An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia

Tanaka, Yoïchi; Yeoh, Allen Eng Juh; Moriyama, Takaya; Li, Chi Kong; Kudo, Ko; Arakawa, Yuki; Buaboonnam, Jassada; Zhang, Hui; Liu, Hsi‐Che; Ariffin, Hany; Chen, Zhiwei; Kham, Shirley Kow Yin; Nishii, Rina; Hasegawa, Daisuke; Fujimura, Junya; Keino, Dai; Kondoh, Kensuke; Satō, Atsushi; Ueda, Takahiro; Yamamoto, Masaki; Taneyama, Yuichi; Hino, Moeko; Takagi, Motoki; Ohara, Akira; Ito, Etsuro; Koh, Katsuyoshi; Hori, Hiroki; Manabe, Atsushi; Yang, Jun J.; Kato, Motohiro

doi:10.3324/haematol.2020.266320

Cited by 8 publications

(13 citation statements)

References 12 publications

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“…14 In one case of homozygous *5 (*5/*5) in the recent study, the patient did not show severe intolerance. 11 However, patients with compound heterozygous variants (*2/*5 or *3/*5) showed strong intolerance to 6-MP. 11,14 Correspondingly, in the analysis, patients with *1/*5 showed a slightly lower NUDT15 expression level than WT and patients with compound heterozygous variants (*2/*5 or *3/*5) showed extremely low expression levels of NUDT15.…”

Section: Sionmentioning

confidence: 99%

“…In a recent international retrospective study on NUDT15, patients with homozygous and biallelic no-function alleles showed prolonged intolerance to 6-MP and excessive disruption of treatment. 11 Previous data showed that high levels of DNAincorporated thioguanine (DNA-TG) in white blood cells (WBCs) in patients with loss-of-function NUDT15 variants was the pharmacological basis of their 6-MP intolerance. 8,12,13 Studies in laboratory model systems suggest that NUD15 variants, particularly p.R139C, result in unstable proteins and thus reduced enzymatic activity.…”

Section: Introductionmentioning

confidence: 99%

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Low NUDT15 expression levels due to biallelic NUDT15 variants and 6‐mercaptopurine intolerance

et al. 2022

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Summary 6‐Mercaptopurine (6‐MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6‐MP–associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA‐incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6‐MP, using sandwich enzyme‐linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6‐MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15‐mediated 6‐MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.

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Section: Sionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low NUDT15 expression levels due to biallelic NUDT15 variants and 6‐mercaptopurine intolerance

et al. 2022

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“…In 6-MP treatment, patients with bi-allelic variants experienced severe bone marrow suppression and required the discontinuation or reduction of significant doses. We recently evaluated the association between 6-MP intolerability and clinical characteristics in 37 children with ALL bearing NUDT15 bi-allelic variants in an Asian international collaboration retrospective study [ 14 ]. Among those with NUDT15 bi-allelic variants, more than 90% of the patients had a WBC count of <2000/mm 3 or a neutrophil count of <1000/mm 3 .…”

Section: Nudt15 Variants and Toxicities In Thiopurine Metabolismmentioning

confidence: 99%

“…We further demonstrated that adjusting the initial 6-MP dose is important to prevent the discontinuation of treatment and to allow the continuation of maintenance therapy, based on the NUDT15 genotype. In patients with NUDT15 bi-allelic variant, those who received an initial 6-MP dose of less than 10 mg/m 2 experienced a shorter duration of therapy interruption than those who received more than 10 mg/m 2 in the first 8 weeks (median range, 0 vs. 16 days) [ 14 ]. Based on the guideline of the Clinical Pharmacogenetics Implementation Consortium (CPIC), an initial 6-MP dose of 10 mg/m 2 is recommended for patients with NUDT15 poor metabolizer diplotypes ( *2/*2 , *2/*3 , and *3/*3 ) ( Table 2 ) [ 6 ].…”

Section: Nudt15 Variants and Toxicities In Thiopurine Metabolismmentioning

confidence: 99%

“…In our study, eight patients inherited non-codon 139 variant alleles. The average 6-MP dose in patients with *2/*5 , *2/*7 , and *3/*5 diplotypes was less than 10 mg/m 2 , while that in patients with *2 / *6 and *5 / *5 were tolerable for more than 10 mg/m 2 [ 14 ]. A patient with *5 / *5 required a reduction in the 6-MP dose because of the decreasing WBC counts, but a tolerable 6-MP dose of 17 mg/m 2 was administered to maintain suitable blood cell counts.…”

Section: Nudt15 Variants and Toxicities In Thiopurine Metabolismmentioning

confidence: 99%

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Importance of NUDT15 Polymorphisms in Thiopurine Treatments

Tanaka

Saito

2021

JPM

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Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 (NUDT15) polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the NUDT15 studies, mainly in Asian countries, and their implementation in several countries.

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Recent progress in pediatric lymphoblastic leukemia

Kato

2022

Int J Hematol

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The probability of long-term survival for children with lymphoblastic leukemia has improved dramatically over recent decades, mainly owing to advances in genomic analysis techniques, which have improved our understanding of the nature of leukemic cells and prognostic prediction based on the evaluation of precise treatment response. Risk-adjusted chemotherapy based on these advances has simultaneously reduced relapse rates and minimized complications. In addition, recent genomic analyses have deepened our understanding of the pathogenesis of leukemia and revealed the involvement of germline variations in the clinical course of leukemia treatment. Additionally, advances in minimal residual disease assays and the introduction of immunotherapy are expected to further improve therapeutic analyses. Further advances in clinical and translational research are anticipated to improve survival to 100% in a healthy state.

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An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia

Abstract: Not available.

Cited by 8 publications

References 12 publications

Low NUDT15 expression levels due to biallelic NUDT15 variants and 6‐mercaptopurine intolerance

Low NUDT15 expression levels due to biallelic NUDT15 variants and 6‐mercaptopurine intolerance

Importance of NUDT15 Polymorphisms in Thiopurine Treatments

Recent progress in pediatric lymphoblastic leukemia

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