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.