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1845 Luspatercept Modulates Inflammation in the Bone Marrow, Restores Effective Erythropoiesis/Hematopoiesis, and Provides Sustained Clinical Benefit Versus Epoetin Alfa (EA): Biomarker Analysis from the Phase 3 COMMANDS Study

Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes – Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Diseases, immune mechanism, Myeloid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Sheida Hayati1*, Amer M. Zeidan, MBBS, MHS2, Guillermo Garcia-Manero, MD3, Uwe Platzbecker, MD4, Aarif Ahsan5*, Amit K. Verma, MD6, Srinivas Aluri, PhD7*, Manuel Ugidos Guerrero1*, Anita K. Gandhi, PhD8, Rajasekhar N.V.S. Suragani, PhD9 and Sadanand Vodala9

1Informatics and Predictive Sciences, Bristol Myers Squibb, Princeton, NJ
2Department of Internal Medicine, Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Hematology, Cell Hematology and Hemostaseology, Leipzig University Hospital, Leipzig, Germany
5Formerly Translational Medicine, Bristol Myers Squibb, Summit, NJ
6Department of Oncology, Albert Einstein College of Medicine, New York, NY
7Montefiore Einstein Cancer Center, Blood Cancer Institute, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
8Bristol Myers Squibb, Summit, NJ
9Hematology, Translational Medicine and Disease Team, Bristol Myers Squibb, Summit, NJ

Introduction: Anemia is common in patients (pts) with myelodysplastic syndromes (MDS) due to ineffective erythropoiesis, characterized by increased dysplastic erythroid precursors (EPs) and abortive differentiation in the bone marrow (BM). Insufficient red blood cells (RBCs) lead to chronic anemia and heart failure due to oxygen deprivation. Luspatercept is approved to treat anemia after erythropoiesis-stimulating agent (ESA) failure in pts with transfusion-dependent, lower-risk MDS (LR-MDS). In the phase 3 COMMANDS trial (NCT03682536), 58.5% of ESA-naive luspatercept treated pts with LR-MDS experienced RBC transfusion independence for ≥ 12 wk with concurrent mean hemoglobin (Hb) increase ≥ 1.5 g/dL during wk 1–24, vs 31.2% of EA-treated pts.

Aims: To differentiate the mechanism of action of luspatercept from EA and determine its correlation with clinical benefit in the COMMANDS study.

Methods: Cytomorphology assessments were performed on BM aspirates at baseline, wk 24 and 48. Complete blood count, Hb, and reticulocytes (retics) were measured in peripheral blood. BM mononuclear cells (BMMC) were subjected to bulk RNA-seq. Serum cytokine analysis was performed at screening and wk 24 using Rules-Based Medicine’s Human Inflammation MAP® v.1.1 and a custom Human MAP ELISA panel.

Results: In ITT population, EPs, retics, and Hb were increased vs baseline in the luspatercept arm at wk 24 (P < 0.001) and wk 48 (P < 0.005). EPs, retics, and Hb were increased in the EA arm at wk 24 (P < 0.01), but this was not sustained to wk 48. Subgroup analysis showed similar trends for ring sideroblast (RS)+ pts in both arms. While RS− pts in the EA arm showed similar trends to the ITT population, luspatercept RS− pts showed trends of EP expansion post-wk 24 only. Retics increased significantly in RS− luspatercept pts at wk 24 (P < 0.005). Hb increased more significantly at wk 24 with EA (P < 0.003) but at wk 48 with luspatercept (P < 0.005).Gene set enrichment analysis of BMMC revealed enrichment of early, mid, and late EP genes at baseline favored response to luspatercept, but enrichment of mid and late EP genes was unfavorable for EA (Figure A). Significant downregulation of REACTOME IL-1 signaling (normalized enrichment score [NES] = −2.27; adjusted [Adj] P < 0.0001 [vs EA = not significant (ns)]), BIOCARTA IL-6 pathway (NES = −1.99; Adj P = 0.0025 [vs EA = ns]) and IFNα response (NES: −2.26; Adj P < 0.0001 [vs EA = ns]) was observed with luspatercept. BIOCARTA IL-1R pathway was more significantly reduced with luspatercept (NES = −1.78; Adj P = 0.0073) compared with EA (NES = −1.79; Adj P = 0.0172), as was IL-10 signaling (luspatercept NES = −2.39; Adj P < 0.001 vs EA NES = −1.82; Adj P = 0.0125). TGF-β, apoptosis, and spliceosome pathways down regulation was also observed with luspatercept. At wk 24, luspatercept responders had a median 640 pg/mL decrease (P = 0.0035) of N‑terminal pro-brain natriuretic peptide (NT-proBNP), produced by the heart, compared with a median 360 pg/mL decrease in EA arm responders (P = 0.37). At wk 24, non-responders had a median increase of 775 pg/mL (P = 0.0032) in the EA arm and 31.5 pg/mL (P = 0.95) in the luspatercept arm.

Conclusions: Multiplatform analysis of primary BM samples from a phase 3 trial of luspatercept revealed novel response-associated biomarkers. Compared with EA, luspatercept led to sustained increase of EPs and retics over 48 wk with a concomitant Hb increase. RS pts showed Hb accumulation peaked at wk 24 in the EA arm. Conversely, luspatercept in RS pts significantly increased retics at wk 24 and EPs past wk 24 with concomitant peaking of Hb at wk 48, suggesting gradual and sustained clinical benefit. Unlike EA, which plays a role in early differentiation of hematopoietic stem cells (HSCs), luspatercept acts on different erythroid stages, leading to EP expansion and maturation. Furthermore, downregulation of IL‑1, IL‑1R, IFNα, IL-6 pro-inflammatory (Figure B), and IL-10 anti-inflammatory signaling with luspatercept suggests modulation of the BM inflammatory environment in MDS to restore HSC function for normal hematopoiesis (Wang J, et al. Front Immunol 2022;13:951937). Additionally, decreased or static levels of NT-proBNP with luspatercept suggest a positive effect in mitigating cardiac damage. These novel insights obtained from analysis of a large controlled clinical trial mechanistically differentiate the superior clinical benefit of luspatercept from EA in treating anemia due to MDS.

Disclosures: Hayati: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zeidan: Celgene/BMS: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Foran: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Shattuck Labs: Research Funding; Otsuka: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Astex: Research Funding; Amgen: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Orum: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria. Garcia-Manero: AbbVie: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Other: Medical writing support, Research Funding. Platzbecker: Servier: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Curis: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; medical writing support, Research Funding; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Celgene: Honoraria; AbbVie: Consultancy; Fibrogen: Research Funding; Janssen Biotech: Consultancy, Research Funding; Geron: Consultancy, Research Funding; BeiGene: Research Funding; BMS: Research Funding. Verma: Curis: Research Funding; GSK: Research Funding; Incyte: Research Funding; Medpacto: Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy; Acceleron: Consultancy; Throws Exception: Current equity holder in private company; Celgene: Consultancy; Janssen: Honoraria; Prelude: Research Funding; Bakx: Consultancy, Current equity holder in private company; Stelexis: Consultancy, Current equity holder in private company, Honoraria; Bristol Myers Squibb: Research Funding. Guerrero: Bristol Myers Squibb: Current Employment. 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. Vodala: Bristol Myers Squibb: Current Employment; Mabgenex: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH