Testing for thiopurine S-methyltransferase and nudix hydrolase 15 gene polymorphism during induction therapy in acute lymphoblastic leukemia

Objectives: 6-Mercaptopurine (6-MP), belonging to the class of thiopurines, is the backbone of the prolonged maintenance phase of acute lymphoblastic leukemia (ALL) therapy and also an essential component of induction and consolidation phases of most ALL protocols. Genetic polymorphisms (GPs) in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are associated with significant thiopurine-associated drug toxicity and can be a major hindrance to optimal delivery of therapy. The objective of the study is to determine the prevalence of TPMT and NUDT15 GP during induction of the ALL treatment protocol, and also to compare the drug’s toxicity profile among those with and without the enzyme gene mutation. Material and Methods: This study was conducted at a tertiary care center in North India, where data of patients between September 2021 and March 2023 were collected retrospectively. As a department protocol, certain predefined criteria are used to select patients undergoing ALL induction for testing of gene polymorphism. Results: Out of 37 patients who fulfilled the inclusion criteria underwent testing for GP, and 13 (35.13%) patients tested positive for GP. 12 out of 13(92.3%) of these patients had NUDT15 GP. Patients with recurrent grade 4 thrombocytopenia and febrile neutropenia had a significantly higher prevalence of GP. Conclusion: Our study is the first of its kind to the best of our knowledge, where we tried to evaluate gene polymorphisms during the induction phase of ALL therapy for early 6MP dose adjustment and minimize treatment interruption. Similar to other Indian data, our study also highlights that NUDT15 GPs are more frequent in the Asian population. Although it is ideal to test all patients before introducing 6MP, if pre-emptive testing of all is not feasible, it is imperative that at least those with recurrent grade 4 thrombocytopenia and febrile neutropenia be tested for GP. However, larger studies are needed to validate the inclusion criteria.