Syed Ali Abutalib, MD
Alan F. List, MD
To complement The ASCO Post’s continued comprehensive coverage of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel therapies for myelodysplastic syndromes (MDS), including the first-in-class erythroid maturation agent luspatercept, lenalidomide plus epoetin alfa, the IDH2 inhibitor enasidenib, the CD47-targeting antibody magrolimab plus azacitidine, and the BCL2 inhibitor venetoclax plus azacitidine. For full details of these study abstracts, visit ashpublications.org.
ABSTRACT 841: Long-term follow-up of the phase III, randomized, double-blind, placebo-controlled trial (MEDALIST) of luspatercept vs placebo in patients with revised International Prognostic Scoring System (R-IPSS) very low-, low-, or intermediate-risk MDS with ring sideroblasts who require red blood cell transfusions and are refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (ClinicalTrials.gov NCT02631070)1
Background: Luspatercept is a first-in-class erythroid maturation agent that binds and neutralizes select transforming growth factor-beta superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythroid maturation.
Methods: The MEDALIST trial assessed the achievement and number of individual periods of red blood cell transfusion independence ≥ 8 weeks. Longer-term efficacy and safety were also evaluated.
Results: Overall, 47.7% of luspatercept-treated patients achieved red blood cell transfusion independence at any time during therapy compared with 15.8% on placebo (P < .0001). The median duration of the longest period of red blood cell transfusion independence ≥ 8 weeks during weeks 1–48 was 30.6 weeks (95% confidence interval [CI] = 20.6–50.9 weeks) with luspatercept and 18.6 weeks (95% CI = 10.9 weeks to not evaluable) with placebo. The median total duration of clinical benefit (red blood cell transfusion independence and > 4 U red blood cell reduction/8 weeks) was 83.6 weeks and 26.8 weeks for patients responding to luspatercept (n = 97) and placebo (n = 20), respectively. Adverse events occurring more frequently with luspatercept than placebo (fatigue, diarrhea, asthenia, dizziness) occurred early (cycles 1–4), were mainly grade 1 or 2, decreased over time, and were not associated with a higher dose level. Progression to acute myeloid leukemia (AML) was similar in patients receiving luspatercept (n = 3 [2.0%]) and those receiving placebo (n = 1 [1.3%]).
Clinical Implications: Treatment with luspatercept resulted in a significantly reduced transfusion burden over an extended period compared with placebo and was generally well tolerated.
ABSTRACT 842: Combined treatment with lenalidomide and epoetin alfa leads to durable responses in patients with epoetin-refractory, lower-risk MDS without deletion 5q: An ECOG-ACRIN Cancer Research Group Study, Grant CA180820, and the National Cancer Institute of the National Institutes of Health2
Background: Lenalidomide restores sensitivity to erythropoietin in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/erythropoietin-receptor complexes.2-5
Methods: In the E2905 intergroup phase III trial, eligible patients had a hemoglobin < 9.5 g/dL, were unresponsive to epoetin alfa treatment or were transfusion-dependent (≥ 2 U/month) with serum erythropoietin levels > 500 mU/mL. Crossover to combined therapy was allowed for monotherapy nonresponders after week 16. Overall, 93% of patients received prior treatment with erythropoietin (epoetin alfa or darbepoetin), and 18% received azanucleosides.
Results: Among the 195 evaluable patients, 96 were assigned to arm A (lenalidomide at 10 mg for 21 days/month) and 99 to arm B (lenalidomide plus subcutaneous epoetin alfa at 60,000 U/wk). In an intent-to-treat analysis, 28 of 99 patients (28.3%) in arm B achieved the primary endpoint of major erythroid response compared with 11 of 96 patients (11.5%) in arm A (P = .004). Among 136 patients who completed 16 weeks of study treatment, 28 of 72 (38.9%) and 10 of 64 (15.6%) achieved a major erythroid response, respectively (P = .004). The overall erythroid response rate was 46.5% with combined therapy compared with 32.3% with lenalidomide alone. A total of 44 nonresponders in arm A crossed over to combination therapy, with 11 patients (25%) experiencing a major erythroid response. Responses were durable, with a major erythroid response lasting a median duration of 23.8 months in arm B vs 13 months in arm A. There was no significant difference in the frequency or distribution of ≥ grade 3, nonhematologic adverse events between the treatment arms.
Treatment with luspatercept resulted in a significantly reduced transfusion burden over an extended period compared with placebo and was generally well tolerated.— SYED ALI ABUTALIB, MD, AND ALAN F. LIST, MD
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Clinical Implications: The addition of lenalidomide and epoetin alfa is an effective strategy for the management of erythropoietin-refractory, low-risk, 5q-negative patients, with a potential duration of benefit extending to years.
ABSTRACT 678: Preliminary results from the multicenter phase II study of enasidenib in patients with IDH2-mutated high-risk MDS, AML with 20% to 30% marrow blasts, or chronic myelomonocytic leukemia6
Background: Enasidenib is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed or refractory AML.
Methods: IDH2-mutated MDS, AML with 20% to 30% marrow blasts, and chronic myelomonocytic leukemia were included in this study. There were two study cohorts: patients naive to hypomethylating agents who had high-risk MDS (including those with high-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations) (arm A; n = 6) received azacitidine plus enasidenib; patients with relapsed or refractory disease after treatment with hypomethylating agents (arm B; n = 12) received enasidenib alone. The primary efficacy endpoint was overall response rate. The primary safety endpoint was the incidence and severity of adverse events.
Results: In six patients who were naive to hypomethylating agents, all (100%) responded to therapy, including two complete remissions and four marrow complete remissions (one with hematologic improvement for neutrophils). In those who failed to respond to hypomethylating agents, 6 of 12 (50%) responded, including 2 complete remissions, 1 partial response, 1 marrow complete remission (with hematologic improvement neutrophil), and 2 with stable disease with hematologic improvement (1 with hematologic improvement neutrophil, 1 with hematologic improvement erythroid). The median times to first response and best response were both 1.3 months (range, 0.9–2.1 months) in arm A and 1.8 months (range, 0.9–3.7 months) and 2.7 months (0.9–4.6 months), respectively in arm B. The most common nonhematologic adverse events were unconjugated hyperbilirubinemia (39%), nausea (33%), fatigue (33%), pneumonia (22%), and diarrhea (17%). Possible differentiation syndrome was reported in three patients on days 31, 38, and 42 of treatment. Four patients developed leukocytosis.
Clinical Implications: Enasidenib is well tolerated and shows promising efficacy in IDH2-mutated high-risk MDS. The overall response rate was 67%, including 100% in newly diagnosed patients receiving the combination of azacitidine plus enasidenib and 50% in patients who failed to respond to hypomethylating agents who received enasidenib alone.
ABSTRACT 569: Magrolimab in combination with azacitidine is effective in MDS (n = 18) and AML (n = 25) patients: ongoing phase Ib results7
Background: Magrolimab is an antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancer cells. Blockade of CD47 permits tumor phagocytosis and reduction in leukemia stem cells in AML models.
Methods: Results from this phase Ib study focused on treatment of magrolimab and azacitidine in untreated IPSS-R intermediate- to very high–risk MDS and untreated AML (induction chemotherapy–ineligible) patients (median age, 73 years).
Results: Treatment-related adverse events (> 15% of patients) for magrolimab and azacitidine were anemia, neutropenia, and thrombocytopenia. Only one patient discontinued treatment due to an adverse event. There were 24 patients with MDS and 22 patients with AML evaluable for efficacy. Of the 24 patients with untreated MDS, 22 (92%) had an objective response, with 12 patients achieving a complete response, 8 patients with a marrow complete response (4 patients also had hematologic improvement), and 2 with hematologic improvement alone. In the 22 patients with AML, 14 (64%) had an objective response, 12 (55%) with complete response or complete response with incomplete cell count recovery, 1 with a partial response, 1 with a morphologic leukemia-free state, and 7 with stable disease. The time to response was faster (median, 1.9 months) than expected with azacitidine alone. Of note, seven of nine evaluable patients with TP53-mutant AML responded (seven complete responses and complete response with incomplete cell count recovery), with a cytogenetic complete response in 67% and MRD negativity in 57% of responders. Neither the median response duration nor overall survival had been reached for either group of patients, with a median follow-up of 6.4 months (range, 2.0–14.4 months) in those with MDS and 8.8 months (range, 1.9–16.9 months) in those with AML.
Clinical Implications: Magrolimab and azacitidine continues to be well tolerated with robust activity in patients with MDS and AML, with an overall response rate of 92% and 64%, respectively. Initial data indicate that magrolimab and azacitidine may be particularly effective in patients with TP53-mutant disease, a treatment-refractory subgroup.
ABSTRACT 568: Phase Ib study evaluating the safety and efficacy of venetoclax with azacitidine in treatment-naive patients (n = 59) with higher-risk MDS (NCT02942290)8
Background: Venetoclax, a selective, potent, orally bioavailable BCL2 inhibitor, has shown synergistic activity with hypomethylating agents in preclinical studies in high-risk MDS9 and clinical studies in AML.10
Methods: Patients (median age, 71 years) were enrolled with escalating doses of venetoclax administered orally for the first 14 days of each 28-day cycle, with cohorts from 100 mg daily up to 400 mg daily. Azacitidine was administered at 75 mg/m2 from days 1 to 7 of the 28-day cycle. Primary study objectives were to evaluate safety and determine the recommended phase II dose schedule.
Results: The most common treatment-emergent adverse events were anemia, neutropenia, and thrombocytopenia. Common gastrointestinal symptoms were constipation, nausea, diarrhea, and vomiting. Infection was predominantly febrile neutropenia. There were 10 deaths, 4 of which were due to infections. A total of 20 patients discontinued the study treatment, including 10 who underwent transplantation. Among 57 patients, the overall response rate was morphologic complete response in 22 and stable disease in 11. Disease progression was observed in two patients. The 18-month estimate for overall survival was 74% (95% CI = 50%–87%). Among 56 patients eligible for hematologic improvement, 28 patients achieved hematologic improvement.
Clinical Implications: The combination therapy of venetoclax and azacitidine demonstrated a tolerable safety profile and promising efficacy in patients with high-risk MDS. The maximum tolerated dose of venetoclax without dose-limiting toxicities was determined to be 400 mg daily, with a routine schedule of azacitidine.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca and Partner Therapeutics. Dr. List has received honoraria from Aileron, Celgene, and Cellular Biomedical Group; has served as a consultant or advisor to Acceleron Pharma, Aileron Therapeutics, Amphivena, Celgene, and Cellular Biomedicine Group; has received research funding from Celgene; and has been reimbursed for travel, accommodations, or expenses by CBMG and Celgene.
1. Fenaux P, et al: Assessment of longer-term efficacy and safety in the phase III, randomized, double-blind, placebo-controlled MEDALIST trial of luspatercept to treat anemia in patients with revised International Prognostic Scoring System (R-IPSS) very low-, low-, or intermediate-risk myelodysplastic syndromes with ring sideroblasts who require red blood cell transfusions. 2019 ASH Annual Meeting & Exposition. Abstract 841. Presented December 9, 2019.
2. List AF, et al: Combined treatment with lenalidomide and epoetin alfa leads to durable responses in patients with epo-refractory, lower risk non-deletion 5q MDS. 2019 ASH Annual Meeting & Exposition. Abstract 842. Presented December 9, 2019.
3. McGraw KL, et al: Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors. PloS One 9:e114249, 2014.
4. Basiorka A, et al: Lenalidomide stabilizes the erythropoietin receptor by inhibiting the E3 ubiquitin ligase RNF41. Cancer Res 76:3531-3540, 2016.
5. Komrokji RS, et al: Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood 120:3419-3424, 2012.
6. Richard-Carpentier G, et al: Preliminary results from the phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes. 2019 ASH Annual Meeting & Exposition. Abstract 678. Presented December 9, 2019.
7. Sallman DA, et al: The first-in-class anti-CD47 antibody magrolimab in combination with azacitidine is effective in MDS and AML patients. 2019 ASH Annual Meeting & Exposition. Abstract 569. Presented December 9, 2019.
8. Wei AH, et al: A phase Ib study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naive patients with higher-risk myelodysplastic syndrome. 2019 ASH Annual Meeting & Exposition. Abstract 568. Presented December 9, 2019.
9. Jilg S, et al: Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients. Leukemia 30:112-123, 2016.
10. DiNardo CD, et al: Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133:7-17, 2019.