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ABSTRACT: Myelodysplastic syndromes (MDS) are malignant clonal disorders of haematopoietic stem cells and their microenvironment, affecting older individuals (median age ∼70 years). Unique features that are associated with MDS - but which are not necessarily present in every patient with MDS - include excessive apoptosis in maturing clonal cells, a pro-inflammatory bone marrow microenvironment, specific chromosomal abnormalities, abnormal ribosomal protein biogenesis, the presence of uniparental disomy, and mutations affecting genes involved in proliferation, methylation and epigenetic modifications. Although emerging insights establish an association between molecular abnormalities and the phenotypic heterogeneity of MDS, their origin and progression remain enigmatic.
Nature Reviews Cancer 11/2012; 12(12):849-59. · 29.54 Impact Factor
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ABSTRACT: During 2004-2006, two hypomethylating agents (HMAs) were approved for the treatment of myelodysplastic syndromes (MDS) in the United States. We assessed the impact of HMAs on the cost of care and survival of MDS patients, by constructing a cohort of patients who were diagnosed during 2001-2007 (n=6556, age ≥66.5 years) and comparable non-cancer controls. We assessed MDS patients' and controls' Medicare expenditures to derive MDS-related cost. We evaluated the two-year survival of patients as a group and by major subtypes. Taking into account the survival probabilities of MDS, the expected MDS-related 5-year cost was $63,223 (95% confidence interval: $59,868-66,432 in 2009 dollars), higher than the reported comparable cost for any of the 18 most prevalent cancers in the United States. Compared with MDS patients diagnosed in the earlier period (January 2001-June 2004) who received no HMAs, patients diagnosed later (July 2004-December 2007) who received HMAs had a significantly higher 24-month cost ($97,977 vs. $42,628 in 2009 dollars) and an improved 24-month survival (especially among patients with refractory anemia or refractory anemia with excess blasts). The magnitude of the cost of care underscores a need for comparative cost-effectiveness studies to reduce the clinical and economic burden of MDS.
Leukemia research 08/2012; 36(11):1370-5. · 2.36 Impact Factor
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Rafael Bejar,
Kristen E Stevenson,
Bennett A Caughey,
Omar Abdel-Wahab,
David P Steensma,
Naomi Galili, Azra Raza,
Hagop Kantarjian,
Ross L Levine,
Donna Neuberg,
Guillermo Garcia-Manero,
Benjamin L Ebert
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ABSTRACT: PURPOSE A subset of patients with myelodysplastic syndromes (MDS) who are predicted to have lower-risk disease as defined by the International Prognostic Scoring System (IPSS) demonstrate more aggressive disease and shorter overall survival than expected. The identification of patients with greater-than-predicted prognostic risk could influence the selection of therapy and improve the care of patients with lower-risk MDS. PATIENTS AND METHODS We performed an independent validation of the MD Anderson Lower-Risk Prognostic Scoring System (LR-PSS) in a cohort of 288 patients with low- or intermediate-1 IPSS risk MDS and examined bone marrow samples from these patients for mutations in 22 genes, including SF3B1, SRSF2, U2AF1, and DNMT3A. Results The LR-PSS successfully stratified patients with lower-risk MDS into three risk categories with significant differences in overall survival (20% in category 1 with median of 5.19 years [95% CI, 3.01 to 10.34 years], 56% in category 2 with median of 2.65 years [95% CI, 2.18 to 3.30 years], and 25% in category 3 with median of 1.11 years [95% CI, 0.82 to 1.51 years]), thus validating this prognostic model. Mutations were identified in 71% of all samples, and mutations associated with a poor prognosis were enriched in the highest-risk LR-PSS category. Mutations of EZH2, RUNX1, TP53, and ASXL1 were associated with shorter overall survival independent of the LR-PSS. Only EZH2 mutations retained prognostic significance in a multivariable model that included LR-PSS and other mutations (hazard ratio, 2.90; 95% CI, 1.85 to 4.52). CONCLUSION Combining the LR-PSS and EZH2 mutation status identifies 29% of patients with lower-risk MDS with a worse-than-expected prognosis. These patients may benefit from earlier initiation of disease-modifying therapy.
Journal of Clinical Oncology 08/2012; 30(27):3376-82. · 18.37 Impact Factor
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ABSTRACT: Approximately 70% of all patients with myelodysplastic syndrome (MDS) present with lower-risk disease. Some of these patients will initially respond to treatment with growth factors to improve anemia but will eventually cease to respond, while others will be resistant to growth factor therapy. Eventually, all lower-risk MDS patients require multiple transfusions and long-term therapy. While some patients may respond briefly to hypomethylating agents or lenalidomide, the majority will not, and new therapeutic options are needed for these lower-risk patients. Our previous clinical trials with ezatiostat (ezatiostat hydrochloride, Telentra®, TLK199), a glutathione S-transferase P1-1 inhibitor in clinical development for the treatment of low- to intermediate-risk MDS, have shown significant clinical activity, including multilineage responses as well as durable red-blood-cell transfusion independence. It would be of significant clinical benefit to be able to identify patients most likely to respond to ezatiostat before therapy is initiated. We have previously shown that by using gene expression profiling and grouping by response, it is possible to construct a predictive score that indicates the likelihood that patients without deletion 5q will respond to lenalidomide. The success of that study was based in part on the fact that the profile for response was linked to the biology of the disease.
RNA was available on 30 patients enrolled in the trial and analyzed for gene expression on the Illumina HT12v4 whole genome array according to the manufacturer's protocol. Gene marker analysis was performed. The selection of genes associated with the responders (R) vs. non-responders (NR) phenotype was obtained using a normalized and rescaled mutual information score (NMI).
We have shown that an ezatiostat response profile contains two miRNAs that regulate expression of genes known to be implicated in MDS disease pathology. Remarkably, pathway analysis of the response profile revealed that the genes comprising the jun-N-terminal kinase/c-Jun molecular pathway, which is known to be activated by ezatiostat, are under-expressed in patients who respond and over-expressed in patients who were non-responders to the drug, suggesting that both the biology of the disease and the molecular mechanism of action of the drug are positively correlated.
Journal of Hematology & Oncology 05/2012; 5:20. · 3.99 Impact Factor
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Azra Raza,
Naomi Galili,
Deborah Mulford,
Scott E Smith,
Gail L Brown,
David P Steensma,
Roger M Lyons,
Ralph Boccia,
Mikkael A Sekeres,
Guillermo Garcia-Manero,
Ruben A Mesa
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ABSTRACT: Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells.
Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1-21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non-hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10 mg doses recommended for future studies.
The tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active.
Journal of Hematology & Oncology 04/2012; 5:18. · 3.99 Impact Factor
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Nelli Bejanyan,
Ramon V Tiu, Azra Raza,
Ania Jankowska,
Matt Kalaycio,
Anjali Advani,
Josephine Chan,
Yogen Saunthararajah,
Lindsey Mooney,
Jaroslaw P Maciejewski,
Mikkael A Sekeres
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ABSTRACT: Primary myelofibrosis (PMF) and overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal hematopoietic disorders that share similar clinical features and molecular abnormalities, such as the Janus kinase 2 (JAK2) valine to phenylalanine mutation at codon 617 (V617F) and the tet methylcytosine dioxygenase 2 (TET2) mutation. There are limited therapeutic options available for these diseases, and single agents have only modest efficacy. In this phase 2 study, the authors combined multiple active agents (thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid [TADA]) to treat patients with these disorders.
This multicenter trial was conducted from January 2005 to July 2007. The primary endpoint was to evaluate the efficacy of TADA therapy. Patients received the combination for one 12-week cycle followed by maintenance thalidomide for an additional 3 months. Response was assessed using International Working Group criteria.
Among 28 enrolled patients, the median age was 66.5 years; 15 patients had MDS/MPN-unclassifiable, 8 patients had chronic myelomonocytic leukemia type 1, and 5 patients had PMF. Approximately 60% of the patients had normal cytogenetics. The JAK2V617F mutation was detected in 5 of 14 tested patients, and TET2 mutations were detected in 2 of 8 tested patients. Almost half of the patients had splenomegaly. With a median on-study follow-up of 5.7 months, 21 patients (75%) completed the entire 12-week course of therapy, and 6 patients (29%) responded to TADA. With a median extended follow-up of 24.1 months for 15 evaluable patients, the median progression-free survival was 14.4 months, and the median overall survival was 21.4 months.
The TADA regimen yielded clinical responses in patients with PMF and MDS/MPN. To the authors' knowledge, this study represents the first trial targeting this patient population. The results indicated that it is reasonable to incorporate multiple novel agents in the treatment of these rare diseases.
Cancer 12/2011; 118(16):3968-76. · 4.77 Impact Factor
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ABSTRACT: Advances in therapy can essentially be measured using two parameters; introduction of a new agent which benefits an increased number of patients over prevailing treatments or more selective use of an existing drug by matching it to the biologic characteristics associated with response. In reviewing the therapeutic landscape of myelodysplastic syndromes (MDS), both should be applied to gauge the advances in therapy. While several new drugs are currently in clinical trials for the treatment of MDS, three drugs were approved for use in the last decade and sufficient time has elapsed to take stock of the benefit they have produced in the outcome of patients both in terms of survival and quality of life. For the two hypomethylating agents, response remains limited to 50% patients at best, and no strategy has evolved to allow for pre-selection of likely responders, however, 5-azacytidine has been associated with improvement in the survival of higher risk patients. The benefit of lenalidomide was found to be greater for del(5q) patients with transfusion dependent anemia and lower risk disease right from the start, although a quarter of the non-del(5q) patients also experienced complete transfusion independence with this agent. It is in this latter group of non-del(5q) cases that a strategy for potentially preselecting likely responders is suggested by the finding of an expression profile associated with response. In this paper, we will focus on defining our current understanding of the mechanisms of action of the existing FDA approved drugs in order to identify therapeutic strategies that are suitable for specific MDS subtypes. We expect that through advancing biologic insights, the use of such therapies will become more selective and refined.
Blood reviews 11/2011; 26(2):73-80. · 7.19 Impact Factor
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Azra Raza,
Naomi Galili,
Scott E Smith,
John Godwin,
Ralph V Boccia,
Han Myint,
Daruka Mahadevan,
Deborah Mulford,
Mark Rarick,
Gail L Brown,
Dale Schaar,
Stefan Faderl,
Rami S Komrokji,
Alan F List,
Mikkael Sekeres
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ABSTRACT: Ezatiostat is a glutathione analog prodrug glutathione S-transferase P1-1 (GSTP1-1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate-1 risk myelodysplastic syndrome (MDS).
Patients were randomized by 1 stratification factor-baseline cytopenia (anemia only vs anemia with additional cytopenias)-to 1 of 2 extended dosing schedules. Multilineage hematologic improvement (HI) responses were assessed by International Working Group 2006 criteria.
Overall, 11 of 38 (29%) red blood cell (RBC) transfusion-dependent patients had HI-Erythroid (HI-E) response. The median duration of HI-E response was 34 weeks. Multilineage responses were observed. There was 1 cytogenetic complete response in a del (5q) MDS patient. An important trend was the effect of prior therapy on response. A 40% HI-E rate (6 of 15 patients) was observed in patients who had prior lenalidomide and no prior hypomethylating agents (HMAs), with 5 of 11 (45%) patients achieving significant RBC transfusion reduction and 3 of 11 (27%) achieving transfusion independence. A 28% HI-E rate (5 of 18 patients) was observed in patients who were both lenalidomide and HMA naive, with 4 of 8 (50%) patients achieving clinically significant RBC transfusion reductions. Most common ezatiostat-related adverse events were grade 1 and 2 gastrointestinal including: nausea (45%, 17%), diarrhea (26%, 7%), and vomiting (30%, 12%).
Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant and sustained reduction in RBC transfusions, transfusion independence, and multilineage responses in MDS patients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS.
Cancer 09/2011; 118(8):2138-47. · 4.77 Impact Factor
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Madhu S Kumar,
Anupama Narla,
Atsushi Nonami,
Ann Mullally,
Nadya Dimitrova,
Brian Ball,
J Randall McAuley,
Luke Poveromo,
Jeffrey L Kutok,
Naomi Galili, Azra Raza,
Eyal Attar,
D Gary Gilliland,
Tyler Jacks,
Benjamin L Ebert
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ABSTRACT: Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q- syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.
Blood 08/2011; 118(17):4666-73. · 9.90 Impact Factor
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ABSTRACT: Myelodysplastic syndromes (MDS) are considered to be stem cell disorders. A number of cytogenetic abnormalities have been
demonstrated in these patients. In the last decade it has become apparent that besides the cytogenetic and molecular abnormalities
at the individual cell level, the global alterations of the bone marrow (BM) microenvironment brought about by shifts in the
cytokine milieu may play a crucial role in defining the pathobiology of these disorders. The combination of factors produced
by adherent stromal cells and hematopoietic cells constitute the web of cytokines meshing a variety of biological processes
including survival, proliferation and differentiation of the hematopoietic cells. Imperatively thus, hematopoiesis in these
patients is a result of a critical balance between the stimulatory and inhibitory signals transduced by these cytokines. Primarily
effects of these cytokines could be chemotatic, stimulatory or inhibitory to hematopoiesis.
07/2011: pages 93-100;
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Rafael Bejar,
Kristen Stevenson,
Omar Abdel-Wahab,
Naomi Galili,
Björn Nilsson,
Guillermo Garcia-Manero,
Hagop Kantarjian, Azra Raza,
Ross L Levine,
Donna Neuberg,
Benjamin L Ebert
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ABSTRACT: Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems.
We used a combination of genomic approaches, including next-generation sequencing and mass spectrometry-based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival.
We identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with normal cytogenetics. Mutations in RUNX1, TP53, and NRAS were most strongly associated with severe thrombocytopenia (P<0.001 for all comparisons) and an increased proportion of bone marrow blasts (P<0.006 for all comparisons). In a multivariable Cox regression model, the presence of mutations in five genes retained independent prognostic significance: TP53 (hazard ratio for death from any cause, 2.48; 95% confidence interval [CI], 1.60 to 3.84), EZH2 (hazard ratio, 2.13; 95% CI, 1.36 to 3.33), ETV6 (hazard ratio, 2.04; 95% CI, 1.08 to 3.86), RUNX1 (hazard ratio, 1.47; 95% CI, 1.01 to 2.15), and ASXL1 (hazard ratio, 1.38; 95% CI, 1.00 to 1.89).
Somatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. (Funded by the National Institutes of Health and others.).
New England Journal of Medicine 06/2011; 364(26):2496-506. · 53.30 Impact Factor
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ABSTRACT: Recent biologic insights support the premise that the myelodysplastic syndromes result from a complex series of interactions between a transformed hematopoietic stem cell and its microenvironment. Excessive apoptosis and defective ribogenesis, two of the unifying characteristics across the various syndromes only focus on the stem cell alone. The recurrent genetic mutations of the abnormal stem cells that have been associated with specific chromosomal changes have been used to produce mouse models of MDS, but none faithfully recapitulates the human phenotype. In one model, targeting a mutation to the marrow stromal cell produced an MDS-like disease of the hematopoietic parenchymal cells. Thus, even though the original lesion may occur in one compartment, its expansion into a full-blown clinical syndrome depends on the co-evolving pathology of the other. A reductionist strategy would be inherently inadequate to address such complexity; rather a systems biology approach would be more suited for a pluralistic solution to the problem.
03/2011: pages 143 - 152; , ISBN: 9781444394016
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ABSTRACT: Myelodysplastic syndromes (MDS) are a group of hematological malignancies with poor survival. Although previous studies have identified the prognostic role of multiple demographic and clinical characteristics, the potential role of lifestyle factors has not been evaluated. In this study, we conducted an extensive assessment of the predictors of MDS survival, with a special focus on lifestyle factors. A total of 616 patients (median survival = 4.1 years) were included in the analysis, and multivariate Cox proportional hazard models were utilized to estimate hazard ratios. Compared with non-smokers, MDS patients who smoked at the initial clinical encounter had a significantly increased risk of death [hazard ratio (HR) = 1.46, 95% confidence intervals (CI): 1.07-2.00]. The elevated risk was restricted to men (HR = 1.76, 95% CI: 1.21-2.56) and not observed among women (HR = 0.98, 95% CI: 0.51-1.85). When patients were stratified by the IPSS categorization, a near three fold increased risk of death was associated with smoking among patients with low-risk MDS (HR = 2.83, 95% CI: 1.48-5.39), whereas smoking did not appear to influence the survival of patients with intermediate- or high-risk MDS. This study was the first to identify smoking as a significant and independent predictor of MDS survival, particularly among low-risk patients.
Cancer Causes and Control 02/2011; 22(4):623-9. · 2.88 Impact Factor
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ABSTRACT: Little is known about how hypomethylating agents (HMAs) have been adopted into the treatment of myelodysplastic syndromes (MDS). We conducted a population-based study to assess the use of HMAs among 4416 MDS patients (age≥66 years) who were diagnosed during 2001-2005 and followed up through the end of 2007. Multivariate logistic regression models were utilized to evaluate the role of various patient characteristics. 475 (10.8%) patients had received HMAs by 2007, with the proportion increasing over time. Patients who were white (odds ratio (OR)=0.66, 95% confidence interval (CI): 0.46-0.95), male (OR=1.47, 95% CI: 1.19-1.82), young (Ptrend<0.01), more recently diagnosed (OR=1.90, 95% CI: 1.54-2.34), had fewer comorbidities (Ptrend<0.01), or had a history of other cancer (OR=1.28, 95% CI: 1.00-1.63) were more likely to receive HMAs. Compared with patients with refractory anemia, those diagnosed with refractory anemia with excess blasts or refractory cytopenia with multilineage dysplasia had a higher chance to be treated with HMAs (OR=3.52 and 2.32, respectively). Relatively few MDS patients were treated with HMAs during the introduction period of these agents, and multiple patient characteristics such as sex, comorbidities, and MDS subtype influence the likelihood a patient receives HMAs.
Leukemia research 11/2010; 35(7):904-8. · 2.36 Impact Factor
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ABSTRACT: Despite the remarkable progress in the treatment of patients with myelodysplastic syndromes (MDS) in the past decade, response to the hypomethylating agents azacitidine and decitabine in non-del(5q) MDS patients remains at approximately 50%, leaving half of patients needing treatment with essentially no options. As biologic insight into the molecular pathways that account for disease evolution and clinical heterogeneity is expanded, the arsenal of potential drugs that may elicit significant response is also increasing. One of the greatest challenges for the treating physician is to decide when to initiate therapy and which therapy (approved drug or newer agents still in clinical trial) is likely to be the most beneficial. While there is no single answer to these issues, there are several approaches that may be considered, and these are addressed in this review.
This review examines the clinical outcomes of the FDA-approved drugs as well as of the promising new therapies that are in current clinical trials.
The clinician now has multiple treatment options for patients with MDS. It is important to consider multiple factors before initiating therapy with disease-modifying drugs. This review presents some of the decision-making approaches that are in practice at present.
For the first time, various treatment options are available for patients with MDS. In light of the intense efforts now in progress, the next decade promises to be one of hope and excitement for both MDS patients and treating clinicians.
Expert Opinion on Pharmacotherapy 08/2010; 11(11):1889-99. · 3.20 Impact Factor
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ABSTRACT: Treatment options for patients with lower risk non-del(5q) myelodysplastic syndromes (MDS) who fail erythroid stimulating agents are restricted to one of the hypomethylating drugs with an expected response rate of approximately 50%. Ezatiostat HCl, an agent with the potential for producing multi-lineage responses in this population is currently in clinical investigation phase. This case report describes a 77 year old male who received less than two cycles of therapy with ezatiostat HCl which had to be aborted due to intolerable side effects, but which produced a sustained normalization of all three blood counts. This trilineage response has now lasted for more than a year. Interestingly, the patient began with a del(5q) abnormality and responded briefly to lenalidomide. Upon relapse of the anemia, a bone marrow showed the disappearance of the del(5q) but the appearance of a new clonal abnormality t(2;3). Given that the patient had a complete cytogenetic response to a truncated exposure to lenalidomide followed by a trilineage response to an even briefer course of ezatiostat HCl suggests a potential role for ezatiostat HCl in del(5q) patients who relapse following lenalidomide.
Journal of Hematology & Oncology 04/2010; 3:16. · 3.99 Impact Factor
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ABSTRACT: Myelodysplastic syndromes (MDS) traditionally have been grouped together as a disease entity based on clinical phenomena seen in association. Despite the similarities, there is great heterogeneity among the syndromes. Recent insights have shown, however, that there exists a biologically cohesive theme that unifies and thereby validates the conceptual interconnectedness. The first suggestion that such a relationship existed where biology could directly explain the observed cytopenias was the finding of excessive premature apoptosis of hematopoietic cells in MDS marrows. This apoptosis was mediated by paracrine as well as autocrine factors implicating both the seed and the soil in the pathology of the disease. Pro-inflammatory cytokines in the marrow microenvironment were mainly the paracrine mediators of apoptosis, but how the clonal cells committed suicide because of autocrine stimulation had remained a mystery for more than a decade. It has been shown now that deregulation of ribosome biogenesis can initiate a stress response in the cell through the p53 signaling pathway. Congenital anemias had been associated with mutations in ribosomal protein genes. The surprise came with the investigation of 5q- syndrome patients where haplo-insufficiency of the ribosomal protein gene RPS14 was found to be the cause of this MDS subtype. Similar ribosomal deregulation was shown to be present in all varieties of MDS patients, serving as another unifying characteristic. In addition to these findings, there are other DNA-related abnormalities such as uniparental disomy, mutations in the TET2 gene, and epigenetic phenomena that are associated with and occur across all types of MDS. This paper summarizes the themes unifying this heterogeneous group of diseases.
Hematology reports. 01/2010; 2(1):e4.
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Haematologica 10/2009; 94(10):1336-8. · 6.42 Impact Factor
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Azra Raza,
Joseph G Jurcic,
Gail J Roboz,
Michael Maris,
Joseph J Stephenson,
Brent L Wood,
Eric J Feldman,
Naomi Galili,
Laurie E Grove,
Jonathan G Drachman,
Eric L Sievers
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ABSTRACT: A multi-institutional, phase 1 dose-escalation trial of lintuzumab (humanized anti-CD33 antibody; SGN-33, HuM195) was performed in patients with CD33-positive myeloid malignancies. In this study, higher doses than previously tested and prolonged duration of treatment for responding patients were evaluated. Over the dose range of 1.5-8 mg/kg/week, lintuzumab was well tolerated, and a maximum tolerated dose was not defined. The most common adverse event was transient chills with the initial lintuzumab infusion (39%). Responses were observed in 7 of 17 patients with acute myeloid leukemia: morphologic complete remission (n = 4), partial remission (n = 2), and morphologic leukemia-free state (n = 1). Of 14 patients with myelodysplastic syndrome or myeloproliferative diseases, 1 patient had major hematologic improvement and 9 patients had stable disease. In contrast to aggressive conventional chemotherapy, lintuzumab was administered in an ambulatory clinic setting with acceptable toxicity.
Leukemia & lymphoma 07/2009; 50(8):1336-44. · 2.40 Impact Factor
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ABSTRACT: Myelodysplastic syndromes (MDS) are a group of haematopoietic stem cell disorders that pose a unique challenge for gene expression profiling by virtue of their inherent heterogeneity. Despite monoclonality of MDS, the marrow picture is complicated by the presence of not only stromal cells but also by varying stages of differentiating diseased cells belonging to all three lineages. Now that reproducible results can be obtained from nanograms of RNA, it is possible to derive useful information from even a limited number of cells; for example, dysregulation of ribosomal and translational genes was detected in MDS patients compared to controls using a small number of CD34+ cells. Gene expression profiling in MDS patients treated with lenalidomide or 5-azacitidine+thalidomide yielded signatures which differentiated responders from non-responders. These biologic and clinical insights are providing the framework on which to build a new model of these diseases which, despite their heterogeneity, manifest certain unifying themes.
Best practice & research. Clinical haematology 07/2009; 22(2):223-37. · 3.13 Impact Factor
