The Role of Genetic Polymorphisms ofTPMTandNUDT15Genes in Adult Patients with Ph-Negative Acute Lymphoblastic Leukemia in Russia

Context:TPMTandNUDT15polymorphisms are involved in the toxicity and therapeutic efficacy of thiopurine drugs (6-mercaptopurine (6-MP)). The frequencies of polymorphisms of these genes are different across diverse populations. The role ofTPMTandNUDT15genes in adult patients (pts) with Ph-negative acute lymphoblastic leukemia (ALL) in Russia is still unclear. Objective:Evaluation of frequency and significance ofTPMTandNUDT15polymorphisms in the cohort of adult Ph-negative ALL pts treated by the RALL-2016 protocol. Design and Patients:Since April 2017 till July 2020 56 adult Ph-negative ALL patients treated by RALL-2016 protocol were included in the research ofTPMTandNUDT15polymorphisms. Median age was 32 у (range, 18-54), m/f: 39 (70%) / 17 (30%). B-ALL/LBL were diagnosed in 26 (46,4%) pts, T-ALL- in 26 (46,4%) and MPAL- in 4 (7,2%). Genomic DNA was extracted from peripheral blood samples of given pts. Genetic polymorphisms inNUDT15(*2, *3)and TPMT(*2, *3A, *3B, *3C)genes were detected using the allele-specific RT-PCR. The dose of 6-MP was calculated only for 54 pts from 56 (one of these pts stopped the therapy and another received the 1 st phase of induction by RALL-2016 without 6-MP). According to the RALL-2016 protocol 6-MP dose correction imply: if the level leukocytes Results:From 54 pts CR rate was 87 % (n=47) and resistance - 13% (n=7). One patient died in CR. The frequency ofTPMTandNUDT15polymorphisms in study group was 17,8 % (n=10): 6 (23%) of 26 pts with B-ALL, 3 (11,5 %) of 26 pts -T-ALL and 1 (25%) of 4 pts - MPAL. In our cohort these polymorphisms were found significantly more frequently in pts with B-ALL (p Conclusions:In our study the frequency ofTPMTandNUDT15polymorphisms in adult pts with Ph-negative ALL was 17,8%. The statistical analysis showed that polymorphisms of these genes were detected more frequently in pts with В-ALL. Only one patient withTPMT*2had significant toxicity on the therapy of 6-MP and died in CR. However, we don’t know whether this is due to deficient 6-MP metabolism. We didn’t find a correlation between the 6-MP toxicity and the polymorphisms in our pts. There is a tendency that OS within 2-years in pts withoutTPMTandNUDT15polymorphisms is better than in the group of pts with them. But our cohorts are small and require further study. Keywords:acute lymphoblastic leukemia, toxicity, 6-mercaptopurine,TPMT,NUDT15 Download : Download high-res image (107KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.