Hitting the brakes on accelerated and blast-phase myeloproliferative neoplasms: current and emerging concepts

Abstract

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) have a variable risk of progressing to accelerated- or blast-phase MPN (MPN-AP/MPN-BP), defined by the presence of 10% to 19% and more than or equal to 20% myeloid blasts in the peripheral blood or bone marrow, respectively. The molecular processes underlying the progression to MPN-AP/MPN-BP are becoming increasingly understood with the acquisition of additional mutations in epigenetic modifiers (eg, ASXL1, EZH2, TET2), TP53, the Ras pathway, or splicing factors (eg, SRSF2, U2AF1), having been described as important steps in this evolutionary process. At least partially driven by the enrichment of these high-risk molecular features, the prognosis of patients with MPN-BP remains inferior to other patients with acute myeloid leukemia, with a median overall survival of 3 to 6 months. Allogeneic hematopoietic cell transplantation remains the only potentially curative therapeutic modality, but only a minority of patients are eligible. In the absence of curative intent, therapeutic strategies or palliative treatment with hypomethylating agents as monotherapy or in combination with ruxolitinib or venetoclax can be considered. Several novel agents are in various stages of clinical development but are not available for routine use at this point, highlighting the need for ongoing research and the prioritization of clinical trial enrollment when feasible.

Graphical abstract

Figure 1.

Potential treatment algorithm for patients with blast-phase MPN. In the absence of high-quality prospective studies specific to patients with blast-phase MPN, treatment recommendations are extrapolated from studies of patients with AML. At the time of diagnosis, molecular testing should be obtained. In patients who are potential candidates for allo-HCT, this constitutes the only potentially curative therapeutic modality and should therefore be considered. Induction chemotherapy prior to transplant is informed by molecular disease features, with the addition of midostaurin in patients with FLT3 mutations. Due to lower response rates with conventional cytotoxic chemotherapy in patients with TP53 mutations, combination therapy with HMAs plus venetoclax could be considered. Patients in remission after induction chemotherapy should proceed to allo-HCT if eligible. which may also be an option for a selected subset of patients who do not achieve a complete remission with induction therapy. For transplant-ineligible patients and those with R/R disease, clinical trial enrollment, HMAs alone or in combination, IDH1/2 inhibitors, or best supportive care are therapeutic options.