Myeloproliferative neoplasms (MPNs) are a group of rare blood disorders characterized by overproduction of cells in the bone marrow. The distinguishing features of these malignancies are underlying clonal genetic abnormalities in the myeloid cell lineage. Recent advances in our understanding of these disorders have resulted in the development of several novel therapies.

In a review article published in Current Hematologic Malignancy Reports, Minas P Economides, MD, of the department of internal medicine at the University of Texas in Houston, and colleagues summarized current literature surrounding the clinical management of MPNs. They reviewed several current and investigational therapies, including Janus kinase (JAK) inhibitors, ruxolitinib- and JAK-combinations, and other targeted agents.

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Pathogenesis and Treatment of Myeloproliferative Neoplasms

The main MPNs are chronic myeloid leukemia, polycythemia vera, myelofibrosis, and essential thrombocythemia. By and large, they differ according to distinct genetic abnormalities caused by specific gene mutations in myeloid precursor cells. The presence of the Philadelphia chromosome is a unique marker of chronic myeloid leukemia, which differs from other Philadelphia-negative MPNs. Heightened JAK2 cell signaling from driver mutations leads to elevated levels of proinflammatory markers and excessive myeloproliferation that result in damage to the bone marrow microenvironment.

Ruxolitinib was the first JAK-STAT pathway inhibitor approved by the US Food and Drug Administration for patients with myelofibrosis. Not long afterward, it was also approved for patients with intolerant or hydroxyurea-resistant polycythemia vera, based on findings from 2 phase 3 studies. Many questions remain surrounding the optimal use of ruxolitinib, particularly regarding its role in other MPNs.

Ruxolitinib may also show synergy with other agents, rationalizing the study of combination approaches in some patients. At present, multiple JAK inhibitor combinations are being evaluated in clinical trials. Some examples of agents being studied in combination with ruxolitinib include azacitidine, parsaclisib, thalidomide, itacitinib, and luspatercept.

Currently, there is no standardized treatment strategy following failure of a JAK inhibitor in patients with late-stage myelofibrosis. The prognosis for these patients is rather poor, with current survival estimates around 14 months. As a result, there is a severe need for novel treatment agents that demonstrate strong efficacy and safety data in late-stage trials.