Genetics, prognosis, and transplantation for myelofibrosis

Abstract

Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) are chronic disorders that may extend over years or decades. Therapy tends to be conservative, but once marrow fibrosis and peripheral cytopenias become the dominant characteristics, prognosis is poor. Hematopoietic cell transplantation (HCT) is the only treatment with curative potential, leading to survival in remission in 35%‐70% of patients. However, HCT is associated with risks, and despite the development of numerous risk scoring systems, optimal timing of HCT remains controversial. The identification of “driver mutations” in JAK2, MPL1, and CALR, and prognostically relevant additional mutations, may assist in the decision‐making process. While patients with type 1 CALR mutations generally have a superior prognosis, absence of all driver mutations is associated with inferior outcome. Mutations in ASXL1, SRSF2, IDH1/2, and EZH2 are linked to more rapid disease progression and, along with biallelic TP53 mutations, leukemic transformation. The strongest risk factor is the presence of multiple mutations. By MIPSS70 criteria, considering mutations, median survival was 27 years for the best risk group, but 2.3 years for the highest‐risk group. The presence of nondriver mutations, particularly in the absence of CALR mutations, and association with adverse cytogenetics, should lead to consideration of HCT. But the role of mutations has to be assessed in the context of the overall presentation. Unfortunately, risk factors that affect the natural history of the disease also impact post‐HCT outcome. Needed are innovative transplant strategies, also including pre‐HCT and post‐HCT adjuvant therapy.