JAK Inhibitors for the Management of Myeloproliferative Neoplasms

The classic, Philadelphia chromosome-negative (Ph⁻) myeloproliferative neoplasms (MPN) are characterized by universal activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling, and the JAK1/2 inhibitor ruxolitinib has shown broad clinical activity across myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). Ruxolitinib is currently approved by regulatory authorities for the treatment of MF and hydroxyurea (HU)-resistant/intolerant PV. Although the cornerstone of management of MF, ruxolitinib has some limitations, which has led to interest in developing other JAK inhibitors, as well as ruxolitinib-based rational combinations. Problems with ruxolitinib include on-target anemia and thrombocytopenia, as well as eventual loss of clinical efficacy. Additionally, while ruxolitinib improves survival of patients with MF, its disease-modifying effects, as evidenced by improvement in bone marrow fibrosis and reduction of the mutant allele burden, appear modest; indeed, this could be a feature of all JAK inhibitors currently in the clinic. Furthermore, there is no evidence that JAK inhibitors prevent or delay disease progression and leukemic transformation. Fedratinib, a JAK2 inhibitor with an efficacy profile similar to that of ruxolitinib, is also approved for the treatment of MF. Currently, fedratinib is primarily used second-line, after ruxolitinib failure, a challenging clinical scenario. Momelotinib, a JAK1/2 and activin receptor type 1 (ACVR1) inhibitor, is being developed in the second-line setting in symptomatic, anemic patients with MF, while development efforts for pacritinib, a relatively nonmyelosuppressive JAK2 inhibitor, are focused on MF patients with severe thrombocytopenia. In HU-resistant/intolerant PV, the benefits of ruxolitinib in terms of hematocrit control, spleen shrinkage, and symptom improvement are durable, and the drug may decrease the incidence of thromboembolic events. Finally, activating mutations in CSF3R and molecular rearrangements that activate JAK-STAT, such as PCM1-JAK2, render certain rare, atypical MPN, e.g., chronic neutrophilic leukemia (CNL) and myeloid/lymphoid neoplasms with eosinophilia (MLNEo) sensitive to ruxolitinib.