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3214 Clonal Hematopoiesis-Related Mutations Are Associated with Favorable Clinical Benefit Following Luspatercept Treatment in Patients with Lower-Risk Myelodysplastic Syndromes: A Subgroup Analysis from the Phase 3 COMMANDS Trial

Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes—Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research, CHIP, Diseases, Myeloid Malignancies, Biological Processes
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Maroof Hasan1*, Sadanand Vodala1*, Sheida Hayati2*, Guillermo Garcia-Manero, MD3, Anita K. Gandhi, PhD4 and Rajasekhar N.V.S. Suragani, PhD1

1Hematology, Translational Medicine and Disease Team, Bristol Myers Squibb, Summit, NJ
2Informatics and Predictive Sciences, Bristol Myers Squibb, Princeton, NJ
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Translational Development and Diagnostics, Bristol Myers Squibb, Summit, NJ

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition arising from somatic mutations in hematopoietic stem cells that leads to mutant cell clonal progeny in the blood (variant allele frequency [VAF] > 2%) and is found in 10%–30% of people > 70 years of age. CHIP-related mutations (eg, DNA methyltransferase 3 alpha [DNMT3A], tet methylcytosine dioxygenase 2 [TET2], ASXL transcriptional regulator 1 [ASXL1], splicing factor 3b subunit 1 [SF3B1]) are associated with increased inflammation and elevated risk of developing hematologic malignancies, including myelodysplastic syndromes (MDS)/acute myeloid leukemia, and are an independent risk factor for cardiovascular complications. Recently, patients with MDS were reported to have high rates of cardiovascular co-morbidities including elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiovascular and all-cause mortality. Currently, no treatments targeting CHIP mutations or associated complications are available. Luspatercept is currently approved for anemia in adult patients with lower-risk MDS (LR-MDS) with ring sideroblasts who require red blood cell (RBC) transfusions (≥ 2 RBC units/8 weeks) after erythropoiesis-stimulating agent (ESA) treatment failure. Recently, the phase 3 COMMANDS trial (NCT03682536) reported superiority of luspatercept over ESAs in reducing transfusion burden in ESA-naive patients with LR-MDS.

Aims: We investigated the association between the most frequent CHIP-related mutations (DNMT3A, TET2, ASXL1, SF3B1) and clinical outcomes in patients treated with luspatercept from the COMMANDS trial.

Methods: Genomic DNA was isolated from bone marrow (BM) mononuclear cells, and 36 myeloid-specific somatic gene mutations were identified by targeted next-generation sequencing (400X; sensitivity 3%; Munich Leukemia Laboratory information system) at baseline. Hematologic parameters (eg, hemoglobin [Hb], complete blood counts), transcriptome data (bulk BM RNA sequencing [RNA-Seq] data) and cytokines/chemokines (peripheral blood) were assessed at baseline and week 24.

Results: Overall, 145 patients in the luspatercept arm of the COMMANDS trial were included in the current analyses, of whom 85% (123/145) (Figure 1A) had the most frequent CHIP-related mutations (eg, DNMT3A, TET2, ASXL1, and SF3B1) with a VAF of 3%–50%. Modest positive correlations were observed between DNMT3A, TET2, and SF3B1 baseline VAF and monocyte percentage (P = 0.024, P = 0.015, and P = 0.005, respectively). Baseline Hb levels were lower in patients with frequent CHIP-related mutations than in those with less frequent/other somatic mutations. Luspatercept treatment significantly reduced anemia from baseline in patients with CHIP-related mutations (primary endpoint response 62%; n/N = 76/123). Concomitant with the Hb increase (∆ = +1.0 mg/dL; P < 0.001), we observed improvements in other cell counts, including white blood cell counts (∆ = +0.7 × 109 cells/L; P = 0.01). In addition, luspatercept treatment in patients with CHIP-related mutations was associated with downregulation of inflammatory gene signatures (Figure 1B) and proinflammatory cytokines/chemokines, including hepcidin (∆ = −43.9 ng/mL; P < 0.001). Furthermore, we observed upregulation of an anti-inflammatory regulator (growth/differentiation factor 15) following treatment. Most importantly, significant downregulation of NT-proBNP levels (∆ = −330 pg/mL; P < 0.05) was observed in patients with LR-MDS who received luspatercept.

Conclusions: This retrospective subgroup analysis of patients in the COMMANDS trial with the most frequent CHIP-related mutations (DNMT3A, TET2, ASXL1, and SF3B1) demonstrated novel effects of luspatercept in clonal hematopoiesis-related consequences including improvements in anemia, cytopenias, and reduced inflammation. Most importantly, NT-proBNP and elevated hepcidin levels were significantly downregulated in responders following luspatercept treatment. These results warrant evaluation of luspatercept in patients with high-risk CHIP mutations including clonal cytopenia of undetermined significance and patients with anemia of inflammation.

Disclosures: Hasan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Vodala: Bristol Myers Squibb: Current Employment; Mabgenex: Membership on an entity's Board of Directors or advisory committees. Hayati: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Garcia-Manero: Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Gandhi: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Suragani: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

*signifies non-member of ASH