Acute Leukemia Arising from the Myeloproliferative Disorders: Challenge and Opportunity

The classical myeloproliferative disorders (MPDs) of essential thrombocythemia, polycythemia vera, and primary myelofibrosis have an increasing predisposition to transform to overt acute leukemia or MPD-blast phase (MPD-BP). Current therapies for the MPDs are limited, and no therapy other than allogeneic stem cell transplantation (alloSCT) has clearly altered the natural history of these disorders. Pathogenetic mechanisms that lead to an MPD progressing to MPD-BP are incompletely understood but seem to correlate with the accumulation of additional karyotypic abnormalities as opposed to increases in MPD-associated molecular lesion burden (such as JAK2^V617F). The development of MPD-BP is heralded by worsening cytopenias, constitutional symptoms, and a poor survival despite therapeutic intervention. Risk factors for developing MPD-BP include features at diagnosis (such as increased peripheral blood blasts, karyotypic abnormalities, and thrombocytopenia) and exposure to established agents that enhance leukemogenesis (ie, P-32 and alkylators). Multiple avenues of therapeutic investigation are ongoing to treat or prevent MPD-BP, including early alloSCT, hypomethylating agents, and JAK2 inhibition. An improved understanding of the pathogenetic underpinnings of MPD-BP are necessary if more effective targeted therapies are to be developed.