Impact of Mutational Landscape and Burden on RBC Transfusion Response in Patients With Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the COMMANDS Study

The COMMANDS trial established luspatercept as a first-line treatment for anemia in transfusion-dependent lower-risk (LR) myelodysplastic syndromes (MDS). Here we report red blood cell (RBC) transfusion response analysis based on somatic mutations profile and disease risk for patients treated with luspatercept or epoetin alfa in the COMMANDS trial. Of 350 evaluable patients, 238 (68.0%) had MDS with multiple lineage dysplasia and ring sideroblasts (RS) according to World Health Organization 2016 criteria, and 320 (91.4%) had somatic mutations in ≥ 1 gene (median, 2) with median variant allele frequencies (VAF) of 2%-59%. Mutation profiles were similar in the treatment groups. Luspatercept had superior responses versus epoetin alfa across multiple mutations (risk difference; RD, [95% confidence interval; CI] 0.25 [0.15-0.35]), including in SF3B1-mutated (0.38 [0.25-0.50]) and SF3B1 wild-type (0.09 [-0.11 to 0.30]). Luspatercept demonstrated superior responses in patients with VAF ≥ 10% (random effect, 0.36 [95% CI, 0.28-0.44]), and in those with 1 (63% vs. 40%; p = 0.040), 2 (70% vs. 27%; p < 0.001), and 3 (72% vs. 40%; p = 0.018) mutations, and across the low (75% vs. 38%), moderate low (61% vs. 38%), moderate high (44% vs. 21%), and high (36% vs. 24%) Molecular International Prognostic Scoring System risk groups (summary effect RD, 0.26 [95% CI, 0.14-0.37]). Across most mutations luspatercept responses were superior (random effect, 0.34 [95% CI, 0.24-0.44]) in patients with RS but were similar between treatments in RS-negative patients. Luspatercept represents an effective treatment option in various mutational backgrounds in LR MDS. Trial Registration: ClinicalTrials.gov Identifier: NCT03682536.