LUSPATERCEPT VERSUS EPOETIN ALFA FOR TREATMENT (TX) OF ANEMIA IN ESA-NAIVE LOWERRISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS (PTS) REQUIRING RBC TRANSFUSIONS: DATA FROM THE PHASE 3 COMMANDS STUDY.

Abstract

Background: LR-MDS pts who require RBC transfusions experience chronic anemia, increased morbidity, iron overload, and poor overall survival. The current standard tx, erythropoiesis-stimulating agents (ESAs), is suboptimal as many pts are ineligible or have limited and/or transient responses. There is an unmet need for effective tx of anemia due to LR-MDS. Luspatercept is approved in the US and EU to treat anemia in LR-MDS following ESA failure and until now has not been directly compared with ESAs in ESA-naive pts. Aim(s): To report interim efficacy and safety data from the phase 3, open-label, randomized COMMANDS trial (NCT03682536) comparing luspatercept with epoetin alfa in ESA-naive LR-MDS pts. Method(s): Eligible pts were >=18 y old, had serum erythropoietin (sEPO) <500 U/L, and required RBC transfusions. Pts received subcutaneous luspatercept (1.0-1.75 mg/kg; once every 3 wk) or epoetin alfa (450-1050 IU/kg; weekly) for >=24 wk. Pts were stratified by baseline (BL) RBC transfusion burden (<4 vs >=4 RBC U/8 wk), BL sEPO (<=200 vs >200 U/L), and RS status (RS+, RS-). The primary endpoint was the proportion of pts who were RBC transfusion independent (RBC-TI) >=12 wk with a concurrent mean hemoglobin increase >=1.5 g/dL during wk 1-24. Secondary endpoints included hematologic improvement-erythroid (HI-E) >=8 wk, RBC TI 24 wk, and >=12 wk in wk 1-24, as well as subgroup analyses, impact of MDS-associated gene mutations on response, and safety. Result(s): 178 pts were randomized to luspatercept and 178 to epoetin alfa (31Aug2022); median tx durations were 41.6 and 27.0 wk, respectively. BL characteristics were balanced between arms. The primary endpoint was achieved by 86/147 (58.5%) luspatercept and 48/154 (31.2%) epoetin alfa pts (P<0.0001; Fig. A); primary endpoint achievement favored luspatercept or was similar to epoetin alfa for all subgroups (Fig. B). Luspatercept tx also favored achievement of HI-E >=8 wk, RBC-TI 24 wk, and RBC-TI >=12 wk in wk 1-24 (Fig. A). Median duration of RBC-TI >=12 wk (wk 1 to end of tx) was longer with luspatercept vs epoetin alfa tx overall (126.6 and 77.0 weeks, respectively), and for clinically relevant subgroups, including RS+ and RS-. Pts with SF3B1, SF3B1alpha , ASXL1, TET2, DNMT3A, EZH2, IDH2, and U2AF1 mutations also demonstrated favorable luspatercept response vs epoetin alfa (Fig. C). Luspatercept pts had a higher probability of achieving clinical benefit, regardless of overall mutational burden. 164 (92.1%) luspatercept and 150 (85.2%) epoetin alfa pts reported tx-emergent adverse events (TEAEs) of any grade; 8 (4.5%) and 4 (2.3%) pts discontinued tx due to TEAEs. The most common TEAEs (any grade) with luspatercept were fatigue (14.6%), diarrhea (14.6%), and hypertension (12.9%), and with epoetin alfa were asthenia (14.2%), diarrhea (11.4%), and anemia (9.7%). The most common TEAEs in luspatercept pts were mild to moderate, non-serious, and generally did not lead to discontinuation. 4 (2.2%) luspatercept and 5 (2.8%) epoetin alfa pts progressed to AML; overall death rates were similar between arms (32 [18.0%] vs 32 [18.2%], respectively). Summary/Conclusion: Luspatercept demonstrated superiority over epoetin alfa with clinically meaningful improvements in RBC-TI and HI-E rates in ESA-naive LR-MDS pts who require transfusions. Luspatercept showed more favorable outcomes compared to epoetin alfa across a spectrum of known MDS mutations. Luspatercept safety profile was comparable with previous reports; no new safety events were identified. Luspatercept may transform the current landscape by establishing a new standard of tx for ESA-naive pts with transfusion dependent LR-MDS.