Improvemf: Phase 1b trial of imetelstat plus ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis

作者：John Mascarenhas, Andrew Kuykendall, Terrence Bradley, Bart L. Scott, Habte Yimer, Yiqun Yang, Fei Huang, Ying Wan, Shyamala Navada, Judy Ho, Tymara Berry, Salman Otoukesh · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-2052 · 被引用次数：2 · 研究领域：Myeloproliferative Neoplasms: Diagnosis and Treatment、Acute Myeloid Leukemia Research、Multiple Myeloma Research and Treatments

Abstract Introduction: Myelofibrosis (MF) is a type of myeloproliferative neoplasm characterized by ineffective hematopoiesis, aberrant expression of inflammatory cytokines, and bone marrow fibrosis. JAK inhibitors (JAKi) block the JAK/STAT-signaling pathway that is dysregulated in patients with MF, resulting in relief of splenomegaly and debilitating MF-related constitutional symptoms. However, JAKi have limited disease-altering activity due to failure to eliminate the malignant clonal stem cells that drive disease progression. Imetelstat is a first-in-class, direct, and competitive inhibitor of telomerase enzymatic activity approved in the United States and Europe for the treatment of certain adult patients with lower-risk myelodysplastic syndromes with red blood cell transfusion–dependent anemia. Given the nonoverlapping mechanisms of action of JAKi and imetelstat, preclinical data showing that sequential therapy with ruxolitinib and imetelstat selectively targeted and reduced MF hematopoietic stem cells and progenitor cells, and the clinical activity and disease-modifying potential of single-agent imetelstat in the relapsed/refractory MF setting demonstrated in MYF2001 (NCT02426086), a combination trial of imetelstat plus ruxolitinib in patients with and without prior JAKi treatment was warranted. IMproveMF (NCT05371964) is an open-label study evaluating imetelstat plus ruxolitinib in patients with intermediate (INT)-1, INT-2, or high-risk (HR) MF. In the dose-finding (Ph...