Despite the identification of JAK mutations and the development of targeted inhibitors, there remain significant unmet needs for patients with myeloproliferative neoplasms. Identification of the myeloproliferative neoplasm populations not currently benefiting from JAK inhibitor therapy highlights the therapeutic deficits still present in this heterogeneous stem cell malignancy. While JAK inhibition has provided significant benefits for patients with intermediate-2 or high-risk myelofibrosis and in patients with polycythemia vera in the second-line setting, JAK inhibitor monotherapy is not approved and not appropriate for all patients with myeloproliferative neoplasms. Continued investigation into additional JAK inhibitors, combination therapy, and novel pathway therapeutics remains key to improving outcomes for all patients with myeloproliferative neoplasms. While therapeutic advances in the JAK inhibitor arena or involving alternative pathways are crucial to improving outcomes in myeloproliferative neoplasms, it is also important to reconsider the role of constitutional symptoms in affected patients as an indication for treatment with agents, such as JAK inhibitors, that can mitigate these debilitating symptoms. In this review, we demonstrate the evolving landscape of clinical investigations that address the important therapeutic needs of patients with myeloproliferative neoplasms.
Myeloproliferative neoplasms are a group of myeloid malignancies caused by a hematopoietic stem cell clonal proliferation, the main result of which is primarily either erythrocytosis in polycythemia vera, thrombocytosis in essential thrombocythemia, or progressive cytopenias and splenomegaly in primary myelofibrosis. This group of neoplasms is characterized by a lack of the BCR-ABL fusion protein that is associated with chronic myelogenous leukemia; instead, they are identified with one of three mutually exclusive mutations: JAK2 (Figure), CALR, or MPL. The identification of these mutations has led, through the subsequent development of JAK inhibitors, to changes in diagnostic paradigms,[6,7] prognostication,[8,9] and therapeutic interventions.