Luspatercept for myelodysplastic syndromes/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis

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 – 5]. Patients with MDS/MPN-RS-T have favorable overall survival compared to patients with MDS-RS [6]; 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) [7]. 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 ef ﬁ cacy

transfusion requirements and adverse events [10]. 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.
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) [12]; ≥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.
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%) [10]. 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 [10].
After 24 weeks of treatment, patients randomized to luspatercept had increases from baseline in mean [standard deviation, SD] hemoglobin ( 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) [10]. 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 × 10 9 /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 [10].
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 [13] and a retrospective analysis of 167 patients [14], 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) [15], 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.