Additive Effects of TPMT and NUDT15 on Thiopurine Toxicity in Children with Acute Lymphoblastic Leukemia Across Multiethnic Populations

Overview

Journal J Natl Cancer Inst

Publisher Oxford University Press

Specialty Oncology

Date 2024 Jan 17

PMID 38230823

Authors

Maud Maillard

Rina Nishii

Wenjian Yang

Keito Hoshitsuki

Divyabharathi Chepyala

Shawn H R Lee

Jenny Q Nguyen

Mary V Relling

Kristine R Crews

Mark Leggas

Meenu Singh

Joshua L Y Suang

Allen E J Yeoh

Sima Jeha

Hiroto Inaba

Ching-Hon Pui

Seth E Karol

Amita Trehan

Prateek Bhatia

Federico G Antillon Klussmann

Deepa Bhojwani

Cyrine E Haidar

Jun J Yang

Affiliations

Soon will be listed here.

Abstract

Background: Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear.

Methods: MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-).

Results: Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP.

Conclusion: We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

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