Results from a biomarker analysis of the phase III COMMANDS study provide “novel insights” that “mechanistically differentiate the superior clinical benefit of luspatercept” from epoetin alfa in patients with low-risk myelodysplastic syndromes (LR-MDS), according to investigators.
Uwe Platzbecker, MD, of the University Hospital in Leipzig, and colleagues presented the research during the Eleventh Society of Hematologic Oncology Annual Meeting in Houston, Texas.
The COMMANDS trial compared the efficacy and safety of luspatercept with epoetin alfa in patients with LR-MDS who were naïve to erythropoiesis-stimulating agents. It showed that 58.5% of patients receiving luspatercept achieved red blood cell transfusion independence for at least 12 weeks with a mean hemoglobin increase of at least 1.5 g/dL during weeks one through 24, while 31.2% of patients receiving epoetin alfa achieved this outcome.
Due to these results, Dr. Platzbecker and colleagues aimed to differentiate the mechanism of action of luspatercept from epoetin alfa and “determine its correlation with primary endpoint achievement.”
They performed cytomorphology assessments on bone marrow aspirates at baseline, at week 24, and at week 48. The researchers measured complete blood count and reticulocytes in peripheral blood. They used bulk RNA sequencing on bone marrow mononuclear cells and used the enzyme-linked immunosorbent assay to measure serum ERFE, GDF11, hepcidin, and GDF15.
In patients who received luspatercept, erythroid precursors increased from baseline to week 24 (P=.031) and week 48 (P=.000017), as did reticulocytes (P<.0001). In patients who received epoetin alfa, erythroid precursors increased from baseline to week 24 (P=.0017), but there was no change reported in reticulocytes.
At week 48, there was a “sustained increase” in erythroid precursors and reticulocytes in patients who received luspatercept (P<.001), but not in patients who received epoetin alfa (P=.056 and P=.67, respectively).
There was an increase in median ERFE levels at week 24 in patients who received luspatercept (7.2 vs 10.1 ng/mL; P<.05) and in those who received epoetin alfa (9.1 vs 10.4 ng/mL; not significant). There was also an increase in median GDF15 levels at week 24 in patients who received luspatercept (5.0 vs 7.0 ng/mL) and in those who received epoetin alfa (4.5 vs 5.4 ng/mL).
A gene set enrichment analysis on bone marrow mononuclear cells showed that enrichment of early, middle, and late erythroid precursor genes at baseline “favored response to luspatercept” while enrichment of middle and late erythroid precursor genes was “unfavorable” for epoetin alfa. The researchers also found that luspatercept downregulated TGFβ, interleukin-6, apoptosis, and spliceosome pathways.
“Compared with [epoetin alfa], response to luspatercept increased [erythroid precursors] and reticulocytes over 48 weeks with concomitant hemoglobin increase,” Dr. Platzbecker and colleagues concluded. “Unlike [epoetin alfa], luspatercept acts on different erythroid stages, leading to expansion and maturation of [erythroid precursors], for superior clinical benefit. These novel insights mechanistically differentiate the superior clinical benefit of luspatercept in patients with LR-MDS from [epoetin alfa].”
Platzbecker U, Hayati S, Ahsan A, et al. Luspatercept restores effective erythropoiesis and provides superior and sustained clinical benefit versus epoetin alfa (EA): biomarker analysis from the phase III COMMANDS study. Abstract MDS-071. Presented at the Eleventh Annual Meeting of the Society of Hematologic Oncology; September 6-9, 2023; Houston, Texas.