Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study

Abstract

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

Keywords: Anemia; Health-related quality of life; Luspatercept; Myelodysplastic syndromes; Red blood cell transfusion independence.

Fig. 1

MEDALIST study design. ^aInvestigator’s assessment of clinical benefit: achievement of RBC-TI ≥ 8 weeks and/or HI-E response during weeks 1–24. AML, acute myeloid leukemia; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; HI-E, hematologic improvement-erythroid; HMA, hypomethylating agent; IMiD, immunomodulatory imide drug; IPSS-R, Revised International Prognostic Scoring System; IWG, International Working Group; MDS, myeloid dysplastic syndromes; RBC, red blood cell; RBC-TI, red blood cell transfusion independence; RS, ring sideroblasts; SC, subcutaneous; SF3B1, splicing factor 3B subunit 1; WHO, World Health Organization

Fig. 2

Expected cumulative number of RBC transfusion units (A, B) and RBC transfusion visits (C, D) by baseline transfusion burden (low vs high). Low baseline RBC transfusion burden was defined as having < 6 RBC transfusion units over 8 weeks and high baseline RBC transfusion burden was defined as having ≥ 6 RBC transfusion units over 8 weeks. Cumulative mean function estimated using nonparametric method with robust variance estimate. The efficacy cutoff date is defined as the minimum date among death date, study discontinuation date, last dose date + 20, and database cut date. RBC, red blood cell

Fig. 3

Expected cumulative number of RBC transfusion units (A, B) and RBC transfusion visits (C, D) by baseline RBC transfusion burden (low vs high) by luspatercept response at week 25. Low baseline RBC transfusion burden was defined as having < 6 RBC transfusion units over 8 weeks and high baseline RBC transfusion burden was defined as having ≥ 6 RBC transfusion units over 8 weeks. Cumulative mean function estimated using nonparametric method with robust variance estimate. The efficacy cutoff date is defined as the minimum date among death date, study discontinuation date, last dose date + 20, and database cut date. RBC, red blood cell

Fig. 4

Mean change from baseline in hemoglobin levels, weeks 25–48, in initial luspatercept nonresponders. Number of patients varies as not every patient underwent hemoglobin assessment each week

Fig. 5

RBC transfusion events in initial luspatercept nonresponders pre- and post-initiation of luspatercept treatment. Periods of response are denoted by blue lines. ^aStart of luspatercept treatment. RBC, red blood cell

Fig. 6

Response indicators across analysis periods. Evaluated in patients who did not achieve RBC-TI for ≥ 8 weeks by week 25 but continued luspatercept treatment (n = 68). HI-E, hematologic improvement-erythroid; RBC-TI, red blood cell transfusion independence