TPMT and ITPA Gene Polymorphism and Their Adverse Events during Chemotherapy of Acute Lymphoblastic Leukemia among Bangladeshi Children

Background: The pharmacogenetic-oriented approach reduces the toxicity and increases the safety of chemotherapeutic agents. 6-mercaptopurin (6-MP) metabolizing enzymes such as thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) contribute to variable responses and adverse effects among leukemia patients treated with 6-MP. The aim of our study was to identify the prevalence of TPMT and ITPA gene polymorphisms among Bangladeshi children with acute lymphoblastic leukemia (ALL) and their association with the adverse effects of 6-MP during the treatment. Methods: We recruited 75 patients with ALL and 75 volunteers with minor illnesses as the control group. Genotyping for TPMT (TPMT*3C, *3B, *2) and ITPA (ITPAc.94C>.A) was performed. The relationship between genotypes and adverse effects of 6-MP was investigated. Results: The frequency of TPMT*3B, TPMT*3C and ITPA polymorphisms among volunteers was 0.006, 0.020, and 0.093, respectively, whereas TPMT*3C and ITPA polymorphisms among ALL patients was 0.010 and 0.153, respectively. ALL patients with the ITPA variant developed fever (OR=6.9, 95% CI=1.99-23.91), neutropenia (OR=7.68, 95% CI=2.21-26.61), hyperbilirubinemia (OR=4.73, 95% CI=1.39-16.07) and raised serum ALT (OR=4.73, 95% CI=1.52-14.68) which were significant in comparison with those without polymorphism. Conclusion: The frequency of ITPAc.94C>A among Bangladeshi children was high. Adverse effects of chemotherapy in patients with ALL suggests the importance of ITPA genotyping in ALL patients prior to starting chemotherapy.