Severely impaired terminal erythroid differentiation as an independent prognostic marker in myelodysplastic syndromes.

Anemia is the defining feature in most patients with myelodysplastic syndromes (MDS), yet defects in erythropoiesis have not been well characterized. We examined freshly obtained bone marrow (BM) samples for stage-specific abnormalities during terminal erythroid differentiation (TED) from 221 samples (MDS, n = 205 from 113 unique patients; normal, n = 16) by measuring the surface expression of glycophorin A, band 3, and integrin α-4. Clinical and biologic associations were sought with presence or absence of TED and the specific stage of erythroid arrest. In 27% of MDS samples (56/205), there was no quantifiable TED documented by surface expression of integrin α-4 and band 3 by terminally differentiating erythroblasts. Absence of quantifiable TED was associated with a significantly worse overall survival (56 vs 103 months, P = .0001) and SRSF2 mutations (7/23, P < .05). In a multivariable Cox proportional hazards regression analysis, absence of TED remained independently significant across International Prognostic Scoring System-Revised (IPSS-R) categories, myeloid/erythroid ratio, and mutations in several genes. In 149/205 MDS samples, the proportion of cells undergoing TED did not follow the expected 1:2:4:8:16 doubling pattern in successive stages. Absence of TED emerged as a powerful independent prognostic marker of poor overall survival across all IPSS-R categories in MDS, and SRSF2 mutations were more frequently associated with absence of TED.

Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts.

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.

Leukaemogenesis induced by an activating ß-catenin mutation in osteoblasts.

Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of ß-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated ß-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased ß-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.

A prospective multicenter study of paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. METHODS: Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones. RESULTS: Granulocyte PNH clones ≥ 1% were detected in 199 of all 5,398 patients (3.7%), 93 of 503 AA patients (18.5%), 50 of 4,401 MDS patients (1.1%), and 3 of 130 other BMF patients (2.3%). Higher-sensitivity analyses detected PNH clones ≥ 0.01% in 167 of 1,746 patients from all groups (9.6%) and in 22 of 1,225 MDS patients (1.8%), 116 of 294 AA patients (39.5%), and four of 54 other BMF patients (7.8%). Among patients with PNH clones ≥ 1%, median clone size was smaller in patients with AA (5.1%) than in those with MDS (17.6%) or other BMF (24.4%), and the percentage of patients with lactate dehydrogenase levels (a marker for intravascular hemolysis) ≥ 1.5 × upper limit of normal was smaller in patients with AA (18.3%) than in those with MDS (42.0%). CONCLUSIONS: These results confirm the presence of PNH clones in high-risk patient groups and suggest that screening of such patients may facilitate patient management and care.

A Prospective Multicenter Study of Paroxysmal Nocturnal Hemoglobinuria Cells in Patients with Bone Marrow Failure.

Background: Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. Methods: Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones. Results: Granulocyte PNH clones ≥ 1% were detected in 199 of all 5398 patients (3.7%), 93 of 503 AA patients (18.5%), 50 of 4401 MDS patients (1.1%), and 3 of 130 other BMF patients (2.3%). Higher-sensitivity analyses detected PNH clones ≥ 0.01% in 167 of 1746 patients from all groups (9.6%) and in 22 of 1225 MDS patients (1.8%), 116 of 294 AA patients (39.5%), and 4 of 54 other BMF patients (7.8%). Among patients with PNH clones ≥ 1%, median clone size was smaller in patients with AA (5.1%) than in those with MDS (17.6%) or other BMF (24.4%), and the percentage of patients with lactate dehydrogenase levels (a marker for intravascular hemolysis) ≥ 1.5 × upper limit of normal was smaller in patients with AA (18.3%) than in those with MDS (42.0%). Conclusions: These results confirm the presence of PNH clones in high-risk patient groups and suggest that screening of such patients may facilitate patient management and care. © 2013 Clinical Cytometry Society.

Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo.

Terminal erythroid differentiation starts from morphologically recognizable proerythroblasts that proliferate and differentiate to generate red cells. Although this process has been extensively studied in mice, its characterization in humans is limited. By examining the dynamic changes of expression of membrane proteins during in vitro human terminal erythroid differentiation, we identified band 3 and α4 integrin as optimal surface markers for isolating 5 morphologically distinct populations at successive developmental stages. Functional analysis revealed that these purified cell populations have distinct mitotic capacity. Use of band 3 and α4 integrin enabled us to isolate erythroblasts at specific developmental stages from primary human bone marrow. The ratio of erythroblasts at successive stages followed the predicted 1:2:4:8:16 pattern. In contrast, bone marrows from myelodysplastic syndrome patients exhibited altered terminal erythroid differentiation profiles. Thus, our findings not only provide new insights into the genesis of the red cell membrane during human terminal erythroid differentiation but also offer a means of isolating and quantifying each developmental stage during terminal erythropoiesis in vivo. Our findings should facilitate a comprehensive cellular and molecular characterization of each specific developmental stage of human erythroblasts and should provide a powerful means of identifying stage-specific defects in diseases associated with pathological erythropoiesis.

The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes.

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.

Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes.

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.

The impact of hypomethylating agents on the cost of care and survival of elderly patients with myelodysplastic syndromes.

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.

Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS).

BACKGROUND: Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells. RESULTS: 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. CONCLUSIONS: 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.

Prediction of response to therapy with ezatiostat in lower risk myelodysplastic syndrome.

BACKGROUND: 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. METHODS: 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). CONCLUSIONS: 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.

A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome.

BACKGROUND: 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). METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

MDS: Refining existing therapy through improved biologic insights.

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.

Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.

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.

Clinical effect of point mutations in myelodysplastic syndromes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.).

Cigarette smoking shortens the survival of patients with low-risk myelodysplastic syndromes.

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.

Pattern of hypomethylating agents use among elderly patients with myelodysplastic syndromes.

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.

Myelodysplastic syndromes with deletions of chromosome 11q lack cryptic MLL rearrangement and exhibit characteristic clinicopathologic features.

Deletions of chromosome 11q[del(11q)] as part of a non-complex karyotype are infrequent in myelodysplastic syndromes (MDS), leaving the clinicopathologic and genetic features largely undefined. From three large medical centers over a 10-year period, we identified 32 MDS cases where del(11q) was present either as a sole (n=23) or associated with another abnormality (n=9), showing an overall 0.6% frequency in MDS. These patients included 15 men and 17 women, with a median age of 68 years. Three were therapy-related, and 29 were primary MDS. These cases were characterized by transfusion-dependent anemia (65%); frequent ring sideroblasts (RS) (59%); bone marrow hypocellularity (22%), and less severe thrombocytopenia. With a median follow-up of 32 months, 9/24 (38%) cases progressed to acute myeloid leukemia (AML), and the overall survival (OS) was 35 months (3-105). Fluorescence in situ hybridization (FISH) showed MLL deletion in 6/10 cases, but no cryptic MLL translocations in all 15 MDS cases tested. In contrast, FISH performed in AML with del(11q) showed MLL rearrangement in 3/17 (18%) cases. In summary, del(11)q occurring in a non-complex karyotype is predominantly associated with primary MDS, lack of cryptic MLL rearrangements, and shows characteristic clinicopathological features. These clinicopathological features are likely attributed to commonly deleted regions of 11q and their involved genes.

Pharmacotherapy of myelodysplastic syndromes.

IMPORTANCE OF THE FIELD: 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. AREAS COVERED 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. WHAT THE READER WILL GAIN: 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. TAKE HOME MESSAGE: 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.