Ascertaining QUAZARs: slow-motion and light-speed development of oral azacitidine and decitabine.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are devastating diseases that frequently rely on the use of parenteral hypomethylating agents (HMAs), either as monotherapy or in combination, as first-line treatment for many patients. Two new oral HMAs, decitabine/cedazuridine (DC) for use in place of azacitidine or decitabine in MDS, and azacitidine (CC-486) for use as maintenance treatment in AML, were recently approved by the FDA. We will discuss the development of these oral HMAs, including the advantages/disadvantages in transitioning to oral HMAs and an in depth look at the pivotal phase III trials that led to their FDA approval - ASCERTAIN for DC and QUAZAR-AML-001 for CC-486. We also review how these agents have been and are being studied in other malignancies, and examine the future role that these exciting novel agents will play in both MDS and AML.

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for older patients with AML.

Evidence suggests that combining immunotherapy with hypomethylating agents may enhance antitumor activity. This phase 2 study investigated the activity and safety of durvalumab, a programmed death-ligand 1 (PD-L1) inhibitor, combined with azacitidine for patients aged ≥65 years with acute myeloid leukemia (AML), including analyses to identify biomarkers of treatment response. Patients were randomized to first-line therapy with azacitidine 75 mg/m2 on days 1 through 7 with (Arm A, n = 64) or without (Arm B, n = 65) durvalumab 1500 mg on day 1 every 4 weeks. Overall response rate (complete response [CR] + CR with incomplete blood recovery) was similar in both arms (Arm A, 31.3%; Arm B, 35.4%), as were overall survival (Arm A, 13.0 months; Arm B, 14.4 months) and duration of response (Arm A, 24.6 weeks; Arm B, 51.7 weeks; P = .0765). No new safety signals emerged with combination treatment. The most frequently reported treatment-emergent adverse events were constipation (Arm A, 57.8%; Arm B, 53.2%) and thrombocytopenia (Arm A, 42.2%; Arm B, 45.2%). DNA methylation, mutational status, and PD-L1 expression were not associated with response to treatment. In this study, first-line combination therapy with durvalumab and azacitidine in older patients with AML was feasible but did not improve clinical efficacy compared with azacitidine alone. ClinicalTrials.gov: NCT02775903.

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for higher-risk myelodysplastic syndromes.

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase the expression of inhibitory immune checkpoint molecules. We conducted the first randomized phase 2 study of azacitidine plus the immune checkpoint inhibitor durvalumab vs azacitidine monotherapy as first-line treatment for higher-risk myelodysplastic syndromes (HR-MDS). In all, 84 patients received 75 mg/m2 subcutaneous azacitidine (days 1-7 every 4 weeks) combined with 1500 mg intravenous durvalumab on day 1 every 4 weeks (Arm A) for at least 6 cycles or 75 mg/m² subcutaneous azacitidine alone (days 1-7 every 4 weeks) for at least 6 cycles (Arm B). After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arm A received a median of 7.9 treatment cycles and those in Arm B received a median of 7.0 treatment cycles with 73.7% and 65.9%, respectively, completing ≥4 cycles. The overall response rate (primary end point) was 61.9% in Arm A (26 of 42) and 47.6% in Arm B (20 of 42; P = .18), and median overall survival was 11.6 months (95% confidence interval, 9.5 months to not evaluable) vs 16.7 months (95% confidence interval, 9.8-23.5 months; P = .74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (Arm A) and 81% (Arm B). Grade 3 or 4 hematologic AEs were reported in 89.5% (Arm A) vs 68.3% (Arm B) of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased programmed cell death ligand 1 (PD-L1 [CD274]) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining azacitidine with durvalumab in patients with HR-MDS was feasible but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. This trial was registered at www.clinicaltrials.gov as #NCT02775903.

Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

PURPOSE: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHODS: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies.

Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for TET2, IDH1, and IDH2 mutations, while nonresponders were associated with FLT3 and RAS mutations. Adaptive resistance was observed through various mechanisms including acquired RAS pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.

Forsaken Pharmaceutical: Glasdegib in Acute Myeloid Leukemia and Myeloid Diseases.

Advancements in the understanding of the pathogenesis of acute myeloid leukemia (AML) have led to the introduction and approval of a number of novel drugs in AML. Glasdegib, an oral hedgehog pathway inhibitor, was approved in 2018 in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients unfit for intensive chemotherapy. In this review, we discuss the preclinical rationale for glasdegib, important clinical trials that led to glasdegib's approval, and future trials of glasdegib in AML and other myeloid diseases. Notably, 2 large randomized, placebo-controlled phase 3 trials (AML BRIGHT 1019) are currently recruiting patients with newly diagnosed AML to evaluate glasdegib in combination with intensive chemotherapy or azacitidine, depending on the patient's ability to tolerate induction chemotherapy. While glasdegib and low-dose cytarabine have been eclipsed by venetoclax and hypomethylating agent combinations for newly diagnosed AML in the United States, we discuss other areas where glasdegib may still have an opportunity to improve outcomes in this devastating disease.

Myelo-deception: Luspatercept & TGF-Beta ligand traps in myeloid diseases & anemia.

Myelodysplastic syndromes (MDS) encompass a clinically heterogenous group of diseases defined by a clonal bone marrow failure state. Patients with lower-risk MDS primarily suffer from the consequences of anemia, with a subset having increased risks of bleeding and infection. There are few good therapeutic options for this patient population, as patients are dependent on cytokine support to improve hematopoiesis. Our review will discuss luspatercept, a transforming growth factor (TGF)-Beta ligand trap, the first new Food & Drug Administration (FDA)-approved treatment in MDS in over a decade. We will explore the different TGF-Beta ligand traps that have been developed for a number of diseases, with a focus on myeloid malignancies.

Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results.

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.

Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study.

Phase 1 results from a Phase 1/2 study comprise 18 patients with myelodysplastic syndromes (MDS; n = 9), acute myeloid leukemia (AML; n = 8), and chronic myelomonocytic leukemia (CMML; n = 1) who were either hypomethylating agent naïve (n = 10) or relapsed/refractory following prior hypomethylating agent therapy (n = 8) (NCT01926587). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle. Patients received parenteral azacitidine (75 mg/m2/day × 7 days) during the second week; the cycle repeated every 4 weeks. The combination was well tolerated for a median of 4 (range 1-41) cycles, with 72% of patients experiencing ≥1 serious adverse events. No dose-limiting toxicities were observed. Thus, no maximum tolerated dose was reached. The most frequently reported adverse events were diarrhea (50%), constipation, fatigue, and nausea (each 44%), and pneumonia and back pain (each 33%). Sequential administration demonstrated an overall response rate of 56% in evaluable patients, with responses observed in 7/9 MDS/CMML patients (78%) and 2/7 AML patients (29%). Further clinical studies are warranted to investigate this doublet therapy in patients with myeloid malignancies.

Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies.

BACKGROUND: After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower-risk myelodysplastic syndromes (LR-MDS). Optimal choice of these agents as front-line therapy in non-del(5q) LR-MDS is unclear. Because azacitidine clinical data mainly describe experience in higher-risk MDS, we performed a meta-analysis of patient-level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion-dependent LR-MDS. MATERIALS AND METHODS: We searched English-language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient-level data from identified relevant studies were provided by investigators. Meta-analyses followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS). RESULTS: Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non-del(5q) LR-MDS. Pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of ≥6 azacitidine treatment cycles was significantly predictive of response. CONCLUSION: Azacitidine effects in these patients, most with non-del(5q) LR-MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front-line therapy and alternatives are limited. IMPLICATIONS FOR PRACTICE: Lower-risk myelodysplastic syndromes (LR-MDS) are primarily characterized by anemia. After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients. This meta-analysis of 233 azacitidine-treated red blood cell (RBC) transfusion-dependent patients with LR-MDS (92.3% non-del[5q]) from 7 studies showed 38.9% became RBC transfusion-independent. There is no clear guidance regarding the optimal choice of lenalidomide or hypomethylating agents for patients with non-del(5q) LR-MDS following ESA failure. Clinical presentation (e.g., number of cytopenias) and potential outcomes after hypomethylating agent failure are factors to consider when making initial treatment decisions for LR-MDS patients.

Randomized study of continuous high-dose lenalidomide, sequential azacitidine and lenalidomide, or azacitidine in persons 65 years and over with newly-diagnosed acute myeloid leukemia.

Therapy of acute myeloid leukemia in older persons is associated with poor outcomes because of intolerance to intensive therapy, resistant disease and co-morbidities. This multi-center, randomized, open-label, phase II trial compared safety and efficacy of three therapeutic strategies in patients 65 years or over with newly-diagnosed acute myeloid leukemia: 1) continuous high-dose lenalidomide (n=15); 2) sequential azacitidine and lenalidomide (n=39); and 3) azacitidine only (n=34). The efficacy end point was 1-year survival. Median age was 76 years (range 66-87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%) had adverse cytogenetics. One-year survival was 21% [95% confidence interval (CI): 0, 43%] with high-dose lenalidomide, 44% (95%CI: 28, 60%) with sequential azacitidine and lenalidomide, and 52% (95%CI: 35, 70%) with azacitidine only. Lenalidomide at a continuous high-dose schedule was poorly-tolerated resulting in a high rate of early therapy discontinuations. Hazard of death in the first four months was greatest in subjects receiving continuous high-dose lenalidomide; hazards of death thereafter were similar. These data do not favor use of continuous high-dose lenalidomide or sequential azacitidine and lenalidomide over the conventional dose and schedule of azacitidine only in patients aged 65 years or over with newly-diagnosed acute myeloid leukemia. (clinicaltrials.gov identifier: 01358734).

A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia.

This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650-1700mg/m2/day in 14-day cycles. Initial dose escalation followed a Fibonacci scheme, followed by recommended phase 2 dose confirmation in an expanded cohort. Rigosertib was well tolerated for up to 23 cycles, with no treatment-related deaths and 18% of patients with related serious adverse events (AEs). Common AEs were fatigue, diarrhea, pyrexia, dyspnea, insomnia, and anemia. Rigosertib exhibited biologic activity, with reduction or stabilization of bone marrow blasts and improved peripheral blood counts in a subset of patients. Ten of 19 evaluable patients (53%) demonstrated bone marrow/peripheral blood responses (n=4 MDS, n=1 AML) or stable disease (n=3 MDS, n=2 AML). Median survival was 15.7 and 2.0 months for responders and non-responders, respectively. Additional studies of rigosertib are ongoing in higher-risk MDS (NCT00854646).

Safety and efficacy of azacitidine in elderly patients with intermediate to high-risk myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) represent a clonal hematopoietic stem cell disorder characterized by morphologic features of dyspoiesis, a hyperproliferative bone marrow, and one or more peripheral blood cytopenias. In patients classified according to the Revised International Prognostic Scoring System (R-IPSS) with intermediate or higher-risk disease, there is an increased risk of death due to progressive bone marrow failure or transformation to acute myeloid leukemia (AML). Azacitidine was the first DNA hypomethylating agent approved by the United States (US) Food and Drug Administration (FDA) for the treatment of MDS and the only therapy that has demonstrated a significant survival benefit over conventional care regimens (CCRs) in patients with intermediate or higher-risk disease. Prolonged survival is independent of achieving a complete remission. Azacitidine has been used in older patients with both clinical and hematological improvement as well as an acceptable side effect profile. The most common adverse effect is myelosuppression. These findings support the use of azacitidine as an effective treatment in older patients with higher-risk MDS.

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.

Design and rationale of the QUAZAR Lower-Risk MDS (AZA-MDS-003) trial: a randomized phase 3 study of CC-486 (oral azacitidine) plus best supportive care vs placebo plus best supportive care in patients with IPSS lower-risk myelodysplastic syndromes and poor prognosis due to red blood cell transfusion-dependent anemia and thrombocytopenia.

BACKGROUND: CC-486 is an oral formulation of the epigenetic modifier azacitidine. In an expanded phase 1 trial, CC-486 demonstrated clinical and biological activity in patients with International Prognostic Scoring System (IPSS) lower-risk (low- and intermediate-1-risk) myelodysplastic syndromes (MDS) with poor prognostic features including anemia and/or thrombocytopenia who may have required red blood cell or platelet transfusions. The overall response rate was 40 %, including hematologic improvement in 28 % of patients and RBC transfusion independence sustained for 56 days in 47 % of patients with baseline transfusion dependence. Based on the results of this study, the randomized, placebo-controlled phase 3 QUAZAR Lower-Risk MDS trial (AZA-MDS-003) was initiated. The design and rationale for this trial comparing CC-486 with placebo for the treatment of patients with IPSS lower-risk MDS with poor prognostic features are described. METHODS: Patients must have IPSS lower-risk MDS with red blood cell (RBC) transfusion-dependent anemia and thrombocytopenia. Eligible patients are randomized 1:1 to receive 300 mg of CC-486 or placebo once daily for the first 21 days of 28-day treatment cycles. Disease status assessments occur at the end of cycle 6 and patients may continue to receive treatment unless there is evidence of progressive disease, lack of efficacy, or unacceptable toxicity. The primary endpoint is RBC transfusion independence for ≥ 84 days, assessed according to International Working Group 2006 criteria. Secondary endpoints include overall survival, hematologic response including platelet response and erythroid response, RBC transfusion independence for ≥ 56 days, duration of RBC transfusion independence, time to RBC transfusion independence, rate of acute myeloid leukemia (AML) progression, time to AML progression, clinically significant bleeding events, safety, health-related quality of life, and healthcare resource utilization. CONCLUSIONS: This study will provide data on the efficacy and safety of CC-486 in the treatment of IPSS lower-risk MDS with poor prognosis due to the presence of both RBC transfusion-dependent anemia and thrombocytopenia. Positive results of the AZA-MDS-003 study may expand treatment options for patients with IPSS lower-risk MDS. TRIAL REGISTRATION: ClinicalTrials.gov NCT01566695, registered March 27, 2012.

Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial.

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