Combining ESA and Luspatercept in Non-RS MDS Patients Having Failed ESA - Results of the Phase 1-2 Part a of the GFM Combola Study

• Published in: Blood 2024-11, Vol.144, p.351-351
• Main Authors: Ades, Lionel, Cluzeau, Thomas, Comont, Thibault, Aguinaga, Lorea, Stamatoullas, Aspasia, Meunier, Mathieu, Gyan, Emmanuel, Garnier, Alice, D'Aveni, Maud, Thépot, Sylvain, Sebert, Marie, Moldovan, Marius, Walter Petrich, Anouk, Lemarie, Karine, Chermat, Fatiha, Fontenay, Michaela, Chevret, Sylvie, Fenaux, Pierre
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-204791

Context The therapeutic landscape of lower risk MDS has recently changed with the approval of Luspatercept to treat anemia in transfusion-dependent patients with ring sideroblast (RS)-positive LR-MDS who are refractory/intolerant to ESAs, following the phase 3 MEDALIST study. More recently, the COMMANDS study has challenged the place of ESA as a first-line treatment for low-risk MDS with or without RS ,showing a superiority of luspatecept over ESA, at least in RS-MDS. To better understand the role of luspatercept in non-RS MDS, we carried out a study evaluating the combination of luspatecept and ESA to assess the safety of the combination and to determine the best doses for the combination in a LR non-RS MDS population having failed ESA, before comparing luspatercept to this combo in a randomized trial (COMBOLA-Part B). Patients & Methods A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted by the GFM in patients with LR-MDS (IPSS low risk and Int-1) without RS or del(5q) and ineligible or having failed to achieve a response (or subsequently relapsed) after ESA without disease progression, and with hemoglobin < 9 g/dl. The primary objective of this dose-finding part of the trial was to determine the optimal dose in terms of both toxicity and efficacy for luspatercept + ESA, for selection in the randomized part B of the trial. Luspatercept was administered subcutaneously every 21 days at dose concentrations ranging from 0.8 to 1.75 mg/kg. Based on a TITE-BOIN-ET design, Epoetin alfa was administered weekly at dose concentrations ranging from 30 000UI to 60 000 UI. Four dose levels were tested: Dose level 1 (n=3): Luspatercept 0.8 mg/kg/21d and EPO alpha 30.000 UI/w; Dose level 2 (n=3): Luspatercept 1.33 mg/kg/21d and EPO alpha 30.000 UI/w; Dose Level 3 (n=3) : Luspatercept 1.75 mg/kg/21d and EPO alpha 30.000 UI/W; Dose Level 4 (n=15): Luspatercept 1.75 mg/kg/21d and EPO alpha60.000 UI/w. The assessment window for efficacy was d-21 days, and for toxicity d-42. Results Thirty-five patients were screened and 24 patients from 10 French centers were included between May 2022 and November 2023. Median age at inclusion was 77.7 y [71.4;84.1] and male/female ratio was 18/6. According to 2016-WHO, 18 had refractory cytopenia with multilineage dysplasia, 2 refractory cytopenia with unilineage dysplasia, and 4 had MDS-EB1. According to historical IPSS, 2 and 22 patients had low and intermediate-1 risk, respectively. According to IPSS-R, 5, 15 and 4 patients