To the Editor:
Myelodysplastic syndromes/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a myeloid disorder with myelodysplastic and myeloproliferative features [1, 2]. MDS/MPN-RS-T-associated anemia causes fatigue, reduced quality of life, and worse survival [3,4,5]. Patients with MDS/MPN-RS-T have favorable overall survival compared to patients with MDS-RS ; however, ~50% of patients require red blood cell (RBC) transfusions resulting in protracted transfusion dependence. Patients with MDS/MPN-RS-T also have a fourfold higher thrombotic event risk compared to patients with MDS with ring sideroblasts (MDS-RS) . Treatment of MDS/MPN-RS-T aims to improve anemia, reduce thrombotic event risk, lower platelets, and/or modify the disease course [6, 8]. However, data supporting the efficacy of these treatments are scarce.
Luspatercept is a first-in-class erythroid maturation agent that binds several transforming growth factor-β superfamily ligands, enhancing late-stage erythropoiesis . The results of the phase 3 MEDALIST study (NCT02631070)  led to its approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of anemia in adults with lower-risk MDS-RS or MDS/MPN-RS-T requiring ≥2 RBC units/8 weeks after erythropoiesis-stimulating agent (ESA) failure . Here, we report a post hoc analysis of luspatercept efficacy and safety in patients with MDS/MPN-RS-T from the MEDALIST study. The MEDALIST study enrolled 229 adults with lower-risk MDS-RS who required ≥2 RBC units/8 weeks and were refractory or intolerant to ESAs . Patients were randomized 2:1 to luspatercept or placebo, administered subcutaneously every 3 weeks for 24 weeks. Luspatercept starting dose was 1.0 mg/kg, with titration to a maximum of 1.75 mg/kg, according to transfusion requirements and adverse events . The diagnosis of patients with MDS/MPN-RS-T in the intention-to-treat population was performed using cytomorphologic, cytogenetic, and molecular genetic results and blood counts.
Of the 229 patients in MEDALIST study, 23 (10.0%) had MDS/MPN-RS-T; 14 were randomized to luspatercept and 9 to placebo. Baseline characteristics that differed between the two arms included lower median leukocyte count (4.8 vs 7.5 × 109/dL) and serum ferritin (1062 vs 1460 µg/dL), and higher serum erythropoietin (sEPO) (71.9 vs 54.0 U/L) (Fig. 1A). Median (range) follow-up times were 27.4 (3.5–35.6) and 13.8 (3.3–32.2) months in the luspatercept and placebo arms, respectively.
The primary endpoint in the MEDALIST study was RBC transfusion independence (RBC-TI) ≥8 weeks during weeks 1–24. Secondary endpoints included: modified hematologic response–erythroid (mHI-E; mean hemoglobin increase ≥1.5 g/dL [patients receiving <4 RBC units/8 weeks at baseline] or a reduction of ≥4 units RBC transfusion [patients receiving ≥4 RBC units/8 weeks at baseline], over 56 consecutive days) ; ≥1.0 g/dL hemoglobin increase from baseline over 56 consecutive days during weeks 1–24; rates of progression to acute myeloid leukemia (AML); and incidence of treatment-emergent adverse events (TEAEs). A post hoc analysis of clinical benefit (defined as RBC-TI ≥8 weeks and/or mHI-E during weeks 1–24) was also performed. All P values are descriptive and not adjusted for multiplicity.
As of July 2019, a significantly higher proportion of patients with MDS/MPN-RS-T randomized to luspatercept achieved RBC-TI ≥8 weeks during weeks 1–24 (64.3 vs 22.2%; P = 0.028); mHI-E (71.4 vs 11.1%; P = 0.006); and clinical benefit (78.6 vs 33.3%; P = 0.034), vs placebo (Fig. 1B). The median (range) time from clinical benefit start to the end of treatment was 94.6 (range 8.0–150.0) weeks in the luspatercept arm and 23.9 (range 23.7–57.9) weeks with placebo. A numerically higher number of low transfusion burden patients (<4 units/8 weeks) randomized to luspatercept vs placebo achieved RBC-TI ≥8 weeks (5/6 [83.3%] vs 2/4 [50.0%]; P = 0.285) during weeks 1–24, and a significantly greater proportion achieved mHI-E (4/6 [66.7%] vs 0/4 [0.0%]; P = 0.046) (Fig. 1C). A numerically higher number of high transfusion burden patients (≥4 units/8 weeks) randomized to luspatercept vs placebo achieved RBC-TI ≥8 weeks (4/8 [50.0%] vs 0/5 [0.0%]; P = 0.068) and mHI-E (6/8 [75.0%] vs 1/5 [20.0%]; P = 0.063) (Fig. 1C). RBC-TI ≥8 weeks during weeks 1–48 was achieved by 64.3% of patients randomized to luspatercept vs 33.3% for placebo (P = 0.088). RBC-TI ≥48 weeks at any time during treatment was achieved by 28.6% of patients randomized to luspatercept vs no placebo patients; among those patients in the luspatercept group who had reached RBC-TI ≥8 weeks at any time during treatment, 40.0% achieved RBC-TI ≥48 weeks, vs no placebo patients (Fig. 2A).
Despite limited numbers, the value of luspatercept for patients with MDS/MPN-RS-T is supported by comparisons with data from the entire MEDALIST study population. The achievement of RBC-TI ≥8 weeks during weeks 1–24 among patients with MDS/MPN-RS-T randomized to luspatercept vs placebo (64.3 vs 22.2%) was higher than in the overall MEDALIST population (37.9 vs 13.2%) . Similarly, mHI-E was achieved in 71.4 vs 11.1% of patients with MDS/MPN-RS-T randomized to luspatercept vs placebo, compared to 52.9 vs 11.8% in the overall MEDALIST population .
After 24 weeks of treatment, patients randomized to luspatercept had increases from baseline in mean [standard deviation, SD] hemoglobin (7.7 [0.5]–9.5 [1.1] g/dL), leukocytes (5.3 [2.6]–7.8 [4.1] × 109/dL), and neutrophils (3.4 [2.4]–5.1 [3.4] × 109/dL), while platelet levels remained stable (515  and 539  × 109/dL) (Fig. 2B). Although the increase in hemoglobin levels after 24 weeks among patients with MDS/MPN-RS-T was not significantly different between luspatercept and placebo, the absolute magnitude of increase was nominally higher (+1.7 vs +0.9 g/dL) . Patients randomized to luspatercept vs placebo had a significantly greater increase in mean leukocyte count but not mean platelet or neutrophil counts. At baseline, patients with MDS/MPN-RS-T had a higher median platelet count than the overall MEDALIST population (447 vs 234 × 109/dL) as expected, had lower median sEPO (59.9 vs 153.2 U/L), were less likely to have received iron chelation therapy (26.1 vs 48.5%), and had lower median transfusion burden (4.0 vs 5.0 units/8 weeks), consistent with their higher RBC-TI and mHI-E response rates .
The most common TEAEs of any grade in the luspatercept arm were dizziness, nausea, diarrhea, and asthenia (Fig. 2C). TEAEs leading to discontinuation occurred in 2 of 14 (14.3%) patients in the luspatercept arm and 3 of 9 (33.3%) in the placebo arm. One patient randomized to luspatercept experienced a transient ischemic attack. One patient randomized to placebo experienced progression to AML (P = 0.202) vs none randomized to luspatercept.
Recommendations for the treatment of patients with MDS/MPN-RS-T include ESAs and transfusions for anemia, and lenalidomide for anemia and platelet-level reduction [7, 8]. Recommendations for the use of lenalidomide for patients with MDS/MPN-RS-T are based on case reports totaling 12 patients  and a retrospective analysis of 167 patients , rather than clinical trials; the use of ESAs is based on a single retrospective study which included 40 patients with MDS/MPN-RS-T, of whom 45% achieved an erythroid response (hemoglobin increase ≥2.0 g/dL or RBC-TI ≥8 weeks for patients who required ≥4 units/8 weeks) , compared to 71.4% of patients treated with luspatercept (refractory or ineligible for ESAs) in the current study. However, this comparison should be undertaken with caution, given the different definitions of erythroid response.
In conclusion, this subgroup analysis provides the first clinical trial data to support the efficacy of luspatercept in patients with MDS/MPN-RS-T, a population who currently have no proven effective treatment options. Overall, luspatercept was found to be effective—significantly reducing transfusion burden and improving mHI-E and leukocyte levels—with a generally well-tolerated safety profile.
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The study was supported by Celgene, a Bristol-Myers Squibb Company, in collaboration with Acceleron Pharma. Writing and editorial assistance were provided by James Matthews, PhD, of Excerpta Medica, funded by Bristol Myers Squibb.
RSK: Advisory board fees from AbbVie, Acceleron, BMS, Geron, Jazz Pharmaceuticals, and Novartis; speakers’ bureau fees from BMS and Jazz Pharmaceuticals. UP: Grant support from Amgen, Janssen Biotech, Merck and Novartis; grant and travel support, and lecture, steering committee, and consulting fees, travel support from Celgene/BMS; and lecture fees from Novartis. PF: Consulting fees from Celgene. AMZ: Grant support, honoraria, clinical trial committee and consulting fees, from AbbVie, Celgene/BMS, and Novartis; consulting fees and honoraria from Acceleron, Agios, Astellas. Beyondspring, Cardinal Health, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Seattle Genetics, Syndax, Taiho, and Tyme; grant support from ADC Therapeutics, Astex and Medimmune/ AstraZeneca; grant support, consulting fees and honoraria from Amgen, Aprea, Boehringer-Ingelheim, Cardiff Oncology, Incyte, Otsuka, Pfizer, Takeda, and Trovagene; honoraria, consulting and clinical trial committee fees from Gilead and Kura; clinical trial committee fees from Geron. GG-M: Grant support and consulting fees from Astex Pharmaceuticals, BMS, Genentech, and Helsinn Healthcare; grant support from AbbVie, Amphivena Therapeutics, Aprea, Curis, Celgene, Forty Seven, H3 Biomedicine, Janssen, Merck, Novartis, and Onconova Therapeutics. GJM: Grant support from Celgene/BMS and Novartis. VS: Advisory board and lecture fees from Celgene/BMS; travel support from Janssen Biotech; advisory board fees from Geron, Gilead, Menarini, Novartis, and Takeda Oncology; grant support from Celgene. MD-C: Consulting fees from Celgene/BMS, Novartis, and Takeda. CF: Grant support, advisory committees, and speaker fees from Celgene/BMS; advisory committee and speaker fees from Novartis; consultancy from Takeda; advisory board fees from Janssen Pharmaceuticals. JGJ: Grant and travel support, and advisory board fees, AbbVie; grant support from Arog Pharmaceuticals, Astellas Pharma, Forma Therapeutics, Genentech USA, Gilead Sciences, PTC Therapeutics, and Syros Pharmaceuticals; advisory board fees from AstraZeneca; grant support, advisory board fees, and travel support from BMS/Celgene; grant support and consulting fees from Daiichi Sankyo; end-point committee fees from Novartis. PLG: Grant support from Celgene. MAS: Advisory boards for BMS, Gilead, Novartis, and Pfizer. AED: No competing financial interests. MRS: Steering committee and data and safety monitoring board fees from Celgene; consultancy and advisory for CTI, Geron, Karyopharm, Novartis, Ryvu, Taiho, Takeda, and TG Therapeutics; grant support from Astex, Incyte, Takeda, and TG Therapeutics; and equity in Karyopharm. JKS: Current employment at and equity in BMS. RI: Former employment and current equity in BMS; current employment and equity in Eli Lilly and Company. GZ and XH: Current employment at BMS. JTB: equity in BMS; current employment and equity in Acceleron Pharma. AV: Equity in Stelexis; consultancy and grant support from BMS; consultancy and honoraria from Acceleron Pharma; grant support from Janssen and Medpacto.
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Komrokji, R.S., Platzbecker, U., Fenaux, P. et al. Luspatercept for myelodysplastic syndromes/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. Leukemia 36, 1432–1435 (2022). https://doi.org/10.1038/s41375-022-01521-4