MPN-375 BET Inhibitor Pelabresib (CPI-0610) Combined With Ruxolitinib in Patients With Myelofibrosis – JAK Inhibitor-Naïe or With Suboptimal Response to Ruxolitinib – Preliminary Data From the MANIFEST Study

John Mascarenhas, Marina Kremyanskaya, Andrea Patriarca, Claire Harrison, Prithviraj Bose, Raajit K. Rampal, Francesca Palandri, Timothy Devos, Francesco Passamonti, Gabriela Hobbs, Moshe Talpaz, Alessandro Vannucchi, Jean Jacques Kiladjian, Srdan Verstovsek, Ron Hoffman, Mohamed E. Salama, Dong Chen, Pietro Taverna, Alex Chang, Gozde ColakSandra Klein, Vikas Gupta

Research output: Contribution to journalArticlepeer-review

Abstract

Context: Myelofibrosis is characterized by splenomegaly, symptoms, cytopenias, and bone marrow (BM) fibrosis. Pelabresib is an investigational, oral, small-molecule BET inhibitor designed to selectively inhibit the BD1 and BD2 bromodomains of BET proteins. Objective: Evaluation of pelabresib combined with ruxolitinib in patients with myelofibrosis. Design: In Arm 3 of the Phase 2 MANIFEST study (NCT02158858), JAKi-naïve myelofibrosis patients are treated with pelabresib combined with ruxolitinib. In Arm 2, myelofibrosis patients with suboptimal response to ruxolitinib are treated with pelabresib as ‘add-on’ to ruxolitinib (Arm 2A: transfusion-dependent [TD]; Arm 2B: non-TD). The primary endpoints are ≥35% spleen volume reduction (SVR35) at Week 24 for Arms 3 and 2B and TD to transfusion independence (TI) in Arm 2A. The key secondary endpoint is ≥50% total symptom score reduction (TSS50) at Week 24; in Arm 2A, SVR35 is an additional key secondary endpoint. BM biopsies to assess BM fibrosis and safety data are also evaluated. Results: As of September 2021, at Week 24 in Arm 3 (N=84), 68% (57/84) of patients achieved SVR35 (median change: –50%), and 56% (46/82) of patients achieved TSS50 (median change: –59%). At Week 24 in Arm 2 (N=86), 20% (16/81; 17% in Arm 2A and 26% in Arm 2B) of patients achieved SVR35 (median change: –18%), and 37% (30/81) of patients achieved TSS50 (median change: –47%). In Arm 2A, the TD to TI rate was 16% (6/38). At Week 24, BM fibrosis improvement ≥ 1 grade was achieved in 28% (16/57) and 26% (12/47) of patients in Arms 3 and 2, respectively. Hematologic treatment-emergent adverse events (TEAEs) included thrombocytopenia, in 52% (≥Grade 3: 12%) and 52% (≥Grade 3: 33%) of patients, and anemia, in 42% (≥Grade 3: 35%) and 27% (≥Grade 3: 19%) of patients in Arms 3 and 2, respectively. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely resulted in discontinuation. Conclusions: In ruxolitinib treatment-naïve and previously treated patients with myelofibrosis, pelabresib combined with ruxolitinib resulted in splenic and symptom responses and BM fibrosis improvement and was generally well tolerated. The Phase 3 MANIFEST-2 study is evaluating pelabresib combined with ruxolitinib in JAKi treatment-naïve patients with myelofibrosis (NCT04603495).

Original languageEnglish (US)
Pages (from-to)S335-S336
JournalClinical Lymphoma, Myeloma and Leukemia
Volume22
DOIs
StatePublished - Oct 2022

Keywords

  • BET
  • epigenetics
  • MPN
  • myelofibrosis
  • pelabresib
  • ruxolitinib
  • Trial-in-Progress

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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