Management of myelofibrosis after ruxolitinib failure
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REVIEW ARTICLE
Management of myelofibrosis after ruxolitinib failure Claire N Harrison 1 & Nicolaas Schaap 2 & Ruben A Mesa 3 Received: 10 March 2020 / Accepted: 12 March 2020 # The Author(s) 2020
Abstract Myelofibrosis is a BCR-ABL1–negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dosedependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2– 3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment. Keywords Myelofibrosis . Ruxolitinib . Fedratinib . Momelotinib . Pacritinib
Introduction Myelofibrosis (MF) is a BCR-ABL1–negative myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, anemia, progressive splenomegaly, extramedullary hematopoiesis, debilitating constitutional symptoms, cachexia, leukemic progression, shortened survival, and compromised quality of life (QoL) [1, 2]. MF may be de novo (primary MF) or secondary to polycythemia vera (PV) or essential thrombocythemia (ET). Approximately 90% of patients with
* Claire N Harrison [email protected] 1
Guy’s and St Thomas’ Hospital Foundation Trust, Westminster Bridge Rd, London SE1 7EH, UK
2
Radboud University Medical Centre, Nijmegen, Netherlands
3
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
MF carry mutations i
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