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Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis

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Abstract

Purpose of Review

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, and inflammatory cytokine overproduction, resulting in progressive cytopenias, splenomegaly, and high symptom burden. Current backbone of care includes JAK inhibitor (JAKi) therapy, which offers limited benefits and significant discontinuation rates. Targeting the epigenetic modifiers bromodomain and extra-terminal domain (BET) proteins is a novel approach for harnessing the expression of genes involved in critical oncogenic signalling pathways implicated in MF and other malignancies. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF.

Recent Findings

BET inhibition has been shown to target multiple MF driver mechanisms in preclinical studies, with synergistic results using combination therapy with JAKi. Pelabresib is currently being evaluated in the phase II MANIFEST study as monotherapy and in combination with ruxolitinib for MF. Interim data showed favourable responses in symptoms and spleen volume after 24 weeks of treatment, with correlated improvements in bone marrow fibrosis and mutant allele fraction reduction. Based on these encouraging results, the Phase III MANIFEST-2 study was initiated.

Summary

Pelabresib offers a much-needed innovative treatment approach for patients with MF, either as monotherapy or in combination with the current standard of care.

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Authors and Affiliations

  1. Department of Haematology, Centro Hospitalar Universitário de Lisboa Ocidental, Lisbon, Portugal

    Guadalupe Ferreira Gomes

  2. Serviço de Hematologia, Estrada Do Forte Do Alto Do Duque, Hospital de São Francisco Xavier - Centro Hospitalar Lisboa Ocidental, 1449-005, Lisbon, Portugal

    Guadalupe Ferreira Gomes

  3. Department of Haematology, Guy’s and St. Thomas’ National Health System Foundation Trust, London, UK

    Claire Harrison

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  1. Guadalupe Ferreira Gomes
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Correspondence to Guadalupe Ferreira Gomes.

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Conflict of Interest

C. N. Harrison reports medical writing and grants and contracts from Celgene (BMS), Constellation and Novartis, consulting fees from Keros, Galecto, AOP and Roche, fees for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Celgene, CTI Biopharma, AbbVie, Janssen and Constellation, support fees from Novartis for attending meetings and/or travel. C. N. Harrison also reports fees for participation on data safety monitoring board or advisory board from Galecto, CTI Biopharma, Roche, Geron, Promedior, AbbVie, AOP Pharma, Sierra Oncology and reports leadership or fiduciary role in other board society, committee or advocacy group for EHA and MPN voice.

G.F. Gomes reports no relevant conflicts of interest.

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Ferreira Gomes, G., Harrison, C. Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis. Curr Hematol Malig Rep 18, 113–120 (2023). https://doi.org/10.1007/s11899-023-00696-6

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