Preliminary Safety and Biomarker Results of the NLRP3 Inflammasome Inhibitor DFV890 in Adult Patients with Myeloid Diseases: A Phase 1b Study

作者：Guillermo Garcia‐Manero, Yasmin Abaza, Peter L. Greenberg, Tamanna Haque, Kyra Velázquez Kennedy, Matteo Della Porta, Melissa Ooi, Maximilian Stahl, Zhuoer Xie, Abhishek A. Mangaonkar, Pinkal Desai, Amy E. DeZern, Alice Garnier, Mathieu Meunier, Anna Maria Pelizzari, Uwe Platzbecker, Katja Sockel, Ashwin Kishtagari, Hongbo Lu, Luca Manganelli, Lexiang Ji, Yan Zheng, Yutong Li, Mike Roy, Ewa Gatlik, Arti Singh, Valérie Beaulieu, Marc R. Pelletier, Philipp J. Rauch, Harinder Gill · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-198326 · 被引用次数：9 · 研究领域：Myeloproliferative Neoplasms: Diagnosis and Treatment、Chronic Myeloid Leukemia Treatments、Cytokine Signaling Pathways and Interactions

Introduction Patients with lower-risk (LR) myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) experience shortened survival and significant unmet medical need due to limited disease-modifying treatments. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms, contributing to ineffective hematopoiesis and clonal progression. DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death. Thus, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to patients by restoring normal hematopoiesis and suppressing clonal myeloproliferation. Methods This open-label, phase 1b, multicenter study evaluates DFV890 in patients with very low, low, or intermediate risk MDS per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). The study comprises 2 parts: dose optimization and dose expansion. Eligible patients ≥18 years, with ECOG performance status ≤2, carrying a diagnosis of (a) IPSS-R-defined LR-MDS or (b) CPSS-defined LR-CMML, and have failed to respond to or not tolerated established first-line therapies as defined in the protocol. Key exclusion criteria include previous treatment with agents targeting the NLRP3 inflammasome and IL-1 pathway. DFV890 is administered orally twice daily (BID) for a mi...