The Role of TPMT, ITPA, and NUDT15 Variants during Mercaptopurine Treatment of Swedish Pediatric Patients with Acute Lymphoblastic Leukemia

Abstract

To evaluate the roles of thiopurine methyltransferase (TPMT), inosine triphosphatase (ITPA), and Nudix hydrolase 15 (NUDT15) in 6-mercaptopurine (6-MP) sensitivity during treatment of pediatric patients with acute lymphoblastic leukemia (ALL). The study included 102 pediatric patients with ALL subject to the Nordic society Of Paediatric Haematology and Oncology (NOPHO) ALL-2000 and ALL-2008 protocols. Episodes of neutropenia and febrile neutropenia, TPMT sequence variants, as well as 6-MP end doses, were collected retrospectively from medical records. TPMT, ITPA, and NUDT15 sequence variants were analyzed using pyrosequencing. TPMT variants were associated with a reduced risk of neutropenia and febrile neutropenia during the maintenance II period (P=.019 and P<.0001, respectively). In addition, a NUDT15 variant was associated with a lower end dose of 6-MP (P=.0097), but not with neutropenia and febrile neutropenia. ITPA variants were not associated with an increased risk of neutropenia, febrile neutropenia, nor lower end dose of 6-MP. However, when analyzing the entire treatment period, ITPA variants were associated with a decreased risk of febrile neutropenia. White blood cell count-based dose adjustments are regularly performed for known TPMT- deficient patients and results in a reduced risk of neutropenia and febrile neutropenia. Also in NUDT15-deficient patients dose adjustments are performed as indicated by low end dose of 6-MP. ITPA-deficient patients had a decreased risk of febrile neutropenia when analyzing the entire treatment period. Our data suggest that NUDT15 plays an important role in 6-MP treatment and the results should be confirmed in larger cohorts. Future studies should also follow up whether white blood cell count-based dose adjustments affect the risk of relapse.