Current landscape and future directions for treatment of accelerated-phase and blast-phase myeloproliferative neoplasms

Abstract

Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders that carry the risk of transformation to accelerated-phase MPN (MPN-AP) and blast-phase MPN (MPN-BP) characterized by 10% to 19% and ≥20% peripheral or circulating blasts, respectively. This leukemic transformation is associated with less than 6 to 9 months of median overall survival and remains a major clinical challenge with limited effective treatment options. The biology of MPN-AP/BP is distinct from the pathophysiology of de novo acute myeloid leukemia (AML) and is characterized by complex clonal evolution with acquired somatic mutations in epigenetic regulators, RNA splicing factors, and TP53. Standardized risk stratification and treatment response frameworks built specifically for this disease group are not yet widely used. This limits optimal clinical trial design and meaningful cross-study comparison. The only curative treatment for MPN-AP/BP remains allogeneic hematopoietic stem cell transplant, but there is no standard of care for transplant-ineligible patients or for bridging therapy prior to transplant. Based on non-randomized trials and retrospective cohorts, less-intensive treatment regimens are often preferred except for fit patients with TP53 wild-type disease who may derive benefit from standard induction chemotherapy. Less-intensive strategies generally combine hypomethylating agents with anti-apoptotic or targeted agents. Given the role of IDH1 and IDH2 mutations in leukemic transformation, targeted therapies with IDH1 or IDH2 inhibitors are another option for selected patients. Current studies are investigating the role of next-generation Janus Kinase (JAK) inhibition, inhibition of epigenetic modulators, and blockade of anti-apoptotic pathways as paradigm shifts to make MPN-AP/BP a more manageable disease.