses on the development of a consensual, prognostic, risk-based analysis system generated by the International MDS Risk Analysis Workshop. In the workshop, cytogenetic, morphological, and clinical data were combined and collated from a relatively large group of patients with primary MDS. Critical prognostic variables were evaluated using the data set. Based on these findings, the International Prognostic Scoring System (IPSS) was developed, compared with other systems, and shown to provide more accurate prognoses regarding survival and evolution to acute myeloid leukemia in MDS patients. The improvement was due to several features of the workshop model: more refined cytogenetic categorization, inclusion of cytopenias, improved subdivision of marrow blast percentages, four subgroups defining outcome, and separate stratification for age. The IPSS should result in better-defined clinical outcomes in MDS and provide a framework for future studies determining the possible role of molecular determinants (e.g. oncogenes, tumor suppressor genes, cytokine expression and responsiveness) for evaluating prognoses. The IPSS will likely prove useful in the design and analysis of therapeutic trials in MDS as well as in patient management.

  View details for Web of Science ID 000075727800002

  View details for PubMedID 9734692

• Prognostic factors and scoring systems in myelodysplastic syndromes HAEMATOLOGICA Sanz, G. F., Sanz, M. A., Greenberg, P. L. 1998; 83 (4): 358-368

  Abstract

  Great prognostic heterogeneity complicates therapy-planning and a correct evaluation of clinical trials in myelodysplastic syndromes (MDS). Thus, the development of a prognostic classification of MDS is of major clinical relevance, especially when the advanced age of most patients and the aggressiveness of the curative treatment modalities currently available are considered. This review summarizes the results of different studies focusing on prognostic factors in MDS and deals with the pros and cons of prognostic scoring systems that have been recently developed. It also discusses the prognostic factors of particular subtypes of patients and those isolated with certain treatment options.The authors of the present review have been working in different areas of the field of MDS for several years, have contributed original papers on the prognostic factors and therapy of these disorders, and have taken part in the recent International MDS Risk Analysis Workshop that has resulted in the development of the International Prognostic Scoring System (IPSS) for MDS.The percentage of marrow blasts, cytogenetic pattern and number and degree of cytopenias are the most powerful prognostic indicators in MDS. Although some limitations are evident, the recently developed scoring systems, and particularly the IPSS, are extremely useful for predicting survival and acute leukemic risk in individuals with MDS and should be incorporated to the design and analysis of therapeutic trials in these disorders. A risk-adapted treatment strategy is now possible and highly recommended for MDS patients.

  View details for Web of Science ID 000073988400012

  View details for PubMedID 9592987

• NCCN Practice Guidelines for Myelodysplastic Syndromes Oncology Greenberg PL, Bishop M, Deeg J, Erba H, Gore S, Nimer S, ODonnell M, Tallman M, Bennett J, Estey E, Stone R 1998; 12 (11A): 53-80
• Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model BRITISH JOURNAL OF HAEMATOLOGY HELLSTROMLINDBERG, E., Negrin, R., Stein, R., Krantz, S., Lindberg, G., Vardiman, J., Ost, A., Greenberg, P. 1997; 99 (2): 344-351

  Abstract

  Previous studies have shown that approximately 40% of patients with myelodysplastic syndrome (MDS) and anaemia respond to treatment with human recombinant granulocyte-CSF (G-CSF) plus erythropoietin (epo). The present study was designed to investigate pre-treatment variables for their ability to predict erythroid responses to this treatment. 98 patients with MDS (30 RA, 31 RARS, 32 RAEB, five RAEB-t) were treated with a combination of G-CSF (0.3-3.0 microg/kg/d, s.c.) and epo (60-300 U/kg/d, s.c.) for at least 10 weeks. Minimum criteria for erythroid response was a 100% reduction of red blood cell (RBC) transfusion need or an increase in haemoglobin level of > or = 1.5 g/dl. 35 patients (36%) showed responses to treatment. Medium duration of response was 11-24 months. In multivariate analysis, serum erythropoietin levels and initial RBC-transfusion need retained high statistical significance (P < 0.01). Using pre-treatment serum epo levels as a ternary variable (< 100, 100-500 or > 500 U/l) and RBC transfusion need as a binary variable (< 2 or > or = 2 units per month), the analysis provided a predictive score for erythroid response. This score divided patients into three groups: one group with a high probability of erythroid responses (74%), one intermediate group (23%) and one group with poor responses to treatment (7%). This predictive scoring system could be used in decisions regarding use of these cytokines for treating the anaemia of MDS, both for defining patients who should not be given the treatment and for selecting patients for inclusion in prospective trials.

  View details for Web of Science ID A1997YG53500019

  View details for PubMedID 9375752

• International scoring system for evaluating prognosis in myelodysplastic syndromes BLOOD Greenberg, P., Cox, C., LEBEAU, M. M., Fenaux, P., Morel, P., Sanz, G., Sanz, M., Vallespi, T., Hamblin, T., Oscier, D., Ohyashiki, K., Toyama, K., Aul, C., Mufti, G., Bennett, J. 1997; 89 (6): 2079-2088

  Abstract

  Despite multiple disparate prognostic risk analysis systems for evaluating clinical outcome for patients with myelodysplastic syndrome (MDS), imprecision persists with such analyses. To attempt to improve on these systems, an International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems. A global analysis was performed on these patients, and critical prognostic variables were re-evaluated to generate a consensus prognostic system, particularly using a more refined bone marrow (BM) cytogenetic classification. Univariate analysis indicated that the major variables having an impact on disease outcome for evolution to acute myeloid leukemia were cytogenetic abnormalities, percentage of BM myeloblasts, and number of cytopenias; for survival, in addition to the above, variables also included age and gender. Cytogenetic subgroups of outcome were as follows: "good" outcomes were normal, -Y alone, del(5q) alone, del(20q) alone; "poor" outcomes were complex (ie, > or = 3 abnormalities) or chromosome 7 anomalies; and "intermediate" outcomes were other abnormalities. Multivariate analysis combined these cytogenetic subgroups with percentage of BM blasts and number of cytopenias to generate a prognostic model. Weighting these variables by their statistical power separated patients into distinctive subgroups of risk for 25% of patients to undergo evolution to acute myeloid leukemia, with: low (31% of patients), 9.4 years; intermediate-1 (INT-1; 39%), 3.3 years; INT-2 (22%), 1.1 years; and high (8%), 0.2 year. These features also separated patients into similar distinctive risk groups for median survival: low, 5.7 years; INT-1, 3.5 years; INT-2, 1.2 years; and high, 0.4 year. Stratification for age further improved analysis of survival. Compared with prior risk-based classifications, this International Prognostic Scoring System provides an improved method for evaluating prognosis in MDS. This classification system should prove useful for more precise design and analysis of therapeutic trials in this disease.

  View details for Web of Science ID A1997WP23100028

  View details for PubMedID 9058730

• Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells BLOOD Rajapaksa, R., Ginzton, N., Rott, L. S., Greenberg, P. L. 1996; 88 (11): 4275-4287

  Abstract

  Ineffective hematopoiesis with associated cytopenias and potential evolution to acute myeloid leukemia (AML) characterize patients with myelodysplastic syndrome (MDS). We evaluated levels of apoptosis and of apoptosis-related oncoproteins (c-Myc, which enhances, and Bcl-2, which diminishes apoptosis) expressed within CD34+ and CD34- marrow cell populations of MDS patients (n = 24) to determine their potential roles in the abnormal hematopoiesis of this disorder. Marrow cells were permeabilized and CD34+ and CD34- cells were separately analyzed by FACS to detect: (1) a subdiploid (sub-G1) DNA population, and (2) expression of Bcl-2 and c-Myc oncoproteins. Within the CD34+ subset, a significantly increased percentage of cells demonstrated apoptotic/sub-G1 DNA content in early (ie. refractory anemia) MDS patients compared with normal individuals and AML patients (mean values: 9.1% > 2.1% > 1.2%). Correlated with these findings, the ratio of expression of c-Myc to Bcl-2 oncoproteins among CD34+ cells was significantly increased for MDS patients compared to those from normal and AML individuals (mean values: 1.6 > 1.2 > 0.9). Bcl-2 and c-Myc oncoprotein levels were maturation stage-dependent, with high levels expressed within CD34+ marrow cells, decreasing markedly with myeloid maturation. Treatment of seven MDS patients with the cytokines granulocyte colony-stimulating factor plus erythropoietin was associated with decreased levels of apoptosis within CD34+ marrow cells and may contribute to the enhanced hematopoiesis in vivo that was shown. These findings are consistent with the hypothesis that altered balance between cell-death (eg, c-Myc) and cell-survival (eg, Bcl-2) programs were associated with the increased degrees of apoptosis present in MDS hematopoietic precursors and may contribute to the ineffective hematopoiesis in this disorder, in contrast to decreased apoptosis and enhanced leukemic cell survival in AML.

  View details for Web of Science ID A1996VV15200024

  View details for PubMedID 8943864

• GM-CSF accelerates neutrophil recovery after autologous hematopoietic stem cell transplantation BONE MARROW TRANSPLANTATION Greenberg, P., Advani, R., Keating, A., Gulati, S. C., Nimer, S., Champlin, R., Karanes, C., Gorin, N. C., Powles, R. L., Smith, A., Lamborn, K., Cuffie, C. 1996; 18 (6): 1057-1064

  Abstract

  Patients with non-myeloid hematologic malignancies (including Hodgkin's and non-Hodgkin's lymphomas, myeloma and acute lymphoid leukemia) or solid tumors underwent cytoreductive conditioning regimens followed by either autologous bone marrow transplantation (ABMT) (n = 343) or transplantation of peripheral blood stem cells (PBSC) with (n = 44) or without bone marrow (BM) (n = 16). In a randomized double-blind phase III multi-center trial, patients received either granulocyte-macrophage colony-stimulating factor (GM-CSF, 10 micrograms/kg/day) or placebo by daily i.v. infusion beginning 24 h after bone marrow infusion and continuing until the absolute neutrophil count (ANC) had recovered to > or = 1000/mm3, or for a maximum of 30 days. Median time to neutrophil recovery was significantly shorter in the GM-CSF group (18 vs 27 days, P < 0.001), and more GM-CSF patients had neutrophil recovery by day 30 (70 vs 48%). Median duration of hospitalization was significantly shorter in the GM-CSF group (29 vs 32 days, P = 0.02). GM-CSF significantly reduced the median time to neutrophil recovery in patients receiving bone marrow only (19 vs 27 days, P < 0.001) or PBSC with or without bone marrow (14 vs 21 days, P < 0.001). The overall incidence of adverse events was comparable in the two groups, although more patients in the GM-CSF group discontinued treatment due to adverse events (17 vs 9%, P < 0.001). No difference was noted in infection incidence or time to platelet independence. GM-CSF had no negative impact on time to relapse or long-term survival. These data indicate the positive influence of GM-CSF on neutrophil recovery and hospital stay in patients receiving ABMT for a variety of clinical indications.

  View details for Web of Science ID A1996VZ81700005

  View details for PubMedID 8971373

• Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: Evidence for in vivo synergy BLOOD Negrin, R. S., Stein, R., Doherty, K., Cornwell, J., Vardiman, J., Krantz, S., Greenberg, P. L. 1996; 87 (10): 4076-4081

  Abstract

  Patients with myelodysplastic syndromes (MDS) have refractory cytopenias leading to transfusion requirements and infectious complications. In vitro marrow culture data have indicated that granulocyte colony stimulating factor (G-CSF) synergizes with erythropoietin (EPO) for the production of erythroid precursors. In an effort to treat the anemia and neutropenia in this disorder, MDS patients were treated with a combination of recombinant human EPO and recombinant human G-CSF. Fifty-five patients were enrolled in the study of which 53 (96%) had a neutrophil response. Forty-four patients were evaluable for an erythroid response of which 21 (48%) responded. An erythroid response was significantly more likely in those patients with relatively low serum EPO levels, higher absolute basal reticulocyte counts and normal cytogenetics at study entry. Seventeen (81%) of the patients who responded to combined G-CSF plus EPO therapy continued to respond during an 8-week maintenance phase. G-CSF was then discontinued and all patients' neutrophil responses were diminished, whereas 8 continued to have an erythroid response to EPO alone. In 7 of the remaining 9 patients, resumption of G-CSF was required for recurrent erythroid responses. The median duration of erythroid responses to these cytokines was 11 months, with 6 patients having relatively prolonged and durable responses for 15 to 36 months. Our results also indicate that approximately one half of responding patients require both G-CSF and EPO to maintain an effective erythroid response, suggesting that synergy between G-CSF and EPO exists in vivo for the production of red blood cells in MDS.

  View details for Web of Science ID A1996UK87900007

  View details for PubMedID 8639764

• Biologic and clinical implications of marrow culture studies in the myelodysplastic syndromes SEMINARS IN HEMATOLOGY Greenberg, P. L. 1996; 33 (2): 163-175

  View details for Web of Science ID A1996UG59700007

  View details for PubMedID 8722686

• Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human G-CSF plus erythropoietin: Evidence for in vivo synergy Blood Negrin RS, Stein R, Doherty K, Cromwell J, Vardiman J, Krantz S, Greenberg PL 1996; 87: 4076-4081
• ENRICHMENT OF BONE-MARROW AND BLOOD PROGENITOR (CD34(+)) CELLS BY DENSITY GRADIENTS WITH SUFFICIENT YIELDS FOR TRANSPLANTATION EXPERIMENTAL HEMATOLOGY Schriber, J. R., DEJBAKHSHJONES, S., KUSNIERZGLAZ, C. R., Ginzton, N., Still, B., Negrin, R. S., Greenberg, P., Strober, S. 1995; 23 (9): 1024-1029

  Abstract

  We have evaluated the use of iso-osmolar Percoll density gradients to enrich CD34+ hematopoietic progenitor cells and to reduce T cells for purposes of bone marrow or mobilized peripheral blood cell transplantation (BMT or PBCT). Samples from 12 normal BM donors and 11 patients undergoing mobilization of PB cells using chemotherapy and G-CSF were placed over a five-step density gradient from 40 to 50% Percoll. In BM, low-density fractions 1 to 3 (40 to 45% Percoll) accounted for 3% of starting nucleated cells with a 10- to 20-fold enrichment of hematopoietic progenitors (CD34+ cells) and a 20-fold reduction of CD4+ and CD8+ T cells. In PB, fractions 1 to 3 accounted for 20 to 30% of the starting nucleated cells with a five-fold enrichment of hematopoietic progenitors. Based on these values, such populations have been used for clinical transplantation using a single apheresis. The reduced cell numbers in the low-density fractions can facilitate tumor purging, and the reduced T cell numbers present in the marrow may ameliorate graft-vs.-host disease.

  View details for Web of Science ID A1995RP11800011

  View details for PubMedID 7543414

• MODULATION OF APOPTOSIS IN HUMAN MYELOID LEUKEMIC-CELLS BY GM-CSF EXPERIMENTAL HEMATOLOGY Han, J. H., Gileadi, C., Rajapaksa, R., Kosek, J., Greenberg, P. L. 1995; 23 (3): 265-272

  Abstract

  Apoptosis (programmed cell death) regulates cell population size. To determine the mechanisms whereby hematopoietic growth factors (HGFs) modulate apoptosis in human myeloid leukemic cells, we evaluated the roles of protein and mRNA synthesis for altering apoptosis in growth factor-stimulated vs. quiescent leukemic TF1 cells. Lysates of cells from the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent myeloid leukemic cell line TF1 were separated into high molecular weight (HMW) pellets of intact DNA and supernatants of fragmented low MW (LMW) DNA, and the DNA purified from these fractions was quantified. In the absence of both GM-CSF and fetal bovine serum (FBS), 70% of the DNA was fragmented after 3 days in culture, with a characteristic apoptotic ladder-like pattern on agarose gel electrophoresis, whereas this proportion had initially been < 5%. In contrast, less than 5% of the DNA was fragmented in cells incubated with GM-CSF plus FBS or GM-CSF alone. Delayed addition of GM-CSF, but not FBS, permitted partial rescue of the cells, inhibiting increasing rates of accumulation of fragmented DNA. When the macro-molecular synthesis inhibitor cycloheximide (CHX) or actinomycin D (Act D) was present for 26 hours in the absence of GM-CSF and FBS, apoptosis was inhibited. In contrast, in the presence of GM-CSF or FBS, apoptosis was enhanced upon addition of CHX or Act D. The latter effect persisted even with the late addition of CHX. These findings indicate that disparate mechanisms of enhancing or inhibiting apoptosis exist in myeloid leukemic cells related to environmental conditions, including HGF-regulated cellular synthesis of distinct proteins and mRNA.

  View details for Web of Science ID A1995QK72300014

  View details for PubMedID 7875243

• THE ROLE OF HEMATOPOIETIC GROWTH-FACTORS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROMES International Symposium on Current Problems of Childhood Panmyelopathies - Focus on Myelodysplastic Syndrome Greenberg, P. MINISTERSTVO ZDRAVOOKHRANENIYA. 1995: 12–13

  View details for Web of Science ID A1995RJ47900010

• EFFECTS OF GRANULOCYTE-COLONY-STIMULATING FACTOR THERAPY ON IN-VITRO HEMATOPOIESIS IN MYELODYSPLASTIC SYNDROMES LEUKEMIA Nagler, A., MacKichan, M. L., Negrin, R. S., Donlon, T., Greenberg, P. L. 1995; 9 (1): 30-39

  Abstract

  We evaluated the effects of 2 months of G-CSF treatment on in vitro hematopoiesis in 17 patients with myelodysplastic syndromes (MDS). Although in vitro marrow myeloid progenitor cell (CFU-GM) growth stimulated by G-CSF generally remained subnormal, in the majority of neutrophil responders significantly augmented incremental change (termed AIC) of CFU-GM numbers occurred after treatment, as did neutrophilic differentiation. The neutrophil non-responders had less prominent in vitro myeloid responses and lower basal neutrophil levels (p < 0.05). Following G-CSF treatment, the initially subnormal erythroid burst-forming unit (BFU-E) values underwent AIC in five of 11 patients along with increased reticulocyte responses in vivo, whereas four of the five patients who lacked AIC of BFU-E did not. Three patients with persisting cytogenetic abnormalities and increased neutrophilic differentiation in vitro also responded in vivo, suggesting that G-CSF induced in vivo cellular differentiation from the abnormal clone. Two of the three patients who developed blastic responses in vivo had increased CFU-GM growth pre- and post-therapy. These results indicate in vivo-in vitro correlations for myeloid and erythroid responses of MDS marrow cells which related to treatment with G-CSF.

  View details for Web of Science ID A1995QH98700007

  View details for PubMedID 7531261

• EXPRESSION OF EVI1 IN MYELODYSPLASTIC SYNDROMES AND OTHER HEMATOLOGIC MALIGNANCIES WITHOUT 3Q26 TRANSLOCATIONS BLOOD Russell, M., List, A., Greenberg, P., Woodward, S., Glinsmann, B., Parganas, E., Ihle, J., Taetle, R. 1994; 84 (4): 1243-1248

  Abstract

  The EVI1 gene encodes a zinc-finger, DNA-binding protein originally described as the transforming gene associated with a common ecotropic viral insertion site in myeloid leukemias. Previous studies demonstrated EVI1 expression in human leukemias in cases with 3q26 translocations, but not in normal blood or bone marrow. These studies also suggested an association between EVI1 expression and chromosome 7 deletion (del). Because of this association, we examined expression of EVI1 using RNA polymerase chain reaction (PCR) in patients with myelodysplastic syndromes (MDS) and acute leukemia with and without 3q26 translocations. EVI1 RNA was expressed in 29% of 34 (95% confidence interval, 20% to 50%) patients with the MDS subtypes refractory anemia (RA), refractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transformation (RAEB-T). The vast majority of these cases occurred in patients with RAEB and RAEB-T. EVI1 expression was not detected in patients with chronic myelomonocytic leukemia (CMML), normal bone marrow or cord blood, or a variety of other hematologic malignancies. EVI1 RNA was detected in three of 18 patients with acute myelogenous leukemia (AML) and in two of four patients with acute promyelocytic leukemia (APL). Karyotypes showed that only one AML patient had karyotype 3q26 abnormalities, indicating that EVI1 expression is associated with cases that do not have structural abnormalities involving chromosome 3q26. These studies document for the first time the abnormal expression of EVI1 RNA by patients with MDS, and suggest an important role for EVI1 in the pathogenesis or progression of some myeloid malignancies.

  View details for Web of Science ID A1994PC40200032

  View details for PubMedID 8049440

• MUTATIONS IN THE RAS PROTOONCOGENES IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES LEUKEMIA Neubauer, A., Greenberg, P., Negrin, R., Ginzton, N., Liu, E. 1994; 8 (4): 638-641

  Abstract

  Activation of the N- and K-ras proto-oncogenes is the most common molecular abnormality in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In retrospective studies, approximately 3-36% of MDS patients were reported to harbor a mutated ras proto-oncogene, with some series suggesting the presence of ras-mutations are associated with progressive disease and a poor prognosis. Since hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) are currently used for therapy in MDS but may stimulate the proliferation of leukemic cells, we assessed the frequency and significance of ras mutations in 27 MDS patients, 15 of whom underwent G-CSF therapy. Patients were analyzed for the presence of mutations in codons 12, 13, and 61 of the N- and K-ras proto-oncogenes. Only three patients (11%, two refractory anemia with excess of blasts (RAEB), one RAEB in transformation (RAEB-T)) harbored activated ras oncogenes with the mutations localized in N-ras codons 12 and 61. Patients were followed for periods of up to 4 years or until death supervened. Patients exhibiting ras mutations were no more likely to develop AML compared to ras-negative patients (1/3 vs. 10/24) or to have decreased survival (p = 0.64). These data indicate that, in this group of MDS patients, ras mutations do not appear to correlate with a poor prognosis, and do not adversely interact with exogenously administered G-CSF.

  View details for Web of Science ID A1994NJ51700016

  View details for PubMedID 7512175

• PHASE-III RANDOMIZED MULTICENTER TRIAL OF G-CSF VS OBSERVATION FOR MYELODYSPLASTIC SYNDROMES (MDS) Greenberg, P., Taylor, K., Larson, R., Koeffler, P., Negrin, R., Saba, H., Ganser, A., Jakubowski, A., Gabrilove, J., Mufti, G., Cruz, J., Hammond, W., Broudy, V., Langley, G. R., Keating, A., Vardiman, J., Lamborn, K., Brown, S. AMER SOC HEMATOLOGY. 1993: A196–A196

  View details for Web of Science ID A1993MJ68200767

• TREATMENT OF THE ANEMIA OF MYELODYSPLASTIC SYNDROMES USING RECOMBINANT HUMAN GRANULOCYTE-COLONY-STIMULATING FACTOR IN COMBINATION WITH ERYTHROPOIETIN BLOOD Negrin, R. S., Stein, R., Vardiman, J., Doherty, K., Cornwell, J., Krantz, S., Greenberg, P. L. 1993; 82 (3): 737-743

  Abstract

  We treated myelodysplastic syndrome patients (MDS) with both recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human erythropoietin (EPO) to determine whether such combination therapy resulted in improvement of their anemias. Twenty-four of 28 patients begun on study completed the protocol and were evaluable for erythroid responses. Therapy was initiated with G-CSF at 1 micrograms/kg administered by daily subcutaneous injection and adjusted to either normalize or double the neutrophil count. EPO was then administered by daily subcutaneous injection at a dose of 100 U/kg and dose-escalated to 150 and 300 U/kg every 4 weeks while continuing the G-CSF. Changes in absolute reticulocyte count, hematocrit level, and need for RBC transfusions were compared with pretreatment values as well as other blood cell counts. Ten of 24 patients (42%) had erythroid responses, whereas all patients had neutrophil responses. Six previously transfused patients no longer required RBC transfusions during the treatment period. Erythroid responses were found to be independent of patient age, French-American-British subtype, duration of disease, prior RBC transfusion requirements, or cytogenetic abnormalities at presentation. Pretreatment serum EPO levels were lower in erythroid-responding as compared with nonresponding patients (median 157 v 600 U/L; P = .05). The combined treatment modality was generally well tolerated. We conclude that a substantial percentage of MDS patients had both erythroid and myeloid responses when treated with the combination of G-CSF and EPO.

  View details for Web of Science ID A1993LQ74100008

  View details for PubMedID 7687889

• T-CELL SUBSETS AND SUPPRESSOR CELLS IN HUMAN BONE-MARROW BLOOD SCHMIDTWOLF, I. G., DEJBAKHSHJONES, S., Ginzton, N., Greenberg, P., Strober, S. 1992; 80 (12): 3242-3250

  Abstract

  To characterize immune suppressive and hematopoietic features of enriched subsets of human marrow cells, we separated these cells on Percoll density gradients. CD4+ and CD8+ T cells (CD3+) were enriched in the high-density marrow cell fractions and reduced in low-density fractions. CD4-CD8- (CD3+) T cells expressing the alpha beta T-cell antigen receptor were at least 10 times less numerous than the CD4+ and CD8+ T cells in all fractions. Purified populations of the CD4-CD8- alpha beta + T cells obtained by flow cytometry suppressed the mixed leukocyte reaction (MLR). Another population of suppressor cells that expressed neither T-cell (CD3) nor natural killer cell (CD16) surface markers was also identified. The latter cells had the phenotypic and functional characteristics of "natural suppressor" cells. Suppressor cell activity was enriched in the low-density fractions along with hematopoietic progenitors (colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid). The progenitor and suppressor cell activities were depleted in high-density fractions. The latter fractions made vigorous responses in the MLR. The low-density fractions, which accounted for less than 10% of the input marrow cells, suppressed the MLR and did not respond. Further evaluation of the low-density fractions may be of value in allogeneic bone marrow transplantation due to the reduction of CD4+ and CD8+ T cells and the enrichment of hematopoietic progenitors as well as immune suppressor cells that may inhibit graft-versus-host disease.

  View details for Web of Science ID A1992KC83800034

  View details for PubMedID 1467527

• INVITRO MARROW CULTURE STUDIES IN THE MYELODYSPLASTIC SYNDROMES SEMINARS IN ONCOLOGY Greenberg, P. L. 1992; 19 (1): 34-46

  View details for Web of Science ID A1992HD44900005

  View details for PubMedID 1736368

• TREATMENT OF MYELODYSPLASTIC SYNDROMES WITH HEMATOPOIETIC GROWTH-FACTORS SEMINARS IN ONCOLOGY Greenberg, P. L. 1992; 19 (1): 106-114

  View details for Web of Science ID A1992HD44900009

  View details for PubMedID 1371018

• Programmed cell death (apoptosis) as a mechanism for regulating haematopoietic cell population size Focus on Growth Factors Greenberg , P. L. 1992; 3 (2): 1-3
• TREATMENT OF MYELODYSPLASTIC SYNDROMES BLOOD REVIEWS Greenberg, P. L. 1991; 5 (1): 42-50

  Abstract

  Therapeutic options have been rapidly evolving for management of patients with the indolent myeloid clonal hemopathies termed myelodysplastic syndromes (MDS). Heterogeneity of MDS has been demonstrated on the basis of marrow morphology and biologic features and has been useful for prognostication into high and low risk groups for transformation to acute leukemia. Such stratification has been important for evaluating responses to various treatments. These therapeutic options include the differentiation-inducing vitamins retinoic acid and vitamin D, and cytokines such as alpha and gamma interferon, to which there has been a generally low response. The use of intensive or low dose chemotherapy has been associated with relatively low response rates, few durable responses and a high degree of hemopoietic toxicity. Allogeneic bone marrow transplantation (BMT) has shown durable responses for a subset of MDS patients, particularly those who are young and who are in the low risk subgroups. however, due to the elderly nature of the majority of MDS patients, and the toxicity associated with BMT, this option has limited utility for most of these patients. Major focus has been on the recent therapeutic use of recombinant human hemopoietic growth factors, particularly G-CSF, GM-CSF and IL3. These agents have been well-tolerated and generally produce a high incidence of sustained improvements in neutrophil counts and marrow morphology, although hemoglobin and platelet counts have generally not been altered. More extensive clinical trials evaluating the impact of these hemopoietic growth factors on the natural history of MDS are ongoing.

  View details for Web of Science ID A1991FD16900006

  View details for PubMedID 1709576

• EFFECTS OF INSULIN-LIKE GROWTH-FACTORS ON HEMATOPOIESIS BLOOD CELLS Greenberg, P. L. 1991; 17 (2): 344-346

  View details for Web of Science ID A1991FN56900012

  View details for PubMedID 1912599

• GRANULOCYTE-MONOCYTE AND GRANULOCYTE-COLONY STIMULATING FACTORS IN MYELODYSPLASTIC SYNDROMES LEUKEMIA & LYMPHOMA Nagler, A., Greenberg, P. L. 1991; 5 (4): 219-230

  View details for Web of Science ID A1991GR69400001

• FUNCTIONAL INTERACTIONS BETWEEN COLONY-STIMULATING FACTORS AND THE INSULIN FAMILY HORMONES FOR HUMAN MYELOID LEUKEMIC-CELLS CANCER RESEARCH Oksenberg, D., DIECKMANN, B. S., Greenberg, P. L. 1990; 50 (20): 6471-6477

  Abstract

  We investigated functional interactions between granulocyte-monocyte-colony-stimulating factor (GM-CSF) and the insulin family hormones using the GM-CSF- and insulin-dependent human acute myeloid leukemia cell line AML-193. Recombinant human GM-CSF and insulin enhanced AML-193 cell proliferation 3- and 5-fold, respectively, and showed a synergistic 10-fold increase when added in combination. Insulin-like growth factors I and II (IGFI and IGFII) increased AML-193 cell proliferation 4-fold and 2-fold, respectively, and also demonstrated synergy when combined with GM-CSF. Blocking experiments with monoclonal antibodies against the insulin and IGFI receptors indicated that the proliferative effects of insulin and IGFI were mediated through both their homologous and heterologous receptors. Pertussis toxin and cholera toxin, which ADP ribosylate GTP-binding proteins (G proteins), and the cyclic AMP analogue, dibutyryl cyclic AMP, decreased the proliferation induced by GM-CSF or insulin. Specific receptor binding of 125I-insulin, -IGFI, and -GM-CSF to AML-193 cells was demonstrated and not affected by preincubation with pertussis toxin or cholera toxin. Radiolabeled GM-CSF, insulin, and IGFI did not cross-compete with the heterologous ligands for receptor binding. These studies demonstrate (a) association between receptor binding and proliferative effects of GM-CSF and the insulin family hormones, (b) involvement of the G proteins in signal transduction provoked by these hormones which occurs at a postreceptor-binding level, and (c) synergistic mitogenic interactions between GM-CSF and the insulin family hormones, suggesting that their receptors are linked to divergent signaling mechanisms in addition to sharing G protein-coupled pathways.

  View details for Web of Science ID A1990EC41000006

  View details for PubMedID 1698537

• IMPACT OF MARROW CYTOGENETICS AND MORPHOLOGY ON INVITRO HEMATOPOIESIS IN THE MYELODYSPLASTIC SYNDROMES - COMPARISON BETWEEN RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR (CSF) AND GRANULOCYTE-MONOCYTE CSF BLOOD Nagler, A., Binet, C., MacKichan, M. L., Negrin, R., Bangs, C., Donlon, T., Greenberg, P. 1990; 76 (7): 1299-1307

  Abstract

  Marrow cells from 36 patients with myelodysplastic syndromes (MDS) (13 refractory anemia [RA], 14 refractory anemia with excess of blasts [RAEB], 9 RAEB in transformation [RAEB-T]) were evaluated for their in vitro proliferative and differentiative responsiveness to recombinant human granulocyte colony-stimulating factor (G-CSF) or granulocyte-monocyte CSF (GM-CSF). GM-CSF exerted a stronger proliferative stimulus than G-CSF for marrow myeloid clonal growth (CFU-GM) in these patients (44 v 12 colonies per 10(5) nonadherent buoyant bone marrow cells [NAB], respectively, P less than .025). GM-CSF stimulated increased CFU-GM growth in the 16 patients with abnormal marrow cytogenetics in comparison with the 20 patients who had normal cytogenetics (52 and 30 colonies per 10(5) NAB, respectively, P less than .05), whereas no such difference could be demonstrated with G-CSF (11 and 16 colonies per 10(5) NAB, respectively). In contrast, granulocytic differentiation of marrow cells was induced in liquid culture by G-CSF in 15 of 32 (47% patients), while GM-CSF did so in only 4 of 18 (22%) patients (P less than .025) including, for RAEB/RAEB-T patients: 9 of 18 versus 0 of 9, respectively (P less than .025). For MDS patients with normal cytogenetics, G-CSF- and GM-CSF-induced marrow cell granulocytic differentiation in 12 of 18 (67%) versus 3 of 11 (27%), respectively (P less than .025), contrasted with granulocytic induction in only 3 of 14 (21%) and 1 of 7 (14%) patients with abnormal cytogenetics, respectively. We conclude that G-CSF has greater granulocytic differentiative and less proliferative activity for MDS marrow cells than GM-CSF in vitro, particularly for RAEB/RAEB-T patients and those with normal cytogenetics.

  View details for Web of Science ID A1990EB07800006

  View details for PubMedID 1698477

• EFFECTS OF CSFS IN PRELEUKEMIA 3RD INTERNATIONAL SYMP ON MINIMAL RESIDUAL DISEASE IN ACUTE LEUKEMIA Greenberg, P. L., Negrin, R., Nagler, A. STOCKTON PRESS. 1990: 121–126

  Abstract

  Based on pre-clinical and in vitro studies demonstrating enhanced granulocytic proliferation and differentiation induced by granulocyte-monocyte and granulocyte-colony stimulating factors (GM-CSF and G-CSF), these recombinant human hormones have been used to treat cytopenic patients with preleukemia [i.e., myelodysplastic syndromes (MDS)]. To date, five studies have been reported using GM-CSF short-term (generally 7-14 days, x 1-5 courses). Thirty-eight of 45 treated patients had improvements in neutrophil counts, 14 had increased reticulocyte counts with three of these individuals having decreased RBC transfusion requirements, and eight had transient increases in platelets. In 12 patients an increase in marrow and/or peripheral blood blasts was noted. Seven patients progressed to acute myeloid leukemia (AML), particularly patients with greater than 15% marrow blasts. In a longer term study, five patients received GM-CSF for 2 to 9 weeks, although only one individual maintained increased neutrophil counts, one developed antibodies to GM-CSF and one evolved into AML. Eighteen patients have been treated for 2 months with G-CSF, 16 of whom had normalization of neutrophil counts with improved marrow maturation, five had increased reticulocyte counts with three having decreased transfusion requirements, no substantial changes in platelet counts were noted. Eleven patients have received maintenance therapy with G-CSF for 6-16 months, ten had persistent increases in neutrophil counts with enhanced marrow myeloid maturation and five had increased reticulocytes. Decreased infectious episodes were notedat times of neutrophil improvements. Four of the 18 individuals have subsequently developed AML after 6-16 months.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1990DU04800030

  View details for PubMedID 1697191

• MAINTENANCE TREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES USING RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR BLOOD Negrin, R. S., HAEUBER, D. H., Nagler, A., Kobayashi, Y., Sklar, J., Donlon, T., Vincent, M., Greenberg, P. L. 1990; 76 (1): 36-43

  Abstract

  Myelodysplastic syndromes (MDS) are characterized by chronic refractory cytopenias resulting in increased risk of infection, bleeding, and conversion to acute leukemia. In an effort to improve these cytopenias we have treated 18 patients over a 6- to 8-week period with increasing daily subcutaneous doses of recombinant human granulocyte colony-stimulating factor (G-CSF). Sixteen patients responded with improvement in neutrophil counts. On cessation of treatment these counts returned to baseline values over a 2- to 4-week period. To maintain these improved blood counts 11 patients were treated with G-CSF for more prolonged periods. Ten patients again responded with an increase in total leukocyte counts (1.6- to 6.4-fold) and absolute neutrophil counts (ANC) (3.6- to 16.3-fold), with responses persisting for 3 to 16 months. A significantly decreased risk of developing bacterial infections was noted during periods with ANC greater than 1,500/mm3 as compared with periods of time with ANC less than 1,500/mm3. Two anemic patients had a greater than 20% rise in hematocrit over the study period, and 2 additional patients had a decrease in red blood cell transfusion requirements during G-CSF treatment. Bone marrow myeloid maturation improved in 7 of 9 maintenance phase patients. Three patients progressed to acute myeloid leukemia during treatment. The drug was generally well-tolerated and no severe toxicities were noted. These data demonstrated that G-CSF administered to MDS patients by daily subcutaneous administration was well-tolerated and effective in causing persistent improvement of the neutrophil levels and marrow myeloid maturation. These effects were associated with a decreased risk of infection and, in some patients, with decreased red blood cell transfusion requirements.

  View details for Web of Science ID A1990DM15500005

  View details for PubMedID 1694702

• BONE-MARROW CELL MODULATION AND INHIBITION OF MYELOPOIESIS BY LARGE GRANULAR LYMPHOCYTES AND NATURAL-KILLER-CELLS INTERNATIONAL JOURNAL OF CELL CLONING Nagler, A., Greenberg, P. L. 1990; 8 (3): 171-183

  Abstract

  Non-adherent Percoll-separated large granular lymphocytes (LGLs) fractionated by fluorescence-activated cell sorter into CD16+ CD4- natural killer (NK) cells and CD16- CD4+ T cells, were co-cultured with bone marrow (BM) cells previously depleted of adherent T and/or NK cells by immunoadsorption (panning) and plated in a clonogenic assay to assess myeloid colony formation (CFU-gm growth). LGLs, NK cells and LGL T cells [low buoyant density (LBD) T cells] each significantly reduced colony-stimulating factor (CSF)-dependent CFU-gm growth to 70% of control values (p less than 0.05). Non-LGL T cells [high buoyant density (HBD) T cells] did not affect this growth. Incubation of the effector cells with human recombinant interleukin 2 prior to co-culturing did not alter these findings. The supernatants obtained from LGLs, NK cells and LBD T cells co-cultured with BM cells also inhibited CFU-gm growth to 70% of the control, whereas supernatants from effector cells which were not co-cultured with BM had no such effect. These supernatants from the LGL:BM co-cultured cells possessed NK cytotoxic factor (NKCF), but lacked alpha and gamma interferons, tissue necrosis factor-alpha, and prostaglandin E2. These results suggest that BM cells stimulate LGLs to produce NKCF, and that LGLs, CD16+ NK cells, and CD4+ CD16- LBD T cells activated by contact with BM cells inhibit CFU-gm growth.

  View details for Web of Science ID A1990DE70100003

  View details for PubMedID 2140585

• EFFECTS OF RECOMBINANT HUMAN GRANULOCYTE COLONY STIMULATING FACTOR AND GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR ON INVITRO HEMATOPOIESIS IN THE MYELODYSPLASTIC SYNDROMES LEUKEMIA Nagler, A., Ginzton, N., Negrin, R., Bang, D., Donlon, T., Greenberg, P. 1990; 4 (3): 193-202

  Abstract

  We evaluated the effects of recombinant human granulocyte colony stimulating factor (rhG-CSF) and granulocyte-monocyte colony stimulating factor (rhGM-CSF) on the in vitro proliferative, differentiative, and regenerative responsiveness of marrow cells from myelodysplastic syndrome patients (MDS) in comparison to those from normal individuals. Our studies showed decreased primary clonogenicity of myeloid (CFU-GM) and erythroid (BFU-E) hemopoietic progenitor cells from the MDS patients. rhGM-CSF had more potent stimulatory effects than rhG-CSF for MDS marrow CFU-GM growth; no enhanced cellular proliferation in the MDS patients was observed in liquid culture with either rhGM-CSF or rhG-CSF. Decreased myeloid clonal cell self-generation and/or recruitment occurred in the MDS patients upon exposure to either rhG-CSF or rhGM-CSF. rhG-CSF demonstrated more potent granulocytic differentiation effects than rhGM-CSF both for normals and MDS patients using marrow enriched for immature myeloid cells with lesser differentiation noted for MDS. Cytogenetic abnormalities, present with or without additional normal karyotypes in native marrow of four MDS patients, persisted after culture with rhG-CSF, indicating induced differentiation of both normal and abnormal clones. Although proliferative and differentiative effects were seen with both factors these data show MDS marrow cells in vitro to have predominantly differentiative responsiveness to rhG-CSF and proliferative responsiveness to rhGM-CSF.

  View details for Web of Science ID A1990DB45100007

  View details for PubMedID 1690318

• HEMATOPOIETIC PROGENITOR-CELL EXPRESSION OF THE H-CAM (CD44) HOMING-ASSOCIATED ADHESION MOLECULE BLOOD LEWINSOHN, D. M., Nagler, A., Ginzton, N., Greenberg, P., BUTCHER, E. C. 1990; 75 (3): 589-595

  Abstract

  We explored the expression of a lymphocyte homing-associated cell adhesion molecule (H-CAM, CD44) on hematopoietic progenitors. We demonstrate that immature myeloid and erythroid leukemic cell lines stain intensely with monoclonal antibodies Hermes-1 and Hermes-3, which define distinct epitopes on lymphocyte surface H-CAM, a glycoprotein involved in lymphocyte interactions with endothelial cells. Using fluorescence-activated cell sorting (FACS), human marrow cells were fractionated into Hermeshi, Hermesmed, and Hermeslo populations according to the expression of both the Hermes-1 and Hermes-3 epitopes. Granulocyte-macrophage colony-forming unit and erythroid burst-forming unit precursors were found predominantly in the brightly positive fractions. Two-color FACS analysis confirmed that the My10 (CD34) positive populations of cells in bone marrow, which contain most of the progenitor cell activity, are brightly positive for Hermes-1. Finally, we demonstrate that among bone marrow cells, the highest levels of H-CAM are expressed on myeloid and erythroid progenitors as well as mature granulocytes and lymphocytes. Thus we provide evidence that molecules related or identical to the H-CAM homing receptor are expressed on marrow progenitor cells. H-CAM may contribute to progenitor cell interactions with marrow endothelial and stromal cell elements important to the maintenance and regulation of hematopoiesis.

  View details for Web of Science ID A1990CL57700009

  View details for PubMedID 1688719

• EFFECTS OF PROLONGED TREATMENT OF MYELODYSPLASTIC SYNDROMES WITH RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR 2ND INTERNATIONAL CONF ON BLOOD CELL GROWTH FACTORS : THEIR BIOLOGY AND CLINICAL APPLICATIONS Greenberg, P., Negrin, R., Nagler, A., Vincent, M., Donlon, T. ALPHAMED PRESS. 1990: 293–302

  Abstract

  In vitro marrow hemopoietic cultures were utilized to determine the possible efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) for treating the refractory cytopenias present in the myelodysplastic syndromes (MDS). Our studies showed responsiveness of enriched hemopoietic precursors in vitro to the proliferative and granulocytic differentiative stimuli of G-CSF, generally without increased clonal self-generation. These in vitro parameters correlated with in vivo hematologic responses in our Phase I and II clinical trials. In this study 18 patients were treated for two months with s.c. administration (0.1-3 micrograms/kg/day) of G-CSF, escalating doses every two weeks. This study indicated normalization of neutrophil courses in 16 patients and reticulocyte responses with decreased red blood cell (RBC) transfusion requirements in three of 12 transfusion-dependent patients. Marrow myeloid maturation improved in the responding patients. Extended treatment for additional six- to 16-month periods has indicated persisting neutrophil responses. The relative risk of developing bacterial infections was significantly decreased in patients whose neutrophil level normalized (absolute neutrophil count greater than 1,500/mm3) during G-CSF therapy, compared to such episodes in their pretreatment neutropenic period. This therapy was well-tolerated, without serious toxicity being noted. In vitro neutrophil function (chemotaxis and phagocytosis) remained normal or improved in six of the eight tested patients. Transformation to acute myelogenous leukemia occurred in two patients with refractory anemia with excess blasts in transformation (RAEB-T) during or within a month of the treatment period. Marrow cytogenetic studies indicate persistence of the initial normal and/or abnormal clones.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1990CT55300028

  View details for PubMedID 1691248

• TREATMENT OF MYELODYSPLASTIC SYNDROMES WITH RECOMBINANT HUMAN GRANULOCYTE COLONY STIMULATING FACTOR - CLINICAL AND MARROW HEMATOPOIETIC RESPONSES SYMP ON HEMATOPOIESIS Greenberg, P., Negrin, R., Nagler, A., Souza, L. WILEY-LISS, INC. 1990: 229–236

  View details for Web of Science ID A1990BQ68K00023

• TREATMENT OF MYELODYSPLASTIC SYNDROMES WITH RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR - A PHASE I-II TRIAL ANNALS OF INTERNAL MEDICINE Negrin, R. S., HAEUBER, D. H., Nagler, A., Olds, L. C., Donlon, T., SOUZA, L. M., Greenberg, P. L. 1989; 110 (12): 976-984

  Abstract

  To determine the hematopoietic effects and toxicity of recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with myelodysplastic syndromes.The G-CSF was administered by daily subcutaneous injection to outpatients in a phase I-II trial. Dose was escalated every 2 weeks between 0.1 to 3.0 micrograms/kg body weight.d over an 8-week treatment period.Outpatient clinical research center at a university hospital.Twelve consecutive patients with myelodysplastic syndromes: two refractory anemia, seven refractory anemia with excess of blasts, three refractory anemia with excess of blasts in transformation.In 10 of 12 patients, elevations in blood leukocyte counts (2- to 10-fold) and absolute neutrophil counts (5- to 40-fold) were seen over the 8-week treatment period. Five of seven severely neutropenic patients (absolute neutrophil count, less than 0.5 x 10(9)/L) had a rise in count to 1.2 to 16.3 x 10(9)/L. Increased reticulocyte counts occurred in 5 patients, and were associated with decreased transfusion requirements in 2 of 9 erythrocyte transfusion-dependent patients. Treatment with G-CSF enhanced marrow myeloid cell maturation in 9 of 11 evaluable patients. Neutrophil chemotaxis and phagocytosis in vitro were improved or unchanged after treatment in 6 of 8 patients tested. In 11 of 12 patients, there were no substantial changes in platelet, lymphocyte, eosinophil, or monocyte counts. Three responding patients initially had abnormal cytogenetics that persisted after G-CSF therapy, suggesting induced differentiation of the abnormal clone. The therapy was associated with minimal toxicity. None of the patients' conditions converted to acute leukemia during treatment or in short-term follow-up.Treatment with G-CSF administered by subcutaneous injection is well tolerated and effective for improving the neutropenia, and less commonly the transfusion-dependent anemia, over 6 to 8 weeks in patients with myelodysplastic syndromes.

  View details for Web of Science ID A1989AB29600006

  View details for PubMedID 2471429

• THE EFFECTS OF RECOMBINANT INTERLEUKIN-2-ACTIVATED NATURAL-KILLER CELLS ON AUTOLOGOUS PERIPHERAL-BLOOD HEMATOPOIETIC PROGENITORS JOURNAL OF EXPERIMENTAL MEDICINE Nagler, A., Greenberg, P. L., Lanier, L. L., Phillips, J. H. 1988; 168 (1): 47-54

  Abstract

  In the present study, we demonstrate that resting and rIL-2-activated NK cells had no inhibitory effects on peripheral blood-derived hematopoietic progenitor (HP) cells. Peripheral blood HP cells were similar to bone marrow progenitors in phenotype and clonogenic colony formation capabilities. Peripheral blood HP cells could be cocultured in vitro with rIL-2-activated autologous NK cells for 3 d without adverse effects on the HP cells. Acute myelogenous leukemia patients in stable remission were shown to have normal percentages of NK cells and elevated percentages of peripheral blood HP cells. NK cells from most of these patients could be activated with rIL-2 to lyse fresh uncultured tumor cells as well as autologous leukemia cells without effecting the peripheral blood HP cells. These results suggest that rIL-2-activated NK cells may be used to purge peripheral blood HP cell preparations of residual tumor cells before hematopoietic reconstitution.

  View details for Web of Science ID A1988P474800005

  View details for PubMedID 3260939

• SELECTIVE GENERATION OF ERYTHROID BURST PROMOTING ACTIVITY BY RECOMBINANT INTERLEUKIN-2 STIMULATED HUMAN LYMPHOCYTES-T AND NATURAL-KILLER CELLS BLOOD Skettino, S., Phillips, J., Lanier, L., Nagler, A., Greenberg, P. 1988; 71 (4): 907-914

  Abstract

  Because T lymphocytes and natural killer (NK) cells produce a variety of growth factors and interleukin 2 (IL2) modulates the activity of both, we assessed the ability of IL2 to stimulate human T cells and NK cells to produce hematopoietic growth factors detectable in clonogenic marrow culture. Human recombinant interleukin 2 (rIL2) added directly to cultures of human bone marrow that had been depleted of monocytes or depleted of both monocytes and T cells caused no significant alteration of myeloid (CFU-GM) or erythroid colony formation. Conditioned media harvested from rIL2-stimulated (greater than 100 U/mL) peripheral blood mononuclear cells, T cells, Leu-2 cells, and Leu-3 cells all had erythroid burst-promoting activity (BPA) but lacked myeloid colony-stimulating factor (GM-CSF) or CFU-GM-inhibitory activity. These T cells were IL2 receptor-negative, and the addition of anti-IL2 receptor monoclonal antibody (anti-Tac) to T cell cultures did not abrogate this IL2-stimulated BPA production. In addition, Percoll gradient-enriched, large granular lymphocytes (LGL) were separated by fluorescence-activated cell sorting into Leu-11+ (NK) cells and Leu-11- (low-density Leu-4+ T) cell fractions. rIL2 stimulated LGL, Leu-11+ and Leu-11- cells to produce BPA but not detectable GM-CSF or CFU-GM-inhibitory activity. Leu-11+ (NK) cells were Tac-negative from days 0 through 14 of culture. We conclude that rIL2 at high concentrations stimulated T cells, Leu-2 and Leu-3 cell subsets, LGL, and NK cells to produce BPA but not GM-CSF and that this stimulation may be mediated by an IL2 receptor distinct from Tac or by an epitope of the IL2 receptor not recognized by the anti-Tac antibody.

  View details for Web of Science ID A1988M985300012

  View details for PubMedID 2833331

• RECEPTOR-BINDING AND MITOGENIC EFFECTS OF INSULIN AND INSULIN-LIKE GROWTH FACTOR-I AND FACTOR-II FOR HUMAN MYELOID LEUKEMIC-CELLS JOURNAL OF CELLULAR PHYSIOLOGY PEPE, M. G., Ginzton, N. H., Lee, P. D., Hintz, R. L., Greenberg, P. L. 1987; 133 (2): 219-227

  Abstract

  Insulin and insulinlike growth factors I and II (IGF-I and IGF-II) influence mesodermal cell proliferation and differentiation. As multiple growth factors are involved in hemopoietic cell proliferation and differentiation, we assessed the receptor binding and mitogenic effects of these peptides on a panel of mesodermally derived human myeloid leukemic cell lines. The promyelocytic cell line HL60 had the highest level of specific binding for these 125I-labeled ligands, with lower binding to the less differentiated myeloblast cell line KG1 and undifferentiated blast variants of these cell lines (HL60blast, KG1a). Insulin binding affinity and receptor numbers were reduced significantly by chemically induced granulocytic differentiation of HL60 cells and was unchanged following induced monocytic differentiation. No substantial alteration in IGF-I or -II binding occurred with induced HL60 cell differentiation. Insulin and IGF-I demonstrated cross competition for receptor binding and down-regulated their homologous receptors without detectable cross modulation of the heterologous receptors on HL60 cells. IGF-I and insulin increased HL60 cell proliferation, as assessed by 3H-thymidine uptake, IGF-I greater than insulin. IGF-I binding and mitogenic effects were blocked by the monoclonal anti-IGF-I receptor antibody IR3, indicating that IGF-I-induced proliferative effects were mediated via its homologous receptor. In contrast, insulin binding and mitogenesis displayed blocking by both anti-IGI-I and anti-insulin receptor antibodies, indicating mediation of its activity through both receptors. These data demonstrate specific binding and mitogenic interactions between insulin, IGFs, and hemopoietic cells which are associated with their state of differentiation.

  View details for Web of Science ID A1987L056600003

  View details for PubMedID 2960684

• BIOLOGIC NATURE OF THE MYELODYSPLASTIC SYNDROMES ACTA HAEMATOLOGICA Greenberg, P. L. 1987; 78: 94-99

  Abstract

  In the myelodysplastic syndromes (MDS) clonogenic marrow cell culture studies have demonstrated intrinsic hemopoietic stem cell and progenitor cell abnormalities consistent with these disorders representing clonal hemopathies. Abnormal responsiveness of these cells to stimulatory and inhibitory growth factors indicate the contribution of regulatory abnormalities in these patients. These in vitro growth abnormalities have prognostic import and the defects progress as subsets of these patients evolve into a blastic transformation stage. Maturation-inducing agents such as retinoic acid and vitamin D alter clonal growth patterns and enhance myeloid differentiation in the MDS, and correlations between in vitro and in vivo responsiveness of hemopoietic cells to retinoic acid have been demonstrated. Studies will be reviewed indicating the role of these biologic parameters for understanding pathogenetic mechanisms underlying the MDS.

  View details for Web of Science ID A1987M133600017

  View details for PubMedID 2829490

• BIOLOGIC ABNORMALITIES IN THE MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE DISORDERS ACTA HAEMATOLOGICA JAPONICA Greenberg, P. L. 1986; 49 (8): 1509-1527

  View details for Web of Science ID A1986F289200005

  View details for PubMedID 3551435

• CHARACTERIZATION OF THE INVITRO STROMAL MICROENVIRONMENT OF HUMAN-BONE MARROW INTERNATIONAL JOURNAL OF CELL CLONING Strobel, E. S., GAY, R. E., Greenberg, P. L. 1986; 4 (5): 341-356

  Abstract

  Utilizing long-term in vitro culture techniques, we characterized the cellular composition and functional attributes of the human in vitro bone marrow stromal microenvironment. Morphologic, specific cytochemical and immunologic methods demonstrated that the marrow stromal adherent layer (AL) reached confluency at two to three weeks, and was comprised of 60%-70% fibroblastic cells, 10%-20% endothelial cells, 10%-20% monocyte/macrophages and 5%-10% fat-laden adherent cells. These proportions of cell types persisted for at least three months concomitant with proliferation of CFU-gm and BFU-e. In contrast, umbilical cord blood cells did not form a stromal AL despite persistence of hemopoietic progenitor cell proliferation. These findings provide a basis for improved understanding of cellular interactions regulating hemopoiesis.

  View details for Web of Science ID A1986E219900006

  View details for PubMedID 3534110

• 13-CIS RETINOIC ACID TREATMENT FOR MYELODYSPLASTIC SYNDROMES JOURNAL OF CLINICAL ONCOLOGY Picozzi, V. J., SWANSON, G. F., Morgan, R., Hecht, F., Greenberg, P. L. 1986; 4 (4): 589-595

  Abstract

  To test the biologic activity of 13-cis retinoic acid (13-CRA) in patients with myelodysplastic states (MDS), we administered 13-CRA orally (2.5 mg/kg/d initially, escalated to 4 mg/kg/d) for 8 weeks to 15 consecutive patients. Eight of 15 patients (53%) experienced an increase in peripheral granulocyte counts of greater than 20% (range, 22% to 700%). In five patients, the absolute increase in peripheral granulocyte count was greater than 500 cells/microL. Two of 15 patients experienced a decrease in the circulating granulocyte count of greater than or equal to 20%. Comparable values for peripheral platelet counts were 27% (4/15 patients) greater than 20% increase and 33% (5/15 patients) greater than 20% decrease. No patient experienced a major change in erythrocyte transfusion requirement while receiving 13-CRA in comparison with pretreatment status. Thirteen patients had morphologic and cytogenetic evaluation of marrow cells before 13-CRA treatment, and with one exception, marrow morphologic and cytogenetic abnormalities persisted following 13-CRA administration. The exception occurred in the patient with the most dramatic response, whose granulocyte count increased from 400 to 2,800 cells/microL along with a normalization of the leukocyte alkaline phosphatase score, a morphologic improvement in granulocyte maturation, and a disappearance of the initial chromosome abnormality. These changes did not persist after cessation of 13-CRA administration, but were reproduced following drug readministration. No patients experienced serious decrements in peripheral blood counts or leukemic transformation while receiving 13-CRA. All patients had mild to marked dermatologic toxicity (cheilosis, skin dryness). No other major toxicity was encountered. We conclude that 13-CRA may be safely administered and may increase peripheral granulocyte counts in a proportion of patients with MDS.

  View details for Web of Science ID A1986A743500023

  View details for PubMedID 3514807

• ABNORMAL INVITRO CLONAL GROWTH-PATTERNS IN THE MYELODYSPLASTIC SYNDROMES AND OTHER HEMATOLOGIC MALIGNANCIES - RESPONSES TO RETINOIC ACID AND VITAMIN-D ACTA HAEMATOLOGICA JAPONICA Greenberg, P. 1986; 49 (2): 181-181

  View details for Web of Science ID A1986A845900005

• RESPONSES OF HEMATOPOIETIC PRECURSORS TO 13-CIS RETINOIC ACID AND 1,25 DIHYDROXYVITAMIN-D3 IN THE MYELODYSPLASTIC SYNDROMES BLOOD Swanson, G., Picozzi, V., Morgan, R., Hecht, F., Greenberg, P. 1986; 67 (4): 1154-1161

  Abstract

  To determine the effects of the "maturation-inducing" agents 13-cis retinoic acid and 1,25 dihydroxyvitamin D3 on marrow cells from normal individuals and patients with myelodysplastic syndromes (MDS), we assessed marrow hemopoietic clonogenicity and differentiation response patterns to these agents. These vitamins caused increased proliferation in vitro of normal clonogenic marrow myeloid precursor cells (CFU-GM), decreased erythroid precursors (BFU-E), and no change in multipotent stem cells (CFU-GEMM). Marrow hemopoietic colony-forming cell incidence was generally subnormal in the 22 MDS patients evaluated. In vitro exposure to both agents caused various patterns of alteration of MDS hemopoietic colony and cluster formation, with similar but more pronounced effects evoked by retinoic acid. In the vast majority of MDS patients, enhanced marrow clonal granulocyte-monocyte differentiation and decreased BFU-E growth were noted after in vitro exposure to these vitamins. Correlation of biological effects was demonstrated between in vivo changes of peripheral neutrophil counts and in vitro responses of myeloid precursors for ten MDS patients treated with an eight-week therapeutic course of retinoic acid. Cytogenetic analyses indicated persisting aneuploidy or coexisting normal and aneuploid karyotypes in the cultured MDS myeloid cells and (with one exception) in native marrow cells from the treated patients. The varying responses of the MDS cells may monitor differing proportions of normal versus leukemic marrow cells susceptible to proliferative and differentiative expression on exposure to these agents.

  View details for Web of Science ID A1986A807600049

  View details for PubMedID 3513868

• CORRELATIVE PATTERNS OF LEUKOCYTE COUNTS AT PRESENTATION AND RELAPSE IN ACUTE MYELOGENOUS LEUKEMIA ACTA HAEMATOLOGICA Schwartz, R. S., MacKintosh, F. R., Greenberg, P. L. 1986; 75 (2): 79-82

  Abstract

  Patients with acute myelogenous leukemia (AML) present with various levels of peripheral leukocyte and myeloblast counts which relate to their clinical outcomes. We have compared leukocyte and blast cell counts at the times of presentation and relapse and demonstrated that the pattern of first relapse in AML is not random; the leukocyte/blast counts at presentation and relapse in AML are associated, indicating the stability of this clinical parameter. Thus, levels of leukocytes and blasts may reflect heritable biologic characteristics of the leukemic clone. Recognition that the magnitude of the initial leukocyte count in AML is a prognostic factor which correlates with the pattern of relapse and remission duration in AML suggests that this feature should provide a useful clinical and biologic index for stratifying patients with AML.

  View details for Web of Science ID A1986D610400003

  View details for PubMedID 3090826

• HUMAN SPLEEN-CELL GENERATION OF FACTORS STIMULATING HUMAN PLURIPOTENT STEM-CELL, ERYTHROID, AND MYELOID PROGENITOR-CELL GROWTH BLOOD Fabian, I., Douer, D., Levitt, L., Kletter, Y., Greenberg, P. L. 1985; 65 (4): 990-996

  Abstract

  Mitogen-stimulated murine spleen cells produce humoral substances capable of supporting murine hematopoiesis and pluripotent stem cell proliferation in vitro. Thus, we evaluated conditioned media generated by human spleen cells (SCM) in the presence or absence of mitogens for factors stimulatory for human pluripotent (CFU-GEMM), erythroid (BFU-E), and myeloid (CFU-GM) precursors. Two and one half percent to 10% SCM stimulated proliferation of all three types of precursor cells from nonadherent buoyant human marrow target cells. Mitogen-stimulated SCM augmented CFU-GM (175% to 225%), whereas CFU-GEMM and BFU-E growth was essentially unchanged. Cell separation procedures used to determine which cells provided these microenvironmental stimuli indicated that nonadherent mononuclear spleen cells provided the bulk of the CSF-GM, whereas adherent cells (95% nonspecific esterase + monocyte-macrophages) and nonadherent cells provided similar proportions of CSF-mix and erythroid burst-promoting activity (BPA). The nonadherent cells generating high levels of CSF-mix, BPA, and CSF-GM were predominantly Leu-1-negative, ie, non-T, cells. In the presence or absence of mitogens, SCM was a more potent source (1.3- to 3.8-fold) than peripheral leukocyte CM of the growth factors for the three progenitor cell types. Specific in situ cytochemical stains for analyzing morphology of myeloid colonies demonstrated that SCM stimulated the proliferation of the same types and proportions of colonies as human placental CM, suggesting that these CMs may contain similar CSF-GMs. These data show the contribution of spleen cell subsets to the generation of hematopoietic growth factors and the responsiveness of these cells to various mitogenic stimuli.

  View details for Web of Science ID A1985AFU4800029

  View details for PubMedID 3872143

• LITHIUM TREATMENT IN ADULTS WITH ACUTE MYELOID-LEUKEMIA RECEIVING CHEMOTHERAPY MEDICAL AND PEDIATRIC ONCOLOGY Horns, R. C., Schrier, S. L., Greenberg, P. L. 1984; 12 (3): 169-172

  Abstract

  To determine whether lithium can shorten chemotherapy-induced neutropenia, 35 adult patients with newly diagnosed acute myeloid leukemia undergoing initial chemotherapy were randomized either to receive oral lithium started at the time of biopsy-proven hypoplasia or to receive no lithium. This study failed to show statistically significant shortening of the duration of chemotherapy-induced neutropenia in the lithium treatment group.

  View details for Web of Science ID A1984SW62300004

  View details for PubMedID 6374402

• MULTIVARIATE-ANALYSIS OF FACTORS ASSOCIATED WITH OUTCOME OF TREATMENT FOR ADULTS WITH ACUTE MYELOGENOUS LEUKEMIA CANCER Schwartz, R. S., MacKintosh, F. R., Halpern, J., Schrier, S. L., Greenberg, P. L. 1984; 54 (8): 1672-1681

  Abstract

  Utilizing multivariate logistic regression statistical analysis, the authors evaluated prognostic features associated with achievement of complete remission (CR) and remission and survival duration in acute myelogenous leukemia (AML). These clinical variables were analyzed in 77 consecutive adult patients who underwent 108 courses of remission induction therapy with daunomycin, cytosine arabinoside, and 6-thioguanine (DAT) chemotherapy for newly diagnosed and first relapse of AML. Eight patients had developed leukemia in the setting of other malignant or immunologic diseases (therapy-linked AML) and 69 patients had not (primary AML). Sixty-three percent of patients with primary AML achieved CR with median remission and survival durations of 11 and 24 months, respectively. Significant unfavorable predictive features for achievement of CR were splenomegaly, and elevated leukocyte count or serum alkaline phosphatase levels. Patients who had leukocyte counts of less than or equal to 10,000/mm3 at diagnosis or less than or equal to 40,000/mm3 at the start of therapy, and those who received greater than 120 mg/m2 of daunomycin had significantly longer remissions and survival than those who did not. Fifty-seven percent of patients in first relapse also achieved CR; however, relative to first remissions, second remission durations were significantly shorter (median, 4.6 months). Sixty-two percent of patients with therapy-linked AML achieved CR, but remission durations (median, 2.8 months) were significantly shorter than first remissions of primary AML patients. These data identify clinical features associated with increased risk of failure to achieve CR and potential for short remission duration and survival. Alternative forms of therapy should be considered for such high-risk patients.

  View details for Web of Science ID A1984TL83900030

  View details for PubMedID 6592033

• MULTIVARIATE-ANALYSIS OF FACTORS ASSOCIATED WITH INVASIVE FUNGAL DISEASE DURING REMISSION INDUCTION THERAPY FOR ACUTE MYELOGENOUS LEUKEMIA CANCER Schwartz, R. S., MacKintosh, F. R., Schrier, S. L., Greenberg, P. L. 1984; 53 (3): 411-419

  Abstract

  The clinical courses of 54 consecutive adult patients with acute myelogenous leukemia (AML) who underwent 67 courses of intensive remission induction therapy were analyzed to assess factors associated with development of serious fungal and bacterial infections. Fever developed in 65 of 67 remission induction attempts and was due to bacterial, bacterial-fungal, and fungal etiologies in 49%, 14%, and 9% of cases, respectively. No etiology of fever was found in 28% of cases. Bacteremia occurred in 54% of remission induction attempts. Invasive fungal disease (IFD) occurred in 22% of cases with an overall mortality of 60%, including 45% of the patients who died during treatment. Using multivariate logistic regression analysis, a mathematical model was constructed which correlated with the risk of IFD. Major factors associated with patients who ultimately develop IFD included the duration of chemotherapy, the number of sites colonized with fungi and the number of fungal species isolated on certain surveillance cultures, particularly Aspergillus species. These studies define characteristics of patients at high risk for development of IFD for whom early initiation of empiric antifungal therapy is strongly recommended.

  View details for Web of Science ID A1984SA97100007

  View details for PubMedID 6581852

• MURINE GRANULOPOIESIS AFTER FRACTIONATED TOTAL LYMPHOID IRRADIATION AND ALLOGENEIC BONE-MARROW TRANSPLANTATION EXPERIMENTAL HEMATOLOGY Feiner, R. H., Strober, S., Greenberg, P. L. 1983; 11 (5): 410-417

  Abstract

  We investigated the effects of fractionated total lymphoid irradiation (TLI) and allogeneic bone marrow transplantation on murine granulopoiesis in order to evaluate the hemopoietic microenvironment of radiation chimeras (RC). BALB/c mice received 3400 rad TLI (17 daily 200 rad fractions) with or without 3 X 10(7) C57Bl/Ka marrow cells injected intravenously. Radiation resulted in prolonged depression of granulocyte-macrophage progenitor cells (CFU-GM) and endosteal colony-stimulating-activity (CSA) production in irradiated humeri. Allogeneic marrow transplantation partially restored endosteal CSA production and led to complete, although delayed, restoration of CFU-GM. Major compensatory granulopoiesis occurred in the spleen. Marrow fat-laden adherent cells (FLAC) were cultured in vitro from RC 30 weeks post TLI and transplantation. As determined by indirect immunofluorescence utilizing anti-H-2 antibodies, 23-25% of these cells reacted with antibodies possessing donor specificity. These findings suggest that the hemopoietic microenvironment, represented functionally by endosteal CSA production and morphologically by cultured FLAC, is transplantable by the intravenous route.

  View details for Web of Science ID A1983QP46000009

  View details for PubMedID 6343108

• PURE WHITE-CELL APLASIA - ANTIBODY-MEDIATED AUTOIMMUNE INHIBITION OF GRANULOPOIESIS NEW ENGLAND JOURNAL OF MEDICINE Levitt, L. J., Ries, C. A., Greenberg, P. L. 1983; 308 (19): 1141-1146

  View details for Web of Science ID A1983QP38800008

  View details for PubMedID 6188052

• RESPONSE OF AGRANULOCYTOSIS TO PROLONGED ANTI-THYMOCYTE GLOBULIN THERAPY JOURNAL OF PEDIATRICS CHUDWIN, D. S., Cowan, M. J., Greenberg, P. L., Wara, D. W., Ammann, A. J. 1983; 103 (2): 223-227

  Abstract

  A girl with a history of autoimmune disease developed life-threatening agranulocytosis. A bone marrow biopsy demonstrated selective granulocytic hypoplasia. No antineutrophil antibodies were found. In vitro bone marrow culture of granulocytic progenitor cells suggested T cell-mediated inhibition of colony formation, which was reduced by in vitro treatment of marrow cells with either hydrocortisone or an antibody directed against T-lymphocytes and complement. The patient responded to treatment with antithymocyte globulin after administration of corticosteroids and other immunosuppressants failed to increase her neutrophil count significantly. Attempts to stop ATG treatment resulted in precipitous drops in her neutrophil counts, which reversed with readministration of ATG. She then received weekly ATG infusions for over 24 months until she was able to maintain a normal neutrophil count. A trial of ATG therapy may be indicated in severe neutropenia when in vitro culture results indicate a possible autoimmune basis.

  View details for Web of Science ID A1983RC04600009

  View details for PubMedID 6875713

• THE SMOLDERING MYELOID LEUKEMIC STATES - CLINICAL AND BIOLOGIC FEATURES BLOOD Greenberg, P. L. 1983; 61 (6): 1035-1044

  View details for Web of Science ID A1983QT32100001

  View details for PubMedID 6340754

• INDUCTION OF HUMAN HEMATOPOIETIC STEM-CELL (CFU-GEMM) GROWTH BY FACTORS RELEASED FROM MITOGEN-STIMULATED SPLEEN-CELLS Fabian, I., Levitt, L., Greenberg, P. ELSEVIER SCIENCE INC. 1982: 167–167

  View details for Web of Science ID A1982NX83200276

• ROLE OF INTRACELLULAR DEGRADATION OF EPIDERMAL GROWTH-FACTOR IN MITOGENESIS EXPERIMENTAL CELL RESEARCH Greenberg, P. L., ROZENGURT, E. 1982; 142 (1): 111-117

  Abstract

  Addition of leupeptin, methylamine and the antitubulin agent nocodazole did not affect the initial rate of association of 125I-labelled epidermal growth factor (125I-EGF) to Swiss mouse 3T3 fibroblast cells in vitro, but continued incubation with these drugs (up to 24 h) led to an increase in cell-associated radioactivity in a time- and dose-dependent fashion. Combinations of these drugs caused additive increments in cell-associated and internalized radioactivity. Throughout the incubation period, 81-89% of the cell-associated 125I-EGF was internalized. Upon incubation of 125I-EGF with 3T3 cells in the presence or absence of the three inhibitors of degradation for periods of up to 24 h, and after removal of the surface-bound material, the internalized 125I-EGF was extracted and 42-53% was found to biochemically intact (by acid precipitation) and 56-65% was antigenically similar to native EGF (using double antibody immunoprecipitation in an EGF radioimmunoassay). The extracted internalized 125I-EGF was capable of binding to fresh 3T3 cells. Despite causing a similar increase in intact internalized 125I-EGF, leupeptin did not interfere with and nocodazole alone or in combination with leupeptin markedly enhanced EGF-stimulated DNA synthesis, whereas methylamine inhibited mitogenesis. These data indicate a dissociation between EGF degradation and DNA synthesis, and are not consistent with the hypothesis that intracellular degradation of EGF is necessary for its mitogenic effects.

  View details for Web of Science ID A1982PS24800014

  View details for PubMedID 6982826

• SPLENIC GRANULOCYTOPOIESIS AND PRODUCTION OF COLONY-STIMULATING ACTIVITY IN LYMPHOMA AND LEUKEMIA BLOOD Greenberg, P. L., STEED, S. M. 1981; 57 (1): 119-129

  Abstract

  Spleen cell production of granulocyte-macrophage colony stimulating activity (CSA) and colony forming capacity (CFU-GM) from 59 patients with Hodgkin's and non-Hodgkin's lymphoma, acute (AML) and chronic myeloid leukemia (CML), and control subjects was quantified to evaluate local cellular potential for modulating splenic granulocytopoiesis. Mononuclear spleen cell conditioned media stimulated myeloid CFU-GM by human nonadherent marrow target cells. In contrast to conditioned media produced by marrow and peripheral blood cells, the vast majority of spleen CSA was generated by nonadherent lymphoid cells rather than adherent monocytic cells. The nonadherent cells producing CSA were non-T cells (assessed by sheep erythrocyte rosetting), with 98% +/- 2% CSA produced by the nonrosetted fraction (B lymphocytes and null cells), and had a peak density heavier than that of the adherent spleen CSA-producing cells. Dose response curves demonstrated significantly increased cellular CSA production from patients with lymphomas and AML in remission. In a high proportion of patients, foci of immature granulocytic cells were found by specific cytochemical staining of histologic sections of spleens. A limited degree of splenic granulocytopoiesis was demonstrated morphologically and by CFU-GM incidence. CSA was not detectable in conditioned medium prepared from nonadherent spleen cells from 5 patients with CML, due to a nondialyzable substances(s) produced by the nonadherent cells which inhibited normal CFU-GM response to CSA. The high CFU-GM incidence and extensive leukemic granulocytopoiesis present in the CML spleens suggests diminished effect of this inhibitor on leukemic as opposed to normal granulocytic precursor cell proliferation.

  View details for Web of Science ID A1981KY75200020

  View details for PubMedID 6969608

• STROMAL COLONY-STIMULATING ACTIVITY PRODUCTION AND MYELOID COLONY-FORMING CELLS IN HUMAN HEMATOPOIETIC AND NON-HEMATOPOIETIC BONE-MARROW BLOOD Schwartz, R. S., Greenberg, P. L. 1981; 57 (4): 771-780

  Abstract

  In order to evaluate the role of the stromal bone marrow microenvironment in regulating granulopoiesis, we have examined the capacity of adult human proximal hemopoietic (PH) and distal nonhemopoietic (DNH) long bone to produce colony-stimulating activity (CSA), characterized the cellular sources of CSA, and quantitated the colony-forming cells (CFU-GM) of marrow from these sites. Stromal elements were obtained from slices of cancellous bone. PH bone marrow stroma contained CFU-GM concentrations similar to aspirated PH marrow and significantly more CFU-GM than DNH bone marrow: 20.7 +/- 4.8/10(5) cells and 25.8 +/- 12.0/mg bone versus 0.81 +/- 0.34/10(5) cells and 0.02 +/- 0.01/mg bone (p less than 0.001). Conditioned media prepared from PH and DNH bone were quantitated for CSA by their ability to promote in vitro granulocyte colony formation of nonadherent human marrow cells. Stromal CSA production was destroyed by freeze--thawing and was radioresistant (4400 rad). Of DNH stromal cells, 15%--30% were monocyte-macrophage, but the slow absolute numbers of these cells suggested alternative CSA cellular sources in distal bones. PH stroma produced significantly more CSA than DNH bone stroma: 0.72 +/- 0.10 versus 0.30 +/- 0.06 U/mg bone (p less than 0.01). The CSA concentration gradient between PH and DNH bones may contribute to the regulation of granulopoiesis in marrow and to the absence of hemopoiesis distally.

  View details for Web of Science ID A1981LK24900022

  View details for PubMedID 6970600

• CHARACTERIZATION OF ANTIGENIC DETERMINANTS ON HUMAN MYELOID COLONY-FORMING CELLS WITH MONOCLONAL-ANTIBODIES EXPERIMENTAL HEMATOLOGY Greenberg, P., Grossman, M., Charron, D., Levy, R. 1981; 9 (7): 781-787

  Abstract

  Immunologic characterization of myeloid progenitor cells (CFUGM) provides a new dimension for identification and separation of this hemopoietic cell population from other cells within marrow and peripheral blood. Monoclonal antibodies against human anti Ia-like (HLA-DR) determinants and against T lymphocytes were utilized to more precisely define the cell surface antigenic structure of human CFUGM. Complement-mediated cytotoxicity testing demonstrated the presence of HLA-DR antigens and absence of a T lymphocyte antigen on the clonogenic CFUGM. Similar degrees of cytotoxicity were noted for B lymphocytes and CFUGM using anti HLA-DR monoclonal antibodies. Our studies with the anti T lymphocyte antibody suggest that T lymphocytes may be selectively removed from marrow cells without depletion of myeloid precursor cells.

  View details for Web of Science ID A1981MB48500012

  View details for PubMedID 6172283

• THE CHRONIC IDIOPATHIC NEUTROPENIA SYNDROME - CORRELATION OF CLINICAL-FEATURES WITH INVITRO PARAMETERS OF GRANULOCYTOPOIESIS BLOOD Greenberg, P. L., MARA, B., Steed, S., Boxer, L. 1980; 55 (6): 915-921

  View details for Web of Science ID A1980JW29400007

  View details for PubMedID 7378580

• CLINICAL RELEVANCE OF INVITRO STUDY OF GRANULOCYTOPOIESIS SCANDINAVIAN JOURNAL OF HAEMATOLOGY Greenberg, P. L. 1980; 25 (5): 369-381

  View details for Web of Science ID A1980KW65600001

  View details for PubMedID 7013018

• SUB-ACUTE MYELOID-LEUKEMIA - CLINICAL REVIEW AMERICAN JOURNAL OF MEDICINE Cohen, J. R., CREGER, W. P., Greenberg, P. L., Schrier, S. L. 1979; 66 (6): 959-966

  Abstract

  The data on 31 patients who fit into the clinical spectrum of subacute myeloid leukemia have been reviewed. The majority of patients were male with a median age of 61 years. The interval from onset of symptoms to actual diagnosis was extremely variable, with a mean of 16 months and a median of six months. Most patients presented with anemia and thrombocytopenia, although the white blood cell count varied from striking leukopenia to marked leukocytosis. Examination of the bone marrow invariably revealed abnormalities of all cell lines with megaloblastoid erythrogenesis and dysplastic megakaryocytopoiesis. Although the white cell line showed prominence of immature forms, there was more maturation than is seen in acute myeloid leukemia. Survival from diagnosis was variable, from less than one month to greater than 68 months, with a median of only six months. Anemia and hepatosplenomegaly were prognosticators of a poor outlook; patients with hepatosplenomegaly in association with either leukocytosis or thrombocytopenia had a particularly poor outlook, with a median survival of only one and a half months. Approximately half the patients received chemotherapy with no demonstrated effect on survival.

  View details for Web of Science ID A1979GZ13700012

  View details for PubMedID 287373

• Intramedullary influences on in vitro granulopoiesis in human acute myeloid leukemia. Haematology and blood transfusion Greenberg, P., MARA, B. 1979; 23: 199-204

  View details for PubMedID 317473

• PRELEUKEMIC SYNDROME - CORRELATION OF INVITRO PARAMETERS OF GRANULOPOIESIS WITH CLINICAL-FEATURES AMERICAN JOURNAL OF MEDICINE Greenberg, P. L., MARA, B. 1979; 66 (6): 951-958

  View details for Web of Science ID A1979GZ13700011

  View details for PubMedID 313154

• MARROW ADHERENT CELL COLONY-STIMULATING ACTIVITY PRODUCTION IN ACUTE MYELOID-LEUKEMIA BLOOD Greenberg, P. L., MARA, B., Heller, P. 1978; 52 (2): 362-378

  View details for Web of Science ID A1978FK31200013

  View details for PubMedID 307417

• REMISSION OF ACUTE MYELOGENOUS LEUKEMIA COMPLICATING WALDENSTROM MACROGLOBULINEMIA WESTERN JOURNAL OF MEDICINE EFFRON, M. K., Rosenbaum, J., Greenberg, P. L. 1978; 129 (4): 337-339

  View details for Web of Science ID A1978FU39400017

  View details for PubMedID 102080

• DENSITY DISTRIBUTION PATTERNS OF MARROW COLONY-FORMING CELLS DURING REMISSION OF ACUTE MYELOGENOUS LEUKEMIA JOURNAL OF THE NATIONAL CANCER INSTITUTE Heller, P., Greenberg, P. 1977; 59 (2): 313-316

  View details for Web of Science ID A1977DR63900005

• CYTOTOXIC EFFECTS OF INTERFERON INVITRO ON GRANULOCYTIC PROGENITOR CELLS CANCER RESEARCH Greenberg, P. L., MOSNY, S. A. 1977; 37 (6): 1794-1799

  Abstract

  We have utilized in vitro marrow culture techniques to evaluate the cytotoxicity for granulocytic progenitor cells of two highly purified human leukocyte interferon preparations. Concentration- and time-related decrements in granulocytic colony-forming capacity in agar occurred with human and mouse marrow. Although mouse marrow cells were less sensitive than were human cells, these data indicate lack of strict species specificity for the cell growth-inhibitory effects of interferon. Similar cytotoxicity was noted for normal and leukemic human clonogenic cells exposed to interferon for prolonged periods. The decrease in the proportion of granulocytic progenitor cells in DNA synthesis, which occurred at high concentrations, and the diminution by interferon of the cytotoxicity caused by cytosine arabinoside demonstrate that interferon decreases DNA synthesis of granulocytic progenitor cells. The lack of enhanced cytotoxicity for rapidly proliferating mouse post-endotoxin marrow cells indicates that interferon is not a cell cycle-stage-specific drug. These data seem useful for evaluating the suppressive effects of interferon on granulopoiesis and for devising clinical trials with this agent.

  View details for Web of Science ID A1977DG87600035

  View details for PubMedID 870186

• DIVERGENT PATTERNS OF MARROW CELL-SUSPENSION CULTURE GROWTH IN MYELOID LEUKEMIAS - CORRELATION OF INVITRO FINDINGS WITH CLINICAL FEATURES BLOOD Elias, L., Greenberg, P. 1977; 50 (2): 263-274

  Abstract

  Cellular recovery, maturation, and colony-forming cell (CFC) generation patterns of bone marrow cells from 23 patients with acute, subacute, and chronic myeloid leukemia (AML, SML, and CML) were studied using liquid and agar culture techniques. Increased recovery of proliferative myeloid cells from liquid culture was noted in 6 of 8 AML patients at diagnosis or relapse and 5 of 7 untreated SML patients. Patients with either AML or SML with rapid clinical progression exhibited greater recovery of cells in vitro with less maturation than patients with more stable disease. Studies from 3 patients with CML showed normal to increased cellular recovery with normal maturation. Three of 4 studies of AML patients followed sequentially in apparent remission, but with impending relapse, exhibited increased numbers of myeloblasts and promyelocytes, whereas 28 of 32 studies performed during stable remission were normal. The normally observed increase in CFC during liquid culture was absent in most leukemic marrow samples studied (3 of 4 AML, 4 of 6 SML, and 2 of 3 CML). Persistent low recovery of CFC during AML remission was associated in 3 patients with short remission duration. These studies indicated the potential utility of these techniques for the clinical evaluation of patients with myeloid leukemia and for studying factors involved in the progression of these diseases.

  View details for Web of Science ID A1977DQ58800009

  View details for PubMedID 266954

• REMISSION MAINTENANCE THERAPY IN ACUTE MYELOGENOUS LEUKEMIA WESTERN JOURNAL OF MEDICINE Embury, S. H., Elias, L., Heller, P. H., HOOD, C. E., Greenberg, P. L., Schrier, S. L. 1977; 126 (4): 267-272

  Abstract

  Because no conclusive evidence as to the efficacy of maintenance chemotherapy in acute myelogenous leukemia (AML) existed, a study to obtain such information was done. Twenty-six adult patients with AML in whom complete remission had been achieved following induction chemotherapy were randomly assigned to receive either maintenance chemotherapy consisting of cytarabine and 6-thioguanine for two days each month or to receive no maintenance therapy. The data showed a significant difference in remission duration between the two groups, with median remission lengths for the maintained and unmaintained groups being 10.3 and 6.7 months, respectively (p<.05). In 46 percent of the maintained patients there were remissions lasting longer than 11 months, whereas in none of the unmaintained patients was there such a prolonged remission. No significant drug-induced toxicity was observed. That the prolonged exposure to these chemotherapeutic agents, which were also used in our induction program, did not adversely affect the rate of successful reinduction therapy was shown by identical 50 percent complete remission rates for second inductions in both groups. In patients with palpable splenomegaly at the time of diagnosis, there was no prolongation of remission with maintenance therapy. These data indicate the potential utility of maintenance chemotherapy for prolonging remission duration in acute myelogenous leukemia.

  View details for Web of Science ID A1977DC47300003

  View details for PubMedID 266313

• MYELOPROLIFERATIVE DISORDERS - CORRELATION BETWEEN CLINICAL EVOLUTION AND ALTERATIONS OF GRANULOPOIESIS AMERICAN JOURNAL OF MEDICINE Greenberg, P., MARA, B., Bax, I., BROSSEL, R., Schrier, S. 1976; 61 (6): 878-891

  Abstract

  Patients with myeloproliferative disorders were prospectively studied by in vitro agar-gel marrow culture technics to evaluate factors involved in the evolution of abnormal granulopoiesis. Marrow granulocytic colony-forming capacity was determined in 78 patients with chronic myeloid leukemia, subacute myeloid leukemia, preleukemia, Di Guglielmo's syndrome, polycythemia vera or essential thrombocythemia. A wide range of marrow colony-forming capacity values was noted early in disease courses; however, in 26 of 33 patients decreased colony-forming capacity was associated with disease transformation into acute myeloid leukemia or other clinically aggressive stages. An increased proportion of abnormally light buoyant density (less than 1.062 g/cm3) colony-forming cells was present in the marrow and peripheral blood of 15 of 16 patients with chronic myeloid leukemia, subacute myeloid leukemia, preleukemia or essential thrombocythemia; in seven of eight patients with greater than 35 per cent abnormally light colony-forming cells their disease subsequently underwent transformation. Elevated levels of urinary colony-stimulating factor output were noted in 17 of 31 patients, and in 10 of 12 patients whose disease subsequently underwent acute transformation within 10 months of study. In six of seven patients who simultaneously had an increased urinary output of colony-stimulating factor and low colony-forming capacity in marrow, transformation occurred within 10 months. These findings indicate that progressive abnormalities of both marrow clonal growth patterns and levels of possible humoral regulatory substances develop during evolution of these diseases. In contrast, patients with idiopathic sideroblastic ineffective erythropoiesis had normal values for marrow colony-forming capacity, proportion of light density colony-forming cells and urinary colony-stimulating factor output, and in none has their disease transformed into acute myeloid leukemia. These in vitro studies appear useful for clinical staging, evaluating prognosis and categorizing patients with myeloproliferative disorders.

  View details for Web of Science ID A1976CP93400009

  View details for PubMedID 1087534

• ALTERATION OF COLONY-STIMULATING FACTOR OUTPUT, ENDOTOXEMIA, AND GRANULOPOIESIS IN CYCLIC NEUTROPENIA AMERICAN JOURNAL OF HEMATOLOGY Greenberg, P. L., Bax, I., Levin, J., Andrews, T. M. 1976; 1 (4): 375-385

  Abstract

  Cellular and humoral factors involved in the regulation of granulopoiesis were evaluated in two patients with cyclic neutropenia by utilizing the agar-gel marrow culture technique to serially study marrow granulocytic colony-forming capacity (CFC) and the urinary output of colony-stimulating factor (CSF). CSF output varied inversely with peripheral neutrophil counts and directly with monocyte counts and evidence for infection (endotoxemia and/or staphylococcal abscesses). Following autologous infusion of one patient's plasma obtained during a period of neutropenia, increased urinary excretion of CSF occurred concomitant with increments in both marrow CFC and the proportion of granulocytic progenitor cells in DNA synthesis. Neutrophil periodicity was not altered by the administration of the neutropenic plasma. These findings are consistent with the hypothesis that cyclic neutropenia is caused by a quantitatively decreased entry of stem cells or granulocytic progenitor cells into granulopoiesis.

  View details for Web of Science ID A1976CM55900002

  View details for PubMedID 1087533

• CYTOTOXIC EFFECTS OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE AND 6-THIOGUANINE INVITRO ON GRANULOCYTIC PROGENITOR CELLS CANCER RESEARCH Greenberg, P. L., VANKERSEN, I., MOSNY, S. 1976; 36 (12): 4412-4417

  Abstract

  We have utilized an in vitro clonogenic assay of mouse and human marrow granulocytic progenitor cells to determine the cytotoxic effects on granulopoiesis of the chemotherapeutic agents 1-beta-D-arabinofuranosylcytosine (ara-C) and 6-thioguanine. Concentration- and time-dependent decrements to plateau levels of granulocytic colony-forming capacity occurred. The sequence of drug administration was important and synergistic cytotoxicity was noted when certain schedules of ara-C and 6-thioguanine combinations were used. Endotoxin-stimulated colony-forming cells had increased sensitivity to the in vitro ara-C exposure. High or intermittent doses of ara-C demonstrated enhanced cytotoxicity when short exposure times (1 to 8 hr) were utilized, whereas low doses were markedly cytotoxic with prolonged exposure (10 days). Normal and leukemic human colony-forming cells had similar susceptibility to the cytotoxic effects of ara-C. Exposure of granulocytic precursors to these drugs in vitro produced effects similar to those previously reported with in vivo drug administration. These techniques appear applicable for providing improved screening models to evaluate chemotherapeutic regimens for clinical use.

  View details for Web of Science ID A1976CM52800008

  View details for PubMedID 1069606

• Cytotoxic effects of cytosine arabinoside and 6-thioguanine in vitro on granulocytic progenitor cells Cancer Res Greenberg, P. L., VanKersen, I., Mosny , S. 1976: 4412-4417
• ALTERATIONS OF GRANULOPOIESIS FOLLOWING CHEMOTHERAPY BLOOD GREENBER, P., Bax, I., MARA, B., Schrier, S. 1974; 44 (3): 375-383

  View details for Web of Science ID A1974U239100008

  View details for PubMedID 4527645

• CLINICAL UTILITY OF INVITRO EVALUATION OF GRANULOPOIESIS ANNUAL REVIEW OF MEDICINE GREENBER, P. L., Schrier, S. L. 1974; 25: 269-278

  View details for Web of Science ID A1974S807000023

  View details for PubMedID 4596230

• GRANULOPOIESIS IN NEUTROPENIC DISORDERS BLOOD GREENBER, P. L., Schrier, S. L. 1973; 41 (6): 753-769

  View details for Web of Science ID A1973P919600002

  View details for PubMedID 4712205

• The anemia of chronic disorders due to renal cell carcinoma: ferrokinetic and morphologic documentation of its surgical correction. The American journal of the medical sciences Greenberg, P. L., CREGER, W. P. 1971; 261 (5): 265-269

  View details for PubMedID 5092153

• Granulopoiesis in acute myeloid leukemia and preleukemia New Engl J Med Greenberg PL, Nichols WC, Schrier SL 1971; 284: 1225-1232
• GRANULOPOIESIS IN ACUTE MYELOID LEUKEMIA AND PRELEUKEMIA NEW ENGLAND JOURNAL OF MEDICINE Greenberg, P. L., Nichols, W. C., Schrier, S. L. 1971; 284 (22): 1225-?

  View details for Web of Science ID A1971J430100001

  View details for PubMedID 5280338