Mutational Burden Could Affect Response to Luspatercept, ESAs in Lower-Risk MDS

Baseline mutational burden (MB) affected response to erythropoiesis-stimulating agents (ESAs) among patients with ESA-naïve, transfusion-dependent, lower-risk myelodysplastic syndrome (LR-MDS) but did not affect response to luspatercept, according to an analysis of the COMMANDS study presented by Rami S. Komrokji, MD, of Moffitt Cancer Center in Tampa, Florida, at the 65th American Society of Hematology Annual Meeting & Exposition.

The COMMANDS trial enrolled 182 patients with Revised International Prognostic Scoring System–defined LR-MDS with <5% bone marrow blasts and serum erythropoietin <500 U/L. Patients were randomly assigned to luspatercept or epoetin alfa. The primary endpoint was achievement of RBC-TI of 12 weeks or longer with a concurrent mean hemoglobin increase of at least 1.5 g/dL.

According to the researchers, patients with LR-MDS usually harbor a median of two to three driver mutations in genes involved in MDS pathogenesis. For this analysis, they sequenced individual patient bone marrow samples and analyzed them for a targeted panel of 82 genes. At baseline, almost all of the patients in the COMMANDS trial (n=322/363) had somatic mutations in one or more genes.

In the intention-to-treat (ITT) population, there was no significant difference in baseline MB between patients who responded to luspatercept and those who did not. Among patients treated with ESAs, responders trended toward a lower MB compared with non-responders.

In the ITT and ring sideroblast (RS)-positive patients, luspatercept showed robust response compared with ESAs in patients with one (Fisher’s P=.040), two (Fisher’s P<.001), and three (Fisher’s P=.018) gene mutations.

“Interestingly, both luspatercept and ESAs had similar clinical benefit across various MBs in the RS subgroup,” the researchers wrote in the abstract. “However, lower MB favored higher responses to ESAs in the RS subgroup, and higher MB in genes associated with poor prognosis significantly impacted response rates in the luspatercept arm.”

Finally, patients with LR-MDS with difficult-to-treat mutations had superior or favorable response to luspatercept compared with ESAs.

Reference

Komrokji RS, Guerrero MU, Garcia-Manero G, et al. Impact of genomic landscape and mutational burden on primary endpoint responses in the COMMANDS study. Abstract #4591. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.