Survival and Prognosis of Chinese Patients with Post-Polycythemia Vera Myelofibrosis

Objective: Polycythemia vera (PV) is a chronic progressive myeloproliferative neoplasm (MPN) characterized by pancytosis, especially the overproduction of red blood cells (RBCs), which is often associated with thrombocytosis and leukocytosis. Post-polycythemia vera myelofibrosis (post-PV MF) is a critical hematologic evolution of PV. Up to 20% of patients with PV evolves into life-threatening myelofibrosis. The current study aims to determine the possible risk factors for the occurrence and prognosis of post-PV MF in Chinese patients with PV. Molecular genetic tests for JAK2V617F and Exon12 of JAK2 are highly informative in the progression of patients with PV. Recently, ASXL1 mutation has been proposed as a prognostic marker for risk stratification in patients with primary myelofibrosis (PMF). We, thus, evaluated the prognostic significance of JAK2V617F allele burden (V617F%) and the concomitant of JAK2 activating mutation and ASXL1 loss of function in the evolution of PV.

Methods: The clinical characteristics of a large cohort of 590 PV Chinese patients were evaluated retrospectively to determine the possible risk factors for the occurrence and prognosis of post-PV MF in Chinese patients with PV. The existence of JAK2V617F mutation in mononuclear cells of PV patients was detected at diagnosis with nested allele-specific PCR. The mutation in Exon12 of JAK2 and ASXL1 were determined by Sanger sequencing, and V617F% were analyzed by Taqman Real-time PCR. 

Results:We have found that the 10-, 15-, and 20-year overall survival (OS) of PV was 89.3%, 75.9%, and 65%. The incidence of thrombosis, post-PV MF and acute myeloid leukemia (AML) was 75.0/1000 (95% CI: 66.3-83.9), 24.1/1000 (95% CI: 19.7-28.4), and 3.0/1000 (95% CI: 1.5-4.5) person/year, respectively.

Up to 19.83% of PV patients (117 of 590) developed post-PV MF. The incidence of 10-, 15-, and 20-year post-PV MF transformation was 19.3%, 33.7%, and 49.3%, respectively. OS was much lower in patients with post-PV MF compared that in the general Chinese population matched by age, sex, and calendar year. Multivariate analyses revealed that splenomegaly, WBC count >13 x 10⁹/L, and platelet count >550 x 10⁹/L were independently associated with post-PV MF transformation.

In the 117 patients with post-PV MF, 13 developed acute myeloid leukemia (AML), and the 5-year leukemia-free survival after diagnosis of post-PV MF was 87.4%. The results of multivariate Cox regression analysis showed that platelet count <100 × 10⁹/L and patient age >65 years were independent risk factors for disease transformation into AML in patients with post-PV MF.

Of the 346 patients with PV screened for JAK2V617F mutation, 273 patients were found to carry the JAK2V617F allele. The V617F% was examined in 104 patients with adequate DNA samples, and the median V617F% was 81.9% and 32.5% for patients with and without post-PV MF, respectively (p < 0.001). Kaplan-Meier analysis showed that myelofibrosis-free-surviva (MFS) was significantly reduced in PV patients with V617F% ≥50% compared with patients with V617F% <50% or no JAK2V617F mutation. Thirteen patients were found to carry ASXL1 mutation among 95 patients screened ASXL1 mutation, and all of these 95 patients were divided into four groups based on V617F% and the status of ASXL1 mutation: V617F% ≥50% with mutant ASXL1 (n=12), V617F% ≥50% with wt ASXL1 (n=48); V617F%<50% with mutant ASXL1 (n=1), and V617F%<50% with wt ASXL1 (n=32). By Kaplan-Meier analysis across all four groups, patients with both V617F% ≥50% and ASXL1 mutation had the worst MFS rates, with a 5-year MFS rate of 75.0%.

Conclusion: PV has a higher incidence of progression to post-PV MF in Chinese patients. The risk factors for post-PV MF transformation included WBC count >13 x 10⁹/L, platelet count >550×10⁹/L and splenomegaly at diagnosis of PV. Anemia (Hg <100 g/L) and age >65 years at diagnosis of post-PV MF were identified as significant risk factors for poor survival of patients with post-PV MF. MFS was significantly lower in patients with V617F% ≥50% than in patients with V617F% <50%, and patients carried both V617F% ≥50% and ASXL1 mutation had the worst MFS rate.