Clinical Benefits of Achieving Hemoglobin (Hb) Levels ≥ 10 g/dL in Transfusion-Dependent (TD) Erythropoiesis-Stimulating Agent (ESA)-Naive Patients (Pts) with Lower-Risk (LR) Myelodysplastic Syndromes (MDS) Treated with Luspatercept in the COMMANDS Trial
Authors: Santini Valeria , Zeidan Amer M. , Platzbecker Uwe , Komrokji Rami S. , Garcia-Manero Guillermo , Miteva Dimana , Yucel Aylin , Pozharskaya Veronika , Rose Shelonitda , Lai Yinzhi , Giuseppi Ana Carolina , Valcárcel Ferreiras David , Fenaux Pierre , Shortt Jake , Della Porta Matteo Giovanni 
Published: December 2024

Introduction
Treatment (tx) goals in pts with LR-MDS are to increase Hb levels, achieve red blood cell (RBC) transfusion independence (TI), and improve quality of life (QoL). Many pts with LR-MDS have short duration of response or become/are refractory to ESAs. In the phase 3 COMMANDS trial (NCT03682536), tx dosing aimed to maintain Hb level at 10−12 g/dL in ESA-naive pts with TD LR-MDS. Luspatercept demonstrated superior response vs epoetin alfa in RBC TI with concurrent mean Hb increase ≥ 1.5 g/dL in weeks 1-24 (60.4% vs 34.8%, P &lt; 0.0001; Della Porta MG, et al. Lancet Haem 2024. In press). Previously, clinically significant improvement in QoL was observed with achievement of Hb ≥ 10 g/dL in pts with LR-MDS (Oliva E, et al. EHA Library 2024. P774). Here, we assess the clinical benefits of achieving Hb level ≥ 10 g/dL and analyze the effects of luspatercept dose escalation on Hb improvement and safety in TD ESA-naive luspatercept-treated pts with LR-MDS in the COMMANDS trial.
Methods
Pts (≥ 18 years) who had a diagnosis of very low-, low-, or intermediate-risk MDS (per Revised International Prognostic Scoring System) and TD were enrolled. Pts were randomized 1:1 to receive luspatercept 1.0 mg/kg (titration up to 1.75 mg/kg) subcutaneously (SC) once every 3 weeks or epoetin alfa 450 IU/kg (titration up to 1050 IU/kg, maximum dose 80,000 IU) SC once weekly. Key secondary endpoints (weeks 1−24) included achievement of RBC-TI ≥ 12 and 24 weeks and hematologic improvement-erythroid ≥ 8 weeks. Hb level was assessed weekly for the first 3 weeks, then every 3 weeks until end of tx [EOT]. Hb outcomes were analyzed on rolling 12-wk intervals. Efficacy and safety outcomes in the luspatercept arm were explored by maximum dose (1.0, 1.33, and 1.75 mg/kg).
Results
Of 182 pts treated with luspatercept, 139 were responders for RBC-TI ≥ 12 weeks (week 1-EOT) and included in this analysis. A total of 108/139 (77.7%) pts achieved RBC-TI ≥ 12 weeks (week 1-EOT) with concurrent mean Hb ≥ 10 g/dL. Among these luspatercept-responsive pts, 92/108 (85.2%) maintained their longest response at the cutoff date (Sept 22, 2023); 99/108 (91.7%) maintained a cumulative response at the data cutoff date; median duration of response was not reached (NR; 95% CI NR−NR) for longest and cumulative response. A total of 31/139 (22.3%) pts achieved RBC-TI ≥ 12 weeks (week 1-EOT) without concurrent mean Hb ≥ 10 g/dL. Of these 31 pts, 12 (38.7%) pts maintained a longest response at the cutoff date; 12/31 (38.7%) maintained a cumulative response at the cutoff date; median duration of response was 37.0 weeks (95% CI 22.6−76.4) for longest and 41.4 weeks (95% CI 23.9−89.9) for cumulative response. Overall, most (80.2%) pts required dose escalation (Santini V, et al. EHA Library 2024. P785) regardless of their baseline characteristics. A trend was noted showing more pts (63.0%) with lower baseline Hb levels (&lt; 8 g/dL) needed dose escalation to 1.75 mg/kg. Among pts who achieved mean Hb ≥ 10 g/dL at luspatercept 1 mg/kg and had subsequent dose escalation, approximately 50% were able to maintain Hb ≥ 10 g/dL during the dosing period with 1.33 mg/kg and 1.75 mg/kg combined (17/29 [58.6%]).
In total, 178/182 (97.8%) pts who received luspatercept experienced tx-emergent adverse events (TEAEs) and grade 3/4 TEAEs were reported in 117/182 (64.3%) pts; no noticeable difference in TEAEs was reported at different luspatercept dose levels. Tx-related TEAEs in the luspatercept group were reported in 64 (35.2%) pts. There was no clinically significant increase in frequency or exposure-adjusted incidence rate (EAIR; per 100 patient-years) of tx-related TEAEs in pts who received higher doses of luspatercept (1.0 mg/kg: 30.1%, EAIR 29.1; 1.33 mg/kg: 41.7%, EAIR 52.5; 1.75 mg/kg: 35.6%, EAIR 32.7). No significant difference in incidence of grade 3/4 tx-related TEAEs and EAIR was observed in pts who received higher doses of luspatercept (1.0 mg/kg: 7.5%, EAIR 6.0; 1.33 mg/kg: 12.5%, EAIR 10.2; 1.75 mg/kg: 8.5%, EAIR 5.9).
Conclusions
This analysis from COMMANDS indicates that luspatercept-treated pts who achieved Hb levels ≥ 10 g/dL had clinically meaningful rates of durable RBC-TI. Luspatercept dose escalation maintained target Hb levels without significantly increasing incidence or severity of TEAEs. Pts with lower Hb levels at baseline showed a trend requiring higher dose, supporting the clinical benefit of luspatercept dose escalation in pts with LR-MDS.