The impact of novel bet inhibitors on the treatment armamentarium of Myelofibrosis.
Key claim: BET inhibitors, particularly pelabresib, show clinically meaningful activity in phase 2-3 trials for myelofibrosis and may complement JAK inhibition by targeting inflammatory, fibrotic, and proliferative transcriptional programs, though hematologic toxicity and long-term survival impact remain unresolved.
Abstract
INTRODUCTION: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm driven by dysregulated JAK - STAT signaling and epigenetic alterations, characterized by chronic inflammation, marrow fibrosis, and limited disease-modifying treatment options. Bromodomain and extra-terminal (BET) proteins regulate transcriptional programs implicated in MF pathogenesis, making BET inhibition a rational therapeutic strategy. AREAS COVERED: This review discusses the biological rationale for BET inhibition in MF and critically appraises clinical development from January 2015 to November 2025. We summarize preclinical evidence and clinical trial data of BET inhibitors, including pelabresib, INCB057643, BMS-986158, and other investigational agents, both as monotherapy and in combination with JAK inhibitors. The literature search included international clinical trial registries (ICTRP, Clinical trial.gov), databases, conference abstracts, and peer-reviewed publications, focusing on efficacy, safety, and potential disease-modifying effects. EXPERT OPINION: BET inhibitors represent a promising investigational class with the potential to complement JAK inhibition by targeting inflammatory, fibrotic, and proliferative pathways. Pelabresib has demonstrated clinically meaningful activity in phase 2-3 trials, supporting its potential role in first-line combination therapy. However, hematologic toxicities, durability of responses, and the impact on survival and leukemic transformation remain unresolved. Biomarker-driven patient selection and rational combination strategies will be essential to optimize the clinical integration of BET inhibitors in MF.
Why this matters
BET inhibition is emerging as one of the most advanced non-JAK combination strategies specifically for PMF, where transcriptional reprogramming of inflammation and fibrosis may address disease-modifying gaps left by JAK inhibitor monotherapy. This review consolidates the case for pelabresib and class peers as upfront ruxolitinib partners in PMF, while delineating cytopenia liability and outstanding survival questions that will shape how the subtype’s frontline standard evolves.