Myelofibrosis is really a BCR-ABL1-negative myeloproliferative neoplasm characterised by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional signs and symptoms, leukemic progression, and shortened survival. Constitutive activation from the Janus kinase/signal transducers and activators of transcription (JAK-STAT) path, along with other cellular pathways downstream, results in myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant may be the only curative choice for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic designs include been designed to facilitate treatment decisions. Before the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only real available JAK inhibitor to treat intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some extent in just about all treated patients however, many patients cannot tolerate ruxolitinib because of dose-dependent drug-related cytopenias, as well as patients with a decent initial response frequently develop potential to deal with ruxolitinib after 2-three years of therapy. Presently, there’s no consensus meaning of ruxolitinib failure. Until fedratinib approval, ways of overcome ruxolitinib resistance or intolerance were mainly different methods to ongoing ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and 2 other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, happen to be proven to induce clinical responses and improve signs and symptoms in patients formerly given ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib might have preferential activity in patients with severe cytopenias. Reviewed listed here are ways of improve ruxolitinib resistance or intolerance, and connection between numerous studies in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.