Polymorphisms of the TPMT, NUDT15 genes and 6-mercaptopurine toxicity profile in adult patients with Ph-negative acute lymphoblastic leukemia/lymphomas on the ALL-2016 protocol

Background. 6-mercaptopurine (6-MP) is a drug that is included in the treatment protocols for children and adults with acute lymphoblastic leukemias/lymphomas (ALL/LBL). It is known that individual differences in 6-MP tolerance can be explained by the TPMT and NUDT15 polymorphisms.

Aim. To determine 6-MP toxicity profile in adult patients with Ph-negative ALL/LBL treated by ALL-2016 protocol, depending on the TPMT and NUDT15 polymorphisms.

Materials and methods. The study included 54 adult patients with Ph-negative ALL/LBL (40 male and 14 female). The median age was 31 (18-51) years. T-ALL/LBL was diagnosed in 29 patients, B-ALL/LBL - in 22, acute leukemia with a mixed immunophenotype - in 3. All patients received treatment according to the multicenter study ALL-2016 (ClinicalTrials.gov, NCT03462095). polymorphisms in NUDT15 (*2, *3) and TPMT (*2, *3A, *3B, *3C) genes were detected using the allele-specific real-time polymerase chain reaction. Genomic DNA was extracted from patients peripheral blood samples. On the induction and consolidation therapy by the protocol, the received and proper 6-MP doses were calculated for all the patients. Drug toxicity was evaluated based on clinical and laboratory data.

Results. TPMT and NUDT15 polymorphisms were detected in 11 (20 %) patients, more often in B-ALL - 7 (32 %) of 22 (p <0.05). A lower dose of 6-MP was received by patients with TPMT, NUDT15 polymorphisms only at consolidation IV (p = 0.01). we didn't find a correlation between the 6-MP toxicity and the polymorphisms in our patients (p >0.05).

Conclusion. There were no differences in the received dose of 6-MP and the incidence of toxicity in adult patients between Ph-negative ALL/LBL with or without TPMT and NUDT15 polymorphisms treated according to ALL-2016 protocol (p >0.05). further studies including evaluation of 6-MP metabolites concentrations are required for a more complete understanding of the metabolism of this drug.

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