Accelerated Phase of Myeloproliferative Neoplasms

Abstract

<b><i>Background:</i></b> Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20–25% of the cases. MPN-AP and MPN-BP are characterized by 10–19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival. <b><i>Summary:</i></b> MPN-AP/BP has a markedly different mutational profile from <i>de novo</i> acute myeloid leukemia (AML). In MPN-AP/BP, <i>TP53</i> and <i>IDH1/2</i> are more frequent, whereas <i>FLT3</i> and <i>DNMT3A</i> are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3–5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 <i>CALR</i>-unmutated status, lack of driver mutations (negative for <i>JAK2, CALR,</i> or <i>MPL</i> genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (<i>ASXL1, EZH2, IDH1/2, SRSF2</i>, and <i>U2AF1</i>^Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. <b><i>Key Messages:</i></b> Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.