Next-generation JAK inhibitors in the treatment of myeloproliferative neoplasms

Janus kinase (JAK) inhibitors have changed the treatment landscape of myeloproliferative neoplasms (MPNs), graft-versus-host disease, and several autoimmune conditions. Although approved JAK inhibitors generally target the JAK2 kinase domain, and several also target the JAK1 kinase domain in active form (type I inhibition), new inhibitors that either exhibit a type II mechanism of inhibition of the kinase domain in an inactive state or that target the pseudokinase domain with potential preference or specificity for the JAK2 V617F mutant have progressed to clinical trials. This is the most prevalent mutation in MPNs. An ideal inhibitor would target persistently activated JAK2 in MPNs, eradicate the clone or induce deep molecular remission in addition to clinical and hematologic remission, and spare wild-type JAK2 that is critical for hematopoiesis and immune response. We discuss perspectives of these and other modes of JAK inhibition, as well as primary and secondary/exploratory study end points in clinical trial design, along with potential biomarker correlates to evaluate the potential efficacy of next-generation vs conventional JAK inhibitors.