PF265 GENE MUTATION PROFILE IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA (APL)

Abstract

Background:Though survival rates have improved in majority of APL patients, some high‐risk or intermediate risk patients still encounter early mortality. The underlying genetic mechanism between the different risk groups remains incompletely understood, therefore bringing necessity to explore.Aims:The aim of this study was to identify mutations in a panel of 114 leukemia‐associated genes in newly diagnosed APL patients and to analyze the correlation between gene mutations and APL patients of different risk groups.Methods:Forty‐six newly diagnosed APL patients were enrolled between October 2015 and December 2018. Mutational assessment of 114 genes was performed using next‐generation sequencing approach. Induction treatment started with all‐trans retinoic acid (ATRA) and arsenic trioxide based double induction. Anthracycline was added when peripheral white blood cell (WBC) ≥10X109/L. Statistical comparisons were made between gene mutations and APL patients of different risk groups (high risk‐ HR, intermediate risk‐ IR and low risk‐ LR).Correlations between gene mutations and patients suffered from early death (ED, defined as patients who died during induction treatment) and patients reached complete remission (CR) were further investigated.Results:Of the 46 APL patients, there were 26.09% (12/46), 54.35% (25/46) and 19.57% (9/46) were HR, IR and LR patients, respectively. Six patients (13.04%, including 3 HR and 3 IR patients) died during induction treatment, while all of the other 40 patients achieved CR by the end of induction treatment. One or more mutations were detected in 91.30% of the patients (42/46). A total of 102 mutations in 52 genes were detected with the median number of gene mutations was 2 (range 0–6) and mutation rate ≥10%. Though it seemed that HR patients had the highest frequency of mutations (median number 3, range 1–5), LR patients had the lowest frequency of mutations (median number 1, range 0–4), and the median mutation number in IR patients was 2 (range 0–6), there were no significant difference between the three risk groups regarding the median gene mutation numbers (P>0.05).There were 5 frequent mutations identified, including FLT3 (36.96%, 17/46), WT1 (15.22%, 7/46), FAT1 (13.04%, 6/46), ARIDIA (13.04%, 6/46), SETBP1 (8.70%, 4/46), etc. A total of 13 mutations in 12 genes including FLT3, WT1, NRAS, KRAS and NOTCH1 etc were detected in 6 ED patients. The median number of gene mutations in ED patients was 2 (range 1–4), which did not show difference with that in non‐ED patients (median number 2, range 0–6). Among these mutations, only NRAS gene mutations were detected in two ED patients (1 HR and 1 IR patients), which was the same mutation NRAS G12C. FLT3 gene mutations (including FLT3‐ITD and FLT3‐TKD) were the most frequently found in HR APL patients. 88.33% of HR patients(10/12) harbored FLT3 mutations, while 20% of IR patients (5/25) and 22.22% of LR patients (2/9) were found harbored FLT3 mutations(P < 0.05). Among the 17 cases of FLT3 mutant patients, only one HR patient (5.88%, 1/17), who carried FLT3‐TKD D835Y mutation, died 3 days after induction treatment. Meanwhile, the less common WT1 gene mutations were all found in IR APL patients.Summary/Conclusion:HR APL patients had the highest frequency of gene mutations, however there were no significant difference between the three risk groups regarding the median mutation numbers. ED patients did not have more gene mutations compared with non‐ED patients. FLT3 gene mutations were the most frequently occurred mutations, especially in HR APL patients, though might have no relation with early mortality.