SOHO State of the Art Updates and Next Questions: Novel Therapies in Development for Myelofibrosis |
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| Institution: | 1. Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand;2. Research Unit in Translational Hematology, Chulalongkorn University, Bangkok, Thailand;3. Department of Medicine, Faculty of Medicine, Mahidol University Ramathibodi hospital, Bangkok, Thailand;4. Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiangmai, Thailand;5. Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;1. Research Service, St Louis Veterans Affairs Medical Center, St Louis, MO;2. Division of Oncology, Washington University School of Medicine, St. Louis, MO;3. Division of Hematology, Mayo Clinic, Rochester, MN;4. Division of Oncology, Stanford Cancer Institute, Stanford, CA;5. Department of Medical Oncology, Centre for Lymphoid Cancer, Vancouver, BC, Canada;6. Divisions of Hematology/Oncology, UCLA, Los Angeles, CA;7. Divisions of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE;8. Divisions of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, MA;9. U Mass Memorial Cancer Center, Worcester, MA;10. Divisions of Hematology/Oncology, University of Chicago, Chicago, IL;11. Division of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY;12. Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Kansas City, KS;1. Department of Medicine, Division of Hematology, The University of North Carolina at Chapel Hill, Chapel Hill, NC;2. Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC;3. Department of Medicine, Division of Hematology-Oncology, University of Rochester, Rochester, NY;1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas;2. UT Health Graduate School of Biomedical Sciences, Houston, Texas |
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| Abstract: | Myeloproliferative neoplasms research has entered a dynamic and exciting era as we witness exponential growth of novel agents in advanced/early phase clinical trials for myelofibrosis (MF). Building on the success and pivotal role of ruxolitinib, many novel agents, spanning a wide range of mechanisms/targets (epigenetic regulation, apoptotic/intracellular signaling pathways, telomerase, bone marrow fibrosis) are in clinical development; several are studied in registrational trials and hold great potential to expand the therapeutic arsenal/shift the treatment paradigm if regulatory approval is granted. Insight into MF pathogenesis and its molecular underpinnings, preclinical studies demonstrating synergism of ruxolitinib with investigational agents, urgent unmet clinical needs (cytopenias, loss of response to JAK inhibitors); and progressive disease fueled the rapid rise of innovative therapeutics. New strategies include pairing ruxolitinib with erythroid maturation agents to manage anemia (luspatercept), designing rational combinations with ruxolitinib to boost responses in both the frontline and suboptimal response settings (pelabresib, navitoclax, parsaclisib), treatment with non-JAK inhibitor monotherapy in the second-line setting (navtemadlin, imetelstat), novel JAK inhibitors tailored to subgroups with challenging unmet needs (momelotinib and pacritinib for anemia and thrombocytopenia, respectively); and agents potentially enhancing longevity (imetelstat).Beyond typical endpoints evaluated in MF clinical trials (spleen volume reduction ≥ 35%, total symptom score reduction ≥ 50%) thus far, emerging endpoints include overall survival, progression-free survival, transfusion independence, anemia benefits, bone marrow fibrosis and driver mutation allele burden reduction. Novel biomarkers and additional clinical features are being sought to assess new agents and tailor emerging therapies to appropriate patients. New strategies are needed to optimize the design of clinical trials comparing novel combinations to standard agent monotherapy. |
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