Abstract 7188: INCB057643, a bromodomain and extra-terminal (BET) protein inhibitor, improved bone marrow function and shifted megakaryopoiesis to erythropoiesis in patients with myeloproliferative neoplasms (MPNs)
Authors: Hamza Celik, Angelo Albertoni, Brittney Wass, Sarita Sehra, Lea Burke, Melody Diamond, Matthew Stubbs, Diana Alvarez Arias
Journal: Cancer Research (2025)

Abstract Patients with MPNs share common characteristics, including overproduction of myeloid cells and dysplastic megakaryocytes (MK) in bone marrow. Aberrant cell differentiation results in chronic inflammation, development of bone marrow fibrosis, and ineffective hematopoiesis, often leading to anemia. Dysregulated gene transcription can drive these disease characteristics (AACR 2023; Abs 6274). BET proteins are key epigenetic factors of oncogene transcription. INCB057643, a novel, orally bioavailable BET inhibitor, is being evaluated in clinical trials as monotherapy and in combination with ruxolitinib in patients with MPNs (NCT02711137; NCT04279847). To understand the INCB057643 mechanism of action including MK differentiation and biomarkers of inflammation and fibrosis, we used a physiologically relevant patient-derived mouse xenograft (PDX) model of myelofibrosis transplanted with patient CD34+ JAK2-V617F+ cells. MK and erythroid progenitors in bone marrow were quantified by flow cytometry for CD61 and CD71 markers, respectively. Reticulin staining was used to assess fibrosis. INCB057643 treatment elicited a robust decrease in JAK2 V617F+ hematopoietic stem progenitor cells and MK in bone marrow. Concordant with depletion of pathogenic cells, a significant reduction in serum proinflammatory cytokines and fibrosis was observed in treated mice. Bone marrow samples from patients enrolled in NCT04279847 (monotherapy) were analyzed for CD61 and CD71 by immunohistochemistry. Patient plasma biomarker analyses were performed using HuMAP 2.0 (IQVIATM panel); total RNAseq was performed on whole blood samples. Consistent with the preclinical models, CD61 staining was decreased in bone marrow after INCB057643 treatment. Moreover, tight MK clusters changed into looser structures with increased distance between MK cells; dysplastic MK morphology changed to a more normal appearance in some patients. Fibrosis score decreased ≥1 grade in 3/5 patients receiving INCB057643 10 mg qd. Moreover, expression of soluble biomarkers and genes associated with fibrosis, such as TIMP3 and Col4A2, were decreased, while adiponectin expression in plasma was increased, especially at ∼week 12, suggesting improved bone marrow function. Notably, erythroid progenitors in patient bone marrow were increased at both doses tested (6 mg qd, n=3; 10 mg qd, n=5). Although all patients who received INCB057643 10 mg qd had anemia at screening, treatment resulted in hemoglobin response in 3/5 patients. In conclusion, the results show that INCB057643 specifically inhibits pathogenic MK differentiation, reduces inflammatory cytokine production, and decreases fibrosis. INCB057643 treatment also improves bone marrow function, which results in increased erythroid differentiation and reduced anemia symptoms. Citation Format: Hamza Celik, Angelo Albertoni, Brittney Wass, Sarita Sehra, Lea Burke, Melody Diamond, Matthew Stubbs, Diana Alvarez Arias. INCB057643, a bromodomain and extra-terminal (BET) protein inhibitor, improved bone marrow function and shifted megakaryopoiesis to erythropoiesis in patients with myeloproliferative neoplasms (MPNs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7188.