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><sup>Q157</sup>). 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.

Reduced intensity hematopoietic stem cell transplantation for accelerated-phase myelofibrosis

“…With respect to outcome, blasts from 10% to 19% define an accelerated phase with clearly inferior outcome from myelofibrosis diagnosis, 3 challenging treatment considerations, especially because this population has been underrepresented in or even generally excluded from most studies on prognosis or interventions. 4,5 In contrast to currently available risk scores using different cutoff points of circulating blasts ranging from ≥1% to ≥3%, 6-9 no significant impact of circulating blasts was identified with respect to posttransplant outcome.…”

Updates on accelerated and blast phase myeloproliferative neoplasms: Are we making progress?

“…These findings, confirmed also by other groups, have led to suggestions that the blast % for defining MPN AP could be lowered to 5% although this has not yet been widely accepted. [3][4][5]…”

Innovative strategies to improve hematopoietic stem cell transplant outcomes in myelofibrosis

“…The optimal timing of HCT remains uncertain with the evolution of novel nontransplant therapies. 19 , 20 If anything, the decision of whom, and when, to transplant for MF has only become more complex. 21 …”

“…Patients ineligible for HCT may be offered a JAKi, clinical trial, transfusion support, splenectomy, or splenic irradiation. The optimal timing of HCT remains uncertain with the evolution of novel nontransplant therapies 19,20 . If anything, the decision of whom, and when, to transplant for MF has only become more complex 21 …”