Impact of NUDT15 genetics on severe thiopurine-related hematotoxicity in patients with European ancestry

Severe hematotoxicity in patients with thiopurine therapy has been associated with genetic polymorphisms in the thiopurine S-methyltransferase (TPMT). While TPMT genetic testing is clinically implemented for dose individualization, alterations in the nudix hydrolase 15 (NUDT15) emerged as independent determinant of thiopurine-related hematotoxicity. Because data for European patients are limited, we investigated the relevance of NUDT15 in Europeans. Additionally to TPMT phenotyping/genotyping, we performed in-depth Sanger sequencing analyses of NUDT15 coding region in 107 European patients who developed severe thiopurine-related hematotoxicity as extreme phenotype. Moreover, genotyping for NUDT15 variants in 689 acute lymphoblastic leukemia (ALL) patients was performed. As expected TPMT was the main cause of severe hematotoxicity in 31% of patients, who were either TPMT deficient (10%) or heterozygous carriers of TPMT variants (21%). By comparison, NUDT15 genetic polymorphism was identified in 14 (13%) patients including one novel variant (p.Met1Ile). Six percent of patients with severe toxicity carried variants in both TPMT and NUDT15. Among patients who developed toxicity within 3 months of treatment, 13% were found to be carriers of NUDT15 variants. Taken together, NUDT15 and TPMT genetics explain ~50% of severe thiopurine-related hematotoxicity, providing a compelling rationale for additional preemptive testing of NUDT15 genetics not only in Asians, but also in Europeans.