Efficacy and Safety of Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent (ESA)-Naive Patients (Pts) with Transfusion-Dependent (TD) Lower-Risk Myelodysplastic Syndromes (LR-MDS): Full Analysis of the COMMANDS Trial
Authors: Garcia-Manero Guillermo , Platzbecker Uwe , Santini Valeria , Zeidan Amer M. , Fenaux Pierre , Komrokji Rami S. , Shortt Jake , Valcarcel David , Jonasova Anna , Dimicoli-Salazar Sophie , Tiong Ing Soo , Lin Chien-Chin , Li Jiahui , Zhang Jennie , Giuseppi Ana Carolina , Kreitz Sandra , Pozharskaya Veronika , Keeperman Karen L. , Rose Shelonitda , Prebet Thomas , Degulys Andrius , Paolini Stefania , Cluzeau Thomas , Della Porta Matteo Giovanni 
Published: December 2023

Introduction: ESAs are an established treatment (tx) for pts with TD LR-MDS and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L; however, eligible pts often do not respond, or the response duration is limited. Luspatercept is approved in the US and EU to treat anemia due to LR-MDS after ESA failure. The preplanned interim analysis of the phase 3 COMMANDS trial (NCT03682536), comparing luspatercept with epoetin alfa in ESA-naive TD pts with anemia due to LR-MDS (with or without ring sideroblasts [RS]) showed for the first time the superiority of another therapy over ESAs in improving red blood cell transfusion independence (RBC-TI) rates (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736[23]00874-7). Here we report the full efficacy and safety analysis of the COMMANDS trial.

Methods: Eligible pts were ≥ 18 y of age, had Revised International Prognostic Scoring System-defined LR-MDS with &lt; 5% bone marrow blasts, sEPO &lt; 500 U/L, and were TD (received 2-6 RBC U/8 wk for ≥ 8 wk before randomization). Pts were randomized 1:1 to luspatercept (1.0-1.75 mg/kg) subcutaneously (SC) Q3W, or epoetin alfa (450-1050 IU/kg) SC Q1W for ≥ 24 wk and stratified by baseline RBC transfusion burden (&lt; 4 vs ≥ 4 RBC U/8 wk), RS status (RS+ vs RS−), and sEPO (≤ 200 vs &gt; 200 U/L). The primary endpoint was the achievement of RBC-TI ≥ 12 wk with a concurrent mean hemoglobin (Hb) increase ≥ 1.5 g/dL (wk 1-24). Key secondary endpoints (wk 1-24) included achievement of RBC-TI ≥ 12 and for 24 wk and hematologic improvement-erythroid (HI-E) ≥ 8 wk. Other endpoints included duration of RBC-TI ≥ 12 wk, progression to acute myeloid leukemia (AML), and safety.

Results: As of Mar 31, 2023, 182 pts were randomized to luspatercept and 181 to epoetin alfa, with a median (range) tx duration of 51.3 (3-196) and 37.0 (1-202) wk and median (range) follow-up of 17.2 (1-46) and 16.9 (0-46) months, respectively. The primary endpoint was achieved by110 (60.4%) pts in the luspatercept arm versus 63 (34.8%) in the epoetin alfa arm ( P &lt; 0.0001). Subgroup analysis of the primary endpoint response showed that response rates achieved with luspatercept versus epoetin alfa, respectively, were greater for SF3B1-mutated and non-mutated pts (Table), greater for pts with baseline sEPO ≤ 200 U/L and with baseline sEPO &gt; 200 to &lt; 500 U/L (Table), and greater for RS+ pts (Table). The response rates were comparable between tx arms for RS− pts (Table).

RBC-TI ≥ 12 wk was achieved by 124 (68.1%) and 88 (48.6%) pts in the luspatercept and epoetin alfa arms, respectively, RBC-TI for 24 wk by 87 (47.8%) and 56 (30.9%) pts, and HI-E ≥ 8 wk by 135 (74.2%) and 96 (53.0%) pts. The median (95% CI) duration of RBC-TI ≥ 12 wk was longer with luspatercept versus epoetin alfa (128.1 wk [108.3-not estimable (NE)] versus 89.7 wk [5.9-157.3]; HR, 0.534; Figure), and longer for clinically relevant subgroups, including RS+ and RS−.

The median duration of tx was longer in the luspatercept arm compared with the epoetin alfa arm (51.3 versus 37.0 wk). Five (2.7%) and 6 (3.3%) pts in the luspatercept and epoetin alfa arms, respectively, progressed to AML. Overall, 178 (97.8%) and 165 (92.2%) pts receiving luspatercept and epoetin alfa reported tx-emergent adverse events (TEAEs) of any grade; 107 (58.8%) and 88 (49.2%) pts reported grade 3/4 TEAEs, respectively. The most common any-grade TEAEs in either arm (≥ 10% of pts) were diarrhea (17.6% luspatercept vs 14.0% epoetin alfa), COVID-19 (14.8% vs 15.6%), asthenia (13.7% vs 16.2%), and anemia (12.1% vs 10.6%). TEAEs of interest were reported by 105 (57.7%) and 81 (45.3%) pts receiving luspatercept and epoetin alfa, respectively, with asthenia including fatigue, malaise, and lethargy (30.8% vs 24.6%), hypertension (15.9% vs 9.5%), malignancies and premalignant disorders (14.3% vs 12.8%), kidney toxicity (8.8% vs 6.7%), and injection site reactions (6.6% vs 2.2%), occurring in &gt; 5% pts. In both tx arms, rates of on-tx deaths (8.2% for luspatercept and 7.2% for epoetin alfa) and post-tx deaths (13.2% and 13.4%) were similar.

Conclusions: Results of this full analysis confirm the findings from the interim analysis; RBC-TI duration and erythroid responses achieved with luspatercept are superior compared with epoetin alfa. Luspatercept safety results were consistent with previous MDS studies. These data show that luspatercept could represent a new standard of care for pts with TD LR-MDS.