PF678 MOLECULAR PROFILE AND RISK OF THROMBOSIS IN JAK2V617F POLYCYTHEMIA VERA PATIENTS
Authors: Angona A. , Fattori G. Corbizi , Rodriguez M.C. Fernandez , Gibert J. , Ibarrondo L. Fernandez , Camacho L. , Gisbert N. Garcia , Pallarols F. Garcia , Longaron R. , Besses C. , Bellosillo B. 
Published: June 2019

Background:The pathogenesis of PV‐associated thrombosis is multifactorial. Prior thrombosis, advanced age, leukocytosis, JAK2V617F mutation, and cardiovascular risk factors are the main factors influencing thrombotic risk. However, there is scarce information regarding the role of mutations in non‐driver genes in the development of thrombotic events during clinical follow‐up.Aims:To investigate the influence of the molecular profile characterized at PV diagnosis in the probability of developing thrombosis during clinical evolution.Methods:A total of 127 JAK2V617F PV patients were included in the study. JAK2V617F allele burden was assessed by quantitative allele specific PCR in the peripheral blood granulocytes at the moment of diagnosis. Targeted NGS was performed on DNA extracted from granulocytes also at diagnosis. Amplicon libraries were constructed using QIAseq Targeted DNA custom panel (Qiagen, Hilden, Germany), covering the full exonic regions of 25 commonly mutated genes in myeloid malignancies and were sequenced using either MiSeq or NextSeq (Illumina, San Diego, CA, USA). Time to event curves were drawn by the method of Kaplan and Meier with the log rank test for comparisons.Results:With a median follow‐up of 50 months (range 1–200), fourteen patients developed 20 thrombotic events after diagnosis (10.9%), 17 corresponding to arterial thrombosis (85% of the total thrombotic episodes) and 3 to venous thrombosis. Five patients presented more than one thrombotic event. Cerebrovascular disease was the most frequent condition in the group of arterial thrombosis (41%). Median time between diagnosis and the appearance of the first thrombosis was 28 months (range 5.8–80). Median JAK2V617F allele burden was 54% (range 5–99). The distribution by quartiles of the JAK2V617F mutational load was as follows: 0–24% n = 15 (11.8%), 25–49% n = 43 (33.9%), 50–74% n = 33 (26%), 75–100% n = 36 (28.3%). There was no statistically significant difference in thrombosis free survival according to the baseline mutational load of JAK2V617F. A total of 104 somatic mutations other than JAK2V617F were detected at diagnosis in 61 patients (48%). The mean number of pathogenic additional mutations was 0.8 mutation/patient. The most frequently mutated genes were TET2 (36%), ASXL1 (13.2%) and DNMT3A (12.5%). Overall, no difference was observed in the probability of developing thrombosis during the follow‐up according to the presence or absence of pathogenic non‐driver mutations at diagnosis (p = 0.89)(Figure 1a). Nevertheless, we showed a significant correlation between the presence of ASXL1 mutations and the probability of thrombosis (35% thrombotic events in ASXL1 mutated patients vs 8% in wild‐type ASXL1 patients, p = 0.002) (Figure 1b). No significant difference was observed in thrombosis‐free survival according to mutations in TET2 or DNTM3A genes.Summary/Conclusion:Overall, no significant association was observed between the genetic profile (including JAK2V617F allele burden and pathogenic non‐driver mutations) of PV patients at diagnosis and the probability of thrombosis during clinical evolution. However, the subset of ASXL1 mutated patients showed a higher risk of thrombosis. Additional studies are needed to confirm this finding.imageThis study was supported in part by grants from ISCIII and Spanish Ministry of Health, PI16/0153, 2017SGR205, PT17/0015/0011. Beca Gilead 2016 and Xarxa de Banc de Tumors de Catalunya