Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.

Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ≥15 × 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.

IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F.

Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50%) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6%) patients displayed only MPL and 164 (54.3%) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95% confidence interval (95% CI) 0.2-0.75), 0.50 (95% CI 0.27-0.95) and 0.53 (95% CI 0.23-1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F.