Risk of progression to myelofibrosis and acute myeloid leukemia in patients with essential thrombocythemia and polycythemia vera with prior malignancy.

Abstract Abstract 2730 Background: Acute myeloid leukemia (AML) is a malignant myeloid disorder with heterogeneous outcomes. A number of factors have been shown to be prognostic; age, white blood cell (WBC), prior malignancy, performance status (Eastern Cooperative Oncology Group; ECOG) and cytogenetics. Methods: We planned to develop and validate a prognostic score for the 5-year (y) overall survival (OS) of adults with AML receiving intensive induction chemotherapy. We used Cox model to estimate the regression coefficients and Kaplan-Meier to estimate the 5-y OS. We used Cox-Snell, Schoenfeld and deviance residuals for model diagnostics and bootstrap validation to estimate the performance measures; Harrell's concordance and deviance residuals. Results: We retrospectively analyzed 779 patients treated between 1998–2008, using a prospectively collected database. The median age was 58 y. Most patients had intermediate risk cytogenetics (61%) and good performance status (ECOG 0–1: 79%). The median follow up for the surviving patients was 26.7 months (95% CI 18.8–32.9 months). The 5-y OS was 26% (22- 30%). All variables were statistically significant in the multivariable Cox regression model; age (y) (Hazard Ratio, HR 1.02; 95% CI 1.018–1.034), WBC (1*10^9/L) (HR 1.004; 1.002–1.006), prior malignancy (HR 1.58; 1.26–2.00), ECOG (ECOG 2 HR 1.41; 1.06–1.88, ECOG 3–4 HR 9.99; 4.72–21.18) and cytogenetics (intermediate risk HR 2.49; 1.41–4.39, poor risk HR 4.74; 2.65–8.50). The score divided patients into four risk groups; good (n=47), intermediate (n=129), poor (n=198) and extremely poor (n=87). The estimated 5-y OS was 0.70 (95% CI: 0.53–0.81), 0.37 (0.28–0.46), 0.15 (0.10–0.21) and 0.03 (0.01–0.10) respectively. The model showed good discrimination with large differences between survival curves and good Harrell concordance of 0.69. It showed good calibration using Cox-Snell and deviance residuals. In the intermediate risk cytogenetic group, the model showed good discrimination with over 45% difference in 5-y OS between the good and extremely poor groups. Conclusions: Our study confirmed the prognostic impact of the 5 variables reported in the literature. Using these factors, we developed a score to predict long term OS that showed good discrimination and calibration. The score added further discrimination in the intermediate risk cytogenetic group. Prospective external validation of the score is needed. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v126.23.1607.1607 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1607-1607

Author(s):

Jie Bai ◽

Yuan Zhou ◽

Lei Zhang ◽

Mengyao Sheng ◽

Rong Li ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Platelet Count ◽

Polycythemia Vera ◽

Myeloid Leukemia ◽

Jak2v617f Mutation ◽

Chinese Patients ◽

Kaplan Meier ◽

Wbc Count ◽

Acute Myeloid

Abstract 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. Disclosures No relevant conflicts of interest to declare.

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