The Rationale for Immunotherapy in Myeloproliferative Neoplasms.

The classic, chronic Philadelphia chromosome negative myeloproliferative neoplasms (MPN)-essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)-are clonal malignancies of hematopoietic stem cells and are associated with myeloproliferation, organomegaly, and constitutional symptoms. Expanding knowledge that chronic inflammation and a dysregulated immune system are central to the pathogenesis and progression of MPNs serves as a driving force for the development of agents affecting the immune system as therapy for MPN. This review describes the rationale and potential impact of anti-inflammatory, immunomodulatory, and targeted agents in MPNs. The advances in molecular insights, especially the discovery of the Janus kinase 2 (JAK2) V617F mutation and its role in JAK-STAT pathway dysregulation, led to the development of the JAK inhibitor ruxolitinib, which currently represents the cornerstone of medical therapy in MF and hydroxyurea-resistant/intolerant PV. However, there remain significant unmet needs in the treatment of these patients, and many agents continue to be investigated. Novel, more selective JAK inhibitors might offer reduced myelosuppression or even improvement of blood counts. The recent approval of a novel, long-acting interferon for PV patients in Europe, might eventually lead to its broader clinical use in all MPNs. Targeted immunotherapy involving monoclonal antibodies, checkpoint inhibitors, or therapeutic vaccines against selected MPN epitopes could further enhance tumor-specific immune responses. Immunotherapeutic approaches are expanding and hopefully will extend the therapeutic armamentarium in patients with myeloproliferative neoplasms.