Durable efficacy and long-term safety with pelabresib plus ruxolitinib in JAK Inhibitor–Naive myelofibrosis: 96-week Results from the Phase III MANIFEST-2 study

作者：Raajit K. Rampal, John Mascarenhas, Sebastian Grosicki, Dominik Chraniuk, Elisabetta Abruzzese, Prithviraj Bose, Aaron T. Gerds, Francesca Palandri, Vikas Gupta, Sung‐Eun Lee, Alessandro Lucchesi, Andrew Kuykendall, Stephen T. Oh, Andrea Patriarca, alberto Alvarez-Larran, David Lavie, Moshe Talpaz, Jean‐Jacques Kiladjian, Ruben A. Mesa, Monika Wroclawska, Xuechan Li, Thomas Lehmann, Harald J. Maier, Claire Harrison, Alessandro M. Vannucchi · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-910 · 被引用次数：6 · 研究领域：Myeloproliferative Neoplasms: Diagnosis and Treatment、Multiple Myeloma Research and Treatments、Protein Degradation and Inhibitors

Abstract Janus kinase inhibitor (JAKi) monotherapy, the standard of care for myelofibrosis (MF), improves splenomegaly and symptom burden but provides limited depth and durability of response. There is a significant unmet need for new combination strategies that adequately address the underlying disease biology and further improve clinical outcomes in MF. Pelabresib (PELA) is an oral, small molecule inhibitor of bromodomain and extraterminal domain (BET) proteins and can act in a complementary manner with the JAK1/2 inhibitor ruxolitinib (RUX) by targeting inflammatory pathways that are regulated by BET-mediated gene expression. PELA+RUX is being investigated in MANIFEST-2 (NCT04603495) in patients (pts) with JAKi-naive MF. The study met its primary endpoint (Rampal RK. Nat Med. 2025). Here, updated 96-wk results from MANIFEST-2 are reported. MANIFEST-2 is a double-blind, randomized, Phase III study in pts with JAKi-naive MF. Pts were randomized 1:1 to PELA or placebo (PBO) once daily with RUX twice daily. Efficacy and safety endpoints were assessed at Wk 96, including ≥35% reduction in spleen volume (SVR35) response, total symptom score (TSS), hemoglobin (Hgb) response, safety, and survival outcomes. As of March 2, 2025, pts had been followed for at least 96 wks, with 56.5% (121/214) of pts in the PELA+RUX arm and 59.3% (128/216) in the PBO+RUX arm completing 96 wks of assigned treatment. With a median follow-up of 115.9 wks at the cutoff date, approximately half of pts were...