MDS-175: Assessment of Dose-Dependent Response to Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) with Ring Sideroblasts (RS) in the Phase 3 MEDALIST Trial

Abstract

Background: A significant proportion of patients in the MEDALIST trial (randomized, placebo-controlled, phase 3 study evaluating luspatercept, an erythroid maturation agent, for treatment of anemia in LR-MDS patients) achieved RBC transfusion independence (RBC-TI) ≥ 8 weeks (Weeks 1–24) ( NCT02631070 ). Aims: To evaluate the effect of luspatercept dose on efficacy and treatment-emergent adverse events (TEAEs). Methods: Of 229 eligible patients (IPSS-R LR-MDS with RS; age ≥ 18 years; unsatisfactory response to or ineligible for EPO-based therapy; regular RBC transfusions), 153 received luspatercept, starting at 1.0 mg/kg, subcutaneously every 3 weeks. Dose titration to 1.33 and 1.75 mg/kg was allowed in the absence of RBC-TI after ≥2 doses at the same dose level. Dose reductions/delays were used to manage excessive hemoglobin increase and safety. Response was defined as RBC-TI ≥ 8 weeks during Weeks 1–48. Results: As of May 8, 2018, 35 (22.9%), 28 (18.3%), and 90 (58.8%) patients received a maximum dose of 1.0, 1.33, and 1.75 mg/kg, respectively. Median time to dose escalation to 1.33 or 1.75 mg/kg in patients achieving RBC-TI ≥8 weeks was approximately twice (105 and 171 days) that of non-responders (43 and 91 days). Of the 69 luspatercept-treated responders, 47 (68.1%) achieved their first response at 1.0 mg/kg, 5 (7.2%) at 1.33 mg/kg, and 7 (10.1%) at 1.75 mg/kg. The majority of patients with baseline transfusion burden ≤ 6 units/8 weeks were responders (63/108; 58.3%). Of these 63 patients, the maximum dose was 1.0 mg/kg in 24 (38.1%) patients, 1.33 mg/kg in 14 (22.2%), and 1.75 mg/kg in 25 (39.7%); first response occurred at 1.0 mg/kg in 47 (74.6%) patients, at 1.33 mg/kg in 2 (3.2%), and at 1.75 mg/kg in 5 (7.9%); 9 patients received luspatercept at ≥2 dose levels during first response. As of July 1, 2019, 74 (48.4%) and 9 (5.9%) luspatercept-treated patients experienced ≥1 dose delay and ≥1 dose reduction, respectively. New onset of luspatercept-related TEAEs generally did not increase with dose increases from 1.0–1.75 mg/kg. Conclusions: The dose range of 1.0–1.75 mg/kg was well tolerated in LR-MDS patients. Dose escalations contributed to maintenance of response or achievement of multiple response episodes.