P03 Germline NUDT15 mutation and thiopurines for children with acute lymphoblastic leukemia: is it a prognostic factor?

Background The nudix hydrolase 15 (NUDT15) polymorphism recently emerges as a biomarker of severe hematological toxicity during 6-mercaptopurine (6-MP) therapy of children with acute lymphoblastic leukemia (ALL). Initially described restricted to Asian population, recent publications highlighted its presence in patients with European ancestry. In November 2018, the Clinical Pharmacogenetics Implementation Consortium (CPIC) updated the guideline for thiopurines dosing based on Thiopurine S-methyl transferase (TPMT) and NUDT15 genotypes. Here, we presented a feedback from a French monocentric experience in ALL patients. Methods We retrospectively genotyped 188 children for NUDT15 c.94C>A treated for ALL at Trousseau hospital, Paris. Parents have given their consent for thiopurines’ therapeutic drug monitoring including performing TPMT genotype (*2, *3B, *3C). We focused, for patients with a mutated NUDT15 genotype, on treatment response in terms of morbi-mortality. Results This NUDT15 polymorphism was found for 6 patients (3.2%): one patient with a European ancestry and the others with an Asian ancestry. Five children had a NUDT15 mutated heterozygous genotype without TPMT alterations and one patient with a mutated homozygous NUDT15 genotype associated with TPMT *1/*3C. Hematological and/or infectious complications were reported for all patients with this variant with hospitalization in intensive care unit for the one with a mutated NUDT15 genotype and TPMT *1/*3C. Reduced 6-MP dose (between 30% to 50% of the standard dose for heterozygous patients and 3% of the standard dose for mutated homozygous patient) was required for maintenance therapy. Two patients had a relapse. Conclusion This report supports CPIC guidelines for screening NUDT15 polymorphism before 6-MP treatment regardless patients‘ race. The impact of this polymorphism on relapse occurrence is worrying and prospective results with dose adjustments at 6-MP initiation will be crucial to understand if treatment interruptions and/or reduced dose were at risk of relapse. Disclosure(s) Nothing to disclose