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Management of myelofibrosis after ruxolitinib failure.

ABSTRACT: Over the last decade, the Janus kinase1/2 (JAK1/2) inhibitor ruxolitinib has emerged as a cornerstone of myelofibrosis (MF) management. Ruxolitinib improves splenomegaly and symptoms regardless of driver mutation status, and confers a survival advantage in patients with intermediate-2/high risk MF. However, cytopenias remain problematic, and evidence for a robust anti-clonal effect is lacking. Furthermore, the median duration of spleen response to ruxolitinib in clinical trials is approximately 3 years, and ruxolitinib does not appear to affect the risk of leukemic transformation. There is no therapy approved specifically for patients whose disease 'progresses' on ruxolitinib, defining which remains challenging. The recent regulatory approval of the JAK2 inihibitor fedratinib partially fulfills this unmet need, but much remains to be done. Other JAK inhibitors and a plethora of novel agents are being studied in the ruxolitinib 'failure' setting, as well as 'add-on' therapies to ruxolitinib in patients having a 'sub-optimal' response.

SUBMITTER: Bose P

PROVIDER: S-EPMC8565616 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Management of myelofibrosis after ruxolitinib failure.

Bose Prithviraj P Verstovsek Srdan S

Leukemia & lymphoma 20200416 8

Over the last decade, the Janus kinase1/2 (JAK1/2) inhibitor ruxolitinib has emerged as a cornerstone of myelofibrosis (MF) management. Ruxolitinib improves splenomegaly and symptoms regardless of driver mutation status, and confers a survival advantage in patients with intermediate-2/high risk MF. However, cytopenias remain problematic, and evidence for a robust anti-clonal effect is lacking. Furthermore, the median duration of spleen response to ruxolitinib in clinical trials is approximately ...[more]

PMID: 32297800

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Project description: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 dose-dependent 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.

Dataset Information

Management of myelofibrosis after ruxolitinib failure.

Publications

Management of myelofibrosis after ruxolitinib failure.

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