Poor Outcome of Patients With Myelodysplastic Syndrome After Azacitidine Treatment Failure

BackgroundLimited data have been reported describing the outcome and prognosis of patients with MDS in whom treatment with azanucleosides has failed. We report our single-institutional experience of patients with higher-risk MDS in whom therapy with azacitidine has failed.Patients and MethodsThis was a retrospective study of MDS patients treated at the Moffitt Cancer Center in whom azacitidine treatment regimens had failed. Patients were identified through the Moffitt database, and clinical data were extracted. Azacitidine failure was defined as failure to achieve hematologic improvement or better after at least 4 cycles of therapy, loss of response, or disease progression during therapy. The objectives were to characterize response to salvage therapies after azacitidine failure and to estimate the overall survival. All responses were defined according to the International Working Group 2006 criteria, and survival was estimated using the Kaplan-Meier method.ResultsA total of 59 patients in whom azacitidine treatment had failed were identified. The median age at treatment failure was 68 years, and most were Caucasian male patients. Thirteen patients received intensive chemotherapy with an overall response rate of 31%. Six patients were treated with decitabine, and none responded. Median overall survival of the entire cohort after azacitidine failure was 5.8 months (95% confidence interval, 1.3-10.3 months), with an estimated 12-month survival of 17%.ConclusionPatients with higher-risk MDS in whom azacitidine treatment has failed have a poor prognosis and low probability of response to salvage treatments. The standard of care after azanucleoside failure should be enrollment in clinical trials.     

Injectable Hypomethylating Agents for Management of Myelodysplastic Syndromes: Patients’ Perspectives on Treatment

BackgroundUntil recently, patients with MDSs could receive HMAs via intravenous (IV) or subcutaneous (SC) administration. An oral HMA was recently approved as an alternative to IV/SC administration. This study assessed the impact of IV/SC HMA on MDS patients, and their experience of, challenges with, and views about oral MDS treatment.Patients and MethodsWe conducted an online cross-sectional survey among adult MDS patients (or caregivers as proxies) invited by 2 U.S. MDS patient advocacy groups. Patients were required to have received IV/SC HMA (ie, azacitidine or decitabine) within 6 months of the survey.ResultsThe survey was completed by 141 participants (120 patients, 21 caregiver proxies). Median patient age was 63.0 years, 53.9% were women, and 19.8%, 62.4%, and 17.7% had lower-, higher-, or unknown risk scores, respectively. HMA treatments received included SC azacitidine (37%), IV azacitidine (36%), and IV decitabine (27%). Among 89 IV HMA recipients, 74.2% and 69.7% reported treatment-related interference with their social and daily activities, respectively, and 66.3% reported pain related to treatment administration. Following an injection, SC HMA recipients reported pain (94.2%) and interference with daily (86.5%) and social (80.8%) activities. Among the 49.6% of patients who were working, 61.4% felt less productive due to treatment. Most (69.5%) MDS patients indicated they would prefer oral MDS treatment to IV/SC therapies.ConclusionPatients receiving IV/SC HMAs experienced pain/discomfort and interference with social and daily activities. The introduction of an oral HMA may alleviate some treatment challenges for MDS patients.     

Hematologic outcomes of myelodysplastic syndromes treatment with hypomethylating agents in community practice

IntroductionHypomethylating agents (HMAs) treat myelodysplastic syndromes (MDS) through suppression of abnormal clones that may cause low hemoglobin (Hgb), platelet (PLT) deficiencies, and reduced absolute neutrophil count (ANC). Our study examined hematologic outcomes in MDS among patients treated with HMAs in a large community hematology-oncology practice.Materials and MethodsA retrospective study using electronic medical record data studied patients who received at least one cycle of a single HMA (decitabine [DAC] or azacitidine [AZA]) for MDS from June 1, 2006, to May 31, 2009, who had pretreatment and end-of-treatment Hgb, PLT counts, and ANC available. Multivariate logistic regression assessed predictors of end-of-treatment response (Hgb ≥ 11g/dL without transfusion or erythrocyte stimulating agent; PLT ≥ 100,000 cells/μL without transfusion; ANC ≥ 1000 cells/mm³ without colony stimulating factor) adjusting for baseline laboratory values, age, gender, and comorbidities. HMA choice was studied as a predictor of outcome.ResultsA total of 137 patients (mean age, 72.2 years; 57% male) met full inclusion criteria (DAC = 84, AZA = 53). Mean number of cycles was four (range, 1-16 cycles) for DAC and five (range, 1-23 cycles) for AZA. Total number of cycles significantly predicted Hgb, PLT, and ANC response (odds ratio [OR] 1.19, P = .029; OR 1.15, P = .031; OR 1.16, P = .047, respectively). Growth factor use at any point during HMA treatment was negatively associated with Hgb and ANC response (OR 0.85, P = .007; OR 0.96, P = .046). There was no difference between treatments in likelihood of PLT or ANC response.ConclusionsPatients treated with HMAs for MDS are more likely to achieve hematologic response when treated with a greater number of cycles.     

Hypomethylating Agent Therapy in Myelodysplastic Syndromes With Chromosome 3 Abnormalities

BackgroundAbnormalities of chromosome 3 in myelodysplastic syndromes (MDS), that is, inversion 3 (inv[3]), translocation 3q (t[3q]), or deletion 3q (del[3q]), are defined as poor-risk karyotypes in the Revised International Prognostic Scoring System (IPSS-R). The objective of this study was to further define the outcomes of patients with MDS with chromosome 3 abnormalities and address the impact of hypomethylating agent (HMA) therapy on this patient subset.Patients and MethodsThrough the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts).ResultsSpecific chromosome 3 aberrations and cytogenetic complexity were predictive of survival; patients with t(3q) and isolated chromosome 3 had improved overall survival (OS), albeit still poor, whereas patients with complex cytogenetics, including those with 3p abnormalities, had inferior OS. Overall response rates to HMAs among this patient population were similar to those of patients with nonchromosome 3–MDS (52%, with a 25% complete remission rate), although with higher response rates in decitabine-treated patients (69% vs. 45%, P = .008). HMA therapy improved the OS of patients with higher-risk MDS compared with intensive chemotherapy (median OS of 15.5 vs. 8.2 months; P = .017). This improvement remained significant in multivariate analyses (hazard ratio, 0.60; P = .018); however, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs.ConclusionPatients with MDS with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.     

Favorable Outcomes With Tumor Burden Reduction Following Administration of Hypomethylating Agents Before Allogeneic Hematopoietic Cell Transplantation in Patients With Higher Risk Myelodysplastic Syndrome

IntroductionThe clinical significance of tumor burden reduction following administration of hypomethylating agents (HMAs) for transplant-eligible patients with higher risk myelodysplastic syndrome (MDS) was evaluated.Patients and MethodsData of 79 transplant-eligible patients (< 65 years) diagnosed with higher-risk MDS between July 2002 and March 2013 were retrospectively analyzed. Among 79 patients, 30 (38%) underwent allogeneic hematopoietic cell transplantation (HCT group), and 49 (62%) were treated with HMA alone (non-HCT group).ResultsThe median follow-up duration was 732 days (range, 28-1952 days), and the 3-year overall survival (OS) rate of all patients was 30.6%. In the HCT group, early HCT showed a better 3-year OS rate than late HCT (67.1% vs. 25.7%; P = .035). In multivariate analysis, time/performance of allogenic transplant (no HCT vs. early HCT, hazard ratio, 0.18; 95% confidence interval, 0.04-0.81; P = .026) and follow-up higher risk International Prognostic Scoring System (hazard ratio, 6.22; 95% confidence interval, 2.09-18.51; P = .001) were significantly correlated with OS.ConclusionTo predict the clinical outcomes of patients with higher risk MDS, the optimal time for tumor burden evaluation is prior to follow-up rather than at the time of initial diagnosis. Patients with lower International Prognostic Scoring System risk groups after HMA treatment or early HCT had favorable OS.     

Early Real-World First-Line Treatment With Venetoclax Plus HMAs Versus HMA Monotherapy Among Patients With AML in a Predominately US Community Setting

BackgroundVenetoclax in combination with hypomethylating agents (HMAs) is standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are ≥ 75 years old or unfit for intensive chemotherapy. We examined early real-world treatment experience among patients with AML receiving venetoclax+HMAs or HMA monotherapy.Patients and methodsThis retrospective cohort study used an electronic health record-derived, deidentified, United States nationwide database comprised of patient-level structured and unstructured data, curated via technology-enabled abstraction. Patients with an AML diagnosis on or after January 1, 2014, who had ≥ 2 clinic visits, and initiated treatment with venetoclax+HMAs from June 1, 2018 to March 31, 2021, or HMA monotherapy from January 1, 2016 to May 31, 2018, were included. Kaplan–Meier analysis was used to estimate time to last administration (TTLA) and overall survival (OS).ResultsOverall, 619 patients treated with venetoclax+HMAs and 480 treated with HMA monotherapy were selected from the database. Median age at diagnosis was 76 and 78 years, respectively, most patients were treated in community practice (83.4% and 89.4%, respectively), and almost half had secondary AML (47.2% and 47.3%, respectively). Adjusted analyses showed both significantly longer TTLA (3.6 months vs. 2.3 months; hazard ratio [HR] = 0.69 [95% confidence interval (CI), 0.60-0.80], P< .0001) and OS (9.3 months vs. 5.9 months; HR = 0.71 [95% CI, 0.61-0.82], P < .0001) in patients treated with venetoclax+HMAs versus HMA monotherapy, respectively.ConclusionThis study shows benefit in real-world outcomes of venetoclax+HMAs relative to HMA monotherapy in patients with newly diagnosed AML, using a predominantly community-based database.     

The Real-Life Efficacy of Fixed-Dose Hypomethylating Agents in Older Patients With Acute Myeloid Leukemia: A 10-Year Experience

BackgroundHypomethylating agent (HMA) is one of recommended treatment for elderly patients with acute myeloid leukemia (AML); however, their high cost precludes their general use, especially in developing countries. Therefore, the fixed-dose HMAs approach was adopted to reduce the expenses. This study focuses on the clinical outcome of various treatment protocols, including intensive chemotherapy, fixed-dose HMAs, and palliative treatment in Thai elderly patients with AML. Fixed-dose HMAs include 5-azacitidine given at 100 mg per day for seven days and decitabine given at 30 mg per day for 5 days.Patients and MethodsWe conducted a 10-year cohort study focused on elderly AML patients aged over 60 years. The exclusion criteria were acute promyelocytic leukemia.ResultsA total of 243 AML patients were enrolled. Comparing 3 groups of treatment regimens (intensive chemotherapy, fixed-dose HMAs, and palliative treatment), the proportions of patients in each category accounted for 23.5%, 21.4%, and 55.1%, respectively. The median overall survival (OS) in each therapeutic option was 7.7, 11, and 2.5 months, respectively. From multivariate analysis, palliative treatment was significantly inferior OS comparing to the fixed-dose HMAs and intensive treatment (hazard ratio [HR]: 0.42; 95% CI, 0.29-0.60; P value <.001 and HR: 0.41; 95% CI, 0.28-0.61; P value <.001, respectively). Nevertheless, the OS outcome in patients with fixed-dose HMAs was comparable to those who received intensive treatment.ConclusionOur study demonstrates that the fixed-dose regimen of HMAs is the reasonable treatment for these patients, and this approach is not inferior to intensive therapy. Thai Clinical Trials Registry identifier: TCTR20210514007.     

Retrospective Analysis of Prognostic Factors Associated With Response and Overall Survival by Baseline Marrow Blast Percentage in Patients With Myelodysplastic Syndromes Treated With Decitabine

BackgroundAfter the World Health Organization (WHO) changed the definition of acute myeloid leukemia (AML) to ≥ 20% blasts, the International Working Group (IWG) response criteria for myelodysplasia were updated. This retrospective analysis evaluated response to decitabine using updated IWG criteria in patients pooled from 2 decitabine trials.Patients and MethodsOutcomes for patients with myelodysplastic syndrome (MDS) with baseline marrow blasts ≥ 20% and < 30% (RAEB-t group) and < 20% (MDS group) were compared.ResultsPatients with RAEB-t (n = 26) had a significantly shorter time from diagnosis to study treatment (7.3 vs. 18.3 months), a higher International Prognostic Scoring System (IPSS) risk (77% vs. 16% high-risk patients), and lower median baseline platelet count (62.3 vs. 112.7 × 10³/μL) vs. patients with MDS (n = 157), yet no significant difference in overall response rate (ORR) (15.4% vs. 28.0%). Patients with MDS had better duration of response (9.9 vs. 5 months; P = .024) and overall survival (OS) (16.6 vs. 9.0 months; P = .021) compared with patients with RAEB-t.ConclusionDecitabine is active in and may benefit patients with > 20% blasts (RAEB-t).     

Clinical Outcomes of Decitabine Treatment for Patients With Lower-Risk Myelodysplastic Syndrome on the Basis of the International Prognostic Scoring System

IntroductionDecitabine has shown clinical benefits in patients with intermediate (INT)-2 or high-risk myelodysplastic syndrome (MDS), determined according to the International Prognostic Scoring System (IPSS), but the benefits have not been well demonstrated in patients with lower-risk (IPSS low or INT-1) disease. Recently, it was proposed that the prognosis for patients with IPSS lower-risk disease is heterogeneous, with a substantial proportion of these patients having poor survival.Patients and MethodsThis study included patients with IPSS lower-risk MDS from the DRAMA (An Observational Study for Dacogen Long-Term Treatment in Patients With Myelodysplastic Syndrome; NCT01400633) and DIVA (A Study for Dacogen Treatment in Patients With Myelodysplastic Syndrome; NCT01041846) studies, which were prospective observational studies on the efficacy and safety of decitabine treatment in patients with MDS. Using the Lower-Risk Prognostic Scoring System [LR-PSS], we classified IPSS lower-risk MDS. Patients in each LR-PSS category were divided according to overall response (OR) to decitabine treatment, and survival outcomes were compared.ResultsOne hundred sixteen patients were enrolled: LR-PSS category 1 (n = 12; 10.3%), category 2 (n = 56; 48.3%), and category 3 (n = 48; 41.4%). Survival outcomes differed among the 3 categories (P = .046). The overall survival according to OR showed a significant difference in total patients (P = .008) and category 3 patients (P = .003). We analyzed predictive factors for OR, but no variable was found to significantly affect OR.ConclusionDecitabine treatment showed a survival benefit in the higher-risk group of IPSS lower-risk MDS patients who responded to treatment, and classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment might alter the natural course of disease in these patients.     

Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation

The hypomethylating agents (HMAs) are standard therapy for patients with higher-risk myelodysplastic syndrome (MDS); however, the majority of the patients will lose their response to HMAs over time due to unknown mechanisms. It has recently been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter correlated with a significantly worse overall response rate (8% vs. 60%, p = 0.014), and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly higher baseline methylation level of the PD-1 promoter was observed in T cells of non-responding patients compared to healthy controls (p = 0.023).Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression on T cells in the MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor.     

Agents déméthylants dans les syndromes myélodysplasiques

DNA hypermethylation is an epigenetic phenomenon that occurs during the oncogenetic process as in myelodysplastic syndromes (MDS). Azacitidine and decitabine, two nucleosidic DNA methyltransferase inhibitors (DNMT), have shown their ability to reverse this process and re-induce the expression of tumour suppressor genes. Early studies in patients with high-risk MDS and treated by these agents report a rate of haematologic response up to 50%. With azacitidine especially, the treatment was shown to reduce also the rate of transformation into acute leukaemia, and to prolong median survival. Moreover, azacitidine and decitabine appear to significantly improve the patients’ quality of life. The good tolerance and the efficacy displayed by these DNMT made their use considered a major therapeutic strategy in high-risk MDS, likely to replace chemotherapy; they could even be used prior to grafting in patients eligible for allografting. In low-risk MDS, azacitidine and decitabine were shown to induce a transfusional independence in 30 to 40% of the cases. In this context, they are accepted as one of the best treatment options after failure of erythropoiesis-stimulating therapy.     

Survival Benefit and Efficiency of Low Dose Decitabine With CEG Regimen Compared to Decitabine Alone in the Elderly MDS – A Multicenter,Retrospective Study

BackgroundDecitabine are used in the treatment of myelodysplastic syndrome (MDS), but none trials reported overall survival improvement.MethodsHigh-risk MDS and MDS transformed AML (sAML) patients (IPSS-R > 4.5, age above 60 years) in 6 medical centers of China were treated and compared a new regimen (decitabine with CEG) consisted of low dose decitabine (15 mg/m², days 1-3), low dose etoposide (30 mg/m², days 4,6,8,10,12), cytarabine (10 mg/m² per day, days 4-12) and granulocyte colony-stimulating factor (G-CSF, 5ug/kg, adjusted by patients’ WBC level, 12 hours prior to decitabine administration) with decitabine alone. The endpoints were death and disease progression.ResultsThe baseline characteristics of these 2 groups were equivalent and none patients received prior chemotherapy. The treatment response rate (P= .048) and progression free survival (PFS, P = .030) all demonstrated significant improvement compared with decitabine alone. Decitabine with CEG regimen had attained a CR rate of 45.7%, a median OS of 36 (19-53) months and a median PFS of 34 (16.7-51.3) months in high-risk MDS patients, a CR rate of 40% in sAML. While decitabine alone only attained a median OS of 26 (24.5-27.5) months and a CR rate of 18.2% as well as a median progression free survival of 20 (17.6-22.4) months in MDS patients. Treatment response to CR or PR and TP53 mutation were 2 prognostic factor for OS and PFS in decitabine with CEG regimen.ConclusionDecitabine with CEG regimen showed some promising advantage in elderly, high-risk MDS.     

Impact of Hypomethylating Agent Use on Hospital and Emergency Room Visits,and Predictors of Early Discontinuation in Patients With Higher-Risk Myelodysplastic Syndromes

BackgroundPrevious analyses using the SEER-Medicare database have reported substantial underutilization of hypomethylating agents (HMAs) among patients with higher-risk myelodysplastic syndromes (MDS), and an association between poor HMA persistence and high economic burden. We aimed to compare rates of hospitalizations and emergency room (ER) visits among patients with higher-risk MDS according to use or non-use of HMA therapy, and to explore factors associated with early discontinuation of HMA therapy.Patients and MethodsWe used the 2010–2016 SEER-Medicare database to identify patients aged ≥66 years with a new diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) between 2011 and 2015. New hospitalizations and ER visits during the 12 months following MDS diagnosis were determined. Treatment discontinuation was defined as stopping HMA therapy before 4 cycles.ResultsOverall, 664 (55.8%) patients were HMA users and 526 (44.2%) non-users. Non-users had more hospitalizations (mean 0.47 vs. 0.30, P < .001) and ER visits (mean 0.69 vs. 0.41, P = .005) per month than HMA users. Among HMA users, 193 (29.1%) discontinued HMA therapy before 4 cycles, and 91 (47.2%) of these after 1 cycle. Older age and poor performance status were associated with higher risk of HMA discontinuation.ConclusionAn increased rate of hospitalizations and ER visits occurred in HMA non-users vs. HMA users. Approximately one-third of patients discontinued HMA therapy early. Predictors of discontinuation included older age and poor performance status. Novel approaches are needed to improve utilization and persistence with HMA therapy and associated outcomes, particularly among these higher-risk groups.     

The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes

Introduction: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndromes (MDS), but patients who relapse or are refractory have a poor prognosis with an estimated survival of 4–6 months. Rigosertib, a Ras mimetic that inhibits the phophoinositide 3-kinase and polo-like kinase pathways, has been tested in patients with higher-risk MDS following treatment with HMAs, where there are no approved second-line therapies.

Areas covered: This review will provide an overview of rigosertib, including safety and efficacy demonstrated in clinical trials.

Expert commentary: There is an urgent need for new treatment options for patients who have failed or progressed on HMAs. Rigosertib is currently undergoing testing as a single agent in certain subsets of higher-risk MDS patients as well as in combination with azacitidine, where preliminary data show efficacy in patients with de novo MDS as well as HMA failures.     

Platelet response during the second cycle of decitabine treatment predicts response and survival for myelodysplastic syndrome patients

Despite the efficacy of decitabine to myelodysplastic syndrome (MDS), there is a wide range of responses, and no definite predictive marker has been identified. This study aimed to describe the efficacy of decitabine and to identify potential predictors of response and survival in patients with MDS. We retrospectively analyzed clinical data of MDS patients at Samsung Medical Center between August 2008 and August 2011. The response assessment was conducted using the International Working Group (IWG) response criteria for MDS. We analyzed 101 MDS patients (total 613 cycles) who received decitabine for a median of four cycles. The overall response was 52.5% (n = 53/101). The median time to any response was two cycles with the median overall survival of 16.7 months. Patients who showed hematologic improvement had significantly longer survival than those who did not (9.8 vs. 22.9 months, p = 0.004). The difference in OS was evident in the Intermediate-2/High risk group (p = 0.002) but not in the Intermediate-1 risk group (p = 0.145). Multivariate analysis confirmed that platelet response (no platelet transfusions for at least 3 days) during the second cycle of treatment was an independent predictor for response, OS and Leukemia free survival. Based on the results of this study, for patients with hematological improvement, recovery of platelet count by the second cycle of therapy can be used as an early predictive marker of improved survival and an increased response rate.     

Activity of azacitidine in chronic myelomonocytic leukemia

BACKGROUND:

Hypomethylating drugs are useful in the management of myelodysplastic syndrome (MDS). Two of these drugs, azacitidine and decitabine, have received FDA approval for the treatment of MDS and chronic myelomonocytic leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS included only a small number of patients with CMML. The objective of this study was to evaluate the efficacy and safety of azacitidine in the treatment of CMML.

METHODS:

The records of thirty‐eight patients diagnosed with CMML and treated with azacitidine at our institution were reviewed. Azacitidine was administered at 75 mg/m²/day for 7 days or 100 mg/m²/day for 5 days every 4 weeks. Patients who received at least 1 cycle of the drug were considered evaluable for response.

RESULTS:

Response was assessed by the modified International Working Group (IWG) criteria. The overall response rate was 39% (14 of 36); complete response (CR) rate was 11% (4 of 36); partial response (PR) rate was 3% (1 of 36); hematologic improvement (HI) was 25% (9 of 36). The median overall survival was 12 months. There was a statistically significant overall survival advantage in responders compared with nonresponders: 15.5 months versus 9 months, respectively (P = .04). Treatment was generally well tolerated. One of 2 patients had complete resolution of a skin rash that was due to monocytic infiltration.

CONCLUSIONS:

Azacitidine is active in the treatment of CMML. The therapy‐associated toxicity is acceptable. Our results support further investigation of azacitidine in CMML, particularly in combination with other agents. Cancer 2011;. © 2010 American Cancer Society.     

A call for action: Increasing enrollment of untreated patients with higher‐risk myelodysplastic syndromes in first‐line clinical trials

Hypomethylating agents (HMAs) have changed the landscape of the management of patients with higher‐risk myelodysplastic syndromes (HR‐MDS). HMAs have improved hematopoiesis and quality of life and, in the case of azacitidine, prolonged survival in a large randomized trial. However, multiple real‐life and registry analyses have demonstrated minimal survival gains at the population level after the approval of HMAs. Furthermore, the 24‐month median survival observed with azacitidine in the landmark AZA‐001 trial has not been replicated in population‐based studies or in other clinical trials using azacitidine monotherapy arms. Herein, we critically review the accumulating data suggesting that the actual survival impact of HMAs, especially azacitidine, in patients with HR‐MDS is significantly lower than what was observed in the AZA‐001 trial and what often is quoted to patients, and discuss the potential explanations for this discrepancy. We also present the rationale for why front‐line clinical trial enrollment should be always considered and discussed with every newly diagnosed patient with HR‐MDS rather than defaulting to the routine use of HMAs. Finally, we review the challenges to wider‐scale enrollment in front‐line HR‐MDS clinical trials and suggest solutions to accelerate this process with the ultimate goal of achieving a real and substantial change in the natural history of this aggressive malignancy. Cancer 2017;123:3662–3672. © 2017 American Cancer Society     

Prognostic Factors Associated With Disease Progression and Overall Survival in Patients With Myelodysplastic Syndromes Treated With Decitabine

BackgroundMyelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML) in approximately 30% of patients. Identification of risk factors for progression to AML and overall survival (OS) would help guide treatment decisions.Patients and MethodsWe investigated prognostic factors for progression to AML and survival in 163 patients with MDS treated with decitabine 15 mg/m² over 3 hours every 8 hours for 3 days every 6 weeks (n = 74) or 20 mg/m² over 1 hour daily for 5 days every 4 weeks (n = 89).ResultsMultivariate analysis of pooled baseline data revealed that only study effect was associated with progression to AML. A hemoglobin value at least 10 g/dL, platelet count at least 50 × 10³/μL, and lack of chromosome 5 or 7 abnormalities were associated with longer OS.ConclusionsPatients with certain prognostic factors should be considered for other interventions in addition to decitabine treatment.