How I individualize selection of JAK inhibitors for patients with myelofibrosis

Abstract The advent of Janus kinase inhibitors (JAKis) inaugurated a novel era in the treatment of myelofibrosis (MF), a myeloproliferative neoplasm with heterogeneous clinical manifestations. Four JAKis have been approved for intermediate or high-risk MF, in the United States. Regulatory approval of the first JAK1/2 inhibitor, ruxolitinib, in 2011, transformed the landscape of MF by markedly controlling splenomegaly and constitutional symptoms, improving patients’ quality of life, and prolonging survival. Fedratinib, the second approved JAKi, is preferred in the second-line setting. Ruxolitinib and fedratinib can cause myelosuppression and are recommended for patients with the myeloproliferative phenotype. The approval of 2 less-myelosuppressive JAKis, pacritinib and momelotinib, provided essential treatment options for patients with severe thrombocytopenia and anemia, respectively. Momelotinib and pacritinib are potent activin A receptor, type 1 inhibitors with consequent significant benefits for patients with anemia. Transfusion independence was achieved with momelotinib in patients who were severely anemic, and the association of transfusion independence with prolonged overall survival was demonstrated. Judicious treatment decisions regarding JAKis can be made with in-depth understanding of the pivotal clinical trials that evaluated JAKis and their therapeutic attributes and should be guided by the dominant clinical manifestations and the type/degree of cytopenia(s) (myeloproliferative/cytopenic phenotypes). This article reviews our clinical approach to treatment with JAKis and their sequencing in patients with MF by presenting 3 clinical vignettes.