How I individualize selection of JAK inhibitors for patients with myelofibrosis

The advent of JAK inhibitors (JAKi) inaugurated a novel era in the treatment of myelofibrosis (MF), a myeloproliferative neoplasm with heterogeneous clinical manifestations. Four JAKi have been approved for intermediate or high-risk MF, in the US. 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' lives, 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 myeloproliferative MF. Approval of 2 less myelosuppressive JAKi, pacritinib and momelotinib, provided essential treatment options for patients with severe thrombocytopenia and anemia, respectively. Pacritinib and momelotinib are potent ACVR1 inhibitors, resulting in significant anemia benefits. Transfusion independence was achieved with momelotinib in severely anemic patients, and association of transfusion independence with prolonged overall survival was demonstrated. Judicious treatment decisions of JAKi can be made with in-depth understanding of the pivotal clinical trials on JAKi and their therapeutic attributes and should be guided by the dominant clinical manifestations and the type/degree of cytopenia(s). This article reviews our clinical approach to treatment with JAKi and their sequencing in MF patients by presenting 3 clinical vignettes.