Preliminary Safety and Efficacy of Luspatercept Initiated at Maximum Approved Dose in Patients with Transfusion Dependent Anemia Due to Very Low, Low and Intermediate Risk MDS with Ring Sideroblasts: First Results of the Lusplus Trial

Background Luspatercept is a first-in-class erythroid maturation agent approved for patients with lower risk MDS with ring sideroblasts (MDS-RS) and transfusion dependent anemia at a starting dose of 1.0 mg/kg based on the results of the phase III randomized placebo-controlled MEDALIST trial (Fenaux et al, N Engl J Med 2020;382:140-51.). Adjustments of luspatercept to a dose of 1.33 mg/kg and a maximum dose of 1.75 mg/kg were allowed based on response and dose delays were initiated at a Hb level above 11.5 g/dl. 37.9% of patients receiving luspatercept achieved the primary endpoint of at least 8 weeks without a need for RBC transfusion. However, 30% of patients in the luspatercept arm of the MEDALIST trial did not receive the planned maximum dose of 1.75 mg/kg. The rationale of the LusPlus trial is thus to exploit the maximum dose of luspatercept from the first dose per patient to achieve an overall increase in response and demonstrate an acceptable safety profile of this dosing regimen. Methods The LusPlus trial is a phase IIIb, open-label, single arm study evaluating the efficacy and safety of luspatercept initiated at a maximum dose of 1.75 mg/kg in transfusion dependent patients with lower-risk MDS and ring-sideroblastic phenotype who are refractory, intolerant, or ineligible to prior erythropoiesis-stimulating agent (ESA) treatment. Patients receive luspatercept at a starting dose of 1.75 mg/kg on day 1 of each 21-day cycle for 24 weeks. The Hb threshold for administration of luspatercept is set at 13 g/dl for females and 14 g/dl for males, above which dosing must be delayed until the Hb falls below these levels. The primary endpoint is red blood cell transfusion independence (RBC-TI) ≥ 8 weeks according to IWG 2018 modified criteria from week 1 through week 24. Secondary endpoints include safety and tolerability of the luspatercept dosing regimen, time to and duration of transfusion independence, increase in mean hemoglobin ≥1 g/dL for ≥8 weeks, and quality of life based on patient reported outcomes. We report preliminary results on safety and secondary efficacy endpoints (i.e. Hb increase ≥1g/dl for ≥8 weeks) for the first 41 of 55 planned patients from 14 sites in Europe treated in the trial. This trial is registered under ClinicalTrials.gov: NCT05181592; EudraCT: 2020-004899-18 Results As of July 28, 2024, 41 patients were treated at the maximum dose of 1.75 mg/kg luspatercept, 22 patients have completed 24 weeks of treatment. Median age was 72 years (range 48-88), 53.7% were male and 90.2% Caucasian. 29.3% of all enrolled patients (12/41) showed a response with a mean Hb increase of ≥1g/dl for ≥8 weeks. Of the 22 patients completing 24 weeks of treatment, 45,5% (n=10) responded. Median time to response was 2 weeks (range 1.0-22.9). 7 patients (17.1%) experienced at least one dose delay. A total of 10 dose delay events were reported, 3 of these for an Hb level above the predetermined threshold. Other reasons for dose delays were adverse events in 4 cases and serious adverse events in 2 cases. All adverse events leading to dose delays were judged as unrelated to luspatercept. No thromboembolic events were observed thus far. Adverse events of special interest that have been reported concerned one patient who progressed to AML during the screening phase and one patient who developed basal cell carcinoma during cycle 2. Conclusion Treatment initiated with luspatercept at the maximum dose of 1.75 mg/kg is well tolerated. Raising the Hb threshold for implementation of dose delay has not led to any new safety signals thus far. Contingent on the final results after complete enrollment, our preliminary data indicate that initiation of luspatercept treatment at maximum dose is safe and may improve response rates. Confirmation of these preliminary findings after at least 50 patients have completed 24 weeks of treatment is necessary.