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1818 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

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
MDS, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Valeria Santini1*, Amer M. Zeidan, MBBS, MHS2, Uwe Platzbecker, MD3, Rami S. Komrokji, MD4, Guillermo Garcia-Manero, MD5, Dimana Miteva6*, Aylin Yucel7*, Veronika Pozharskaya7*, Shelonitda Rose7, Yinzhi Lai7*, Ana Carolina Giuseppi7*, David Valcárcel Ferreiras8*, Pierre Fenaux, MD9, Jake Shortt10* and Matteo Giovanni Della Porta, MD11*

1University of Florence Medical School, Florence, Italy
2Department of Internal Medicine, Section of Hematology, Yale University, New Haven, CT
3University Hospital Leipzig, Leipzig, Germany
4Moffitt Cancer Center, Tampa, FL
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
6Bristol Myers Squibb, Boudry, Switzerland
7Bristol Myers Squibb, Princeton, NJ
8Hospital Vall d'Hebron, Barcelona, Spain
9Service d'Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France
10Monash University and Monash Health, Melbourne, VIC, Australia
11Humanitas University, Milan, Italy

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.

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