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 < 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 (< 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.

Disclosures

Santini:AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Zeidan:Astellas: Consultancy, Honoraria; Shattuck Labs: Research Funding; Astex: Research Funding; Vinerx: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Medus: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Treadwell: Consultancy, Honoraria; Faron: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; ALX Oncology: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Kura: Consultancy, Honoraria, Research Funding; Orum: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Hikma: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Lava Therapeutics: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Schroedinger: Consultancy, Honoraria; Sumitomo: Consultancy, Honoraria; Keros: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Akeso Pharma: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Geron: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria. Platzbecker:Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Komrokji:DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servio: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; Keros: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Onconova: Research Funding; Amphivena: Research Funding; Astex: Research Funding; Genentech: Other: Personal fees; Forty Seven: Research Funding; Astex: Other: Personal fees; Merck: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Helsinn: Other: Personal fees; Helsinn: Research Funding; Curis: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Janssen: Research Funding; Aprea: Research Funding; H3 Biomedicine: Research Funding; Novartis: Research Funding. Miteva:Bristol Myers Squibb: Current Employment. Yucel:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pozharskaya:Bristol Myers Squibb: Other: Stock options with BMS; Merck: Other: Stock options with BMS. Rose:Celgene Corporation: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lai:Bristol Myers Squibb: Current Employment. Giuseppi:Bristol Myers Squibb: Current Employment. Fenaux:Astex: Research Funding; Servier: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Janssen: Research Funding; Agios: Research Funding. Shortt:Mundipharma: Speakers Bureau; Bristol Myers Squibb: Consultancy; Astex/Taiho: Research Funding; Novartis: Honoraria, Speakers Bureau; Astellas: Other: Advisory Board; Otsuka: Other: Advisory Board; Pfizer: Honoraria. Della Porta:Bristol Myers Squibb: Consultancy.

This content is only available as a PDF.
2024
Sign in via your Institution