Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations

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 stro...

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Bibliographic Details
Published in:JNCI : Journal of the National Cancer Institute 2024-05, Vol.116 (5), p.702-710
Main Authors: Maillard, Maud, Nishii, Rina, Yang, Wenjian, Hoshitsuki, Keito, Chepyala, Divyabharathi, Lee, Shawn H R, Nguyen, Jenny Q, Relling, Mary V, Crews, Kristine R, Leggas, Mark, Singh, Meenu, Suang, Joshua L Y, Yeoh, Allen E J, Jeha, Sima, Inaba, Hiroto, Pui, Ching-Hon, Karol, Seth E, Trehan, Amita, Bhatia, Prateek, Antillon Klussmann, Federico G, Bhojwani, Deepa, Haidar, Cyrine E, Yang, Jun J
Format: Article
Language:English
Subjects:
Adolescent
Animals
Antimetabolites, Antineoplastic - administration & dosage
Antimetabolites, Antineoplastic - adverse effects
Child
Child, Preschool
Female
Genotype
Humans
Male
Mercaptopurine - administration & dosage
Mercaptopurine - adverse effects
Methyltransferases - genetics
Methyltransferases - metabolism
Mice
Nudix Hydrolases
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Pyrophosphatases - genetics
Pyrophosphatases - metabolism
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Summary: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. 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+/-). 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 
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/djae004