DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial

Nielsen, Stine Nygaard; Grell, Kathrine; Nersting, Jacob; Abrahamsson, Jonas; Lund, Bendik; Kanerva, Jukka; Jónsson, Òlafur G.; Vaitkevičienė, Goda; Pruunsild, Kaie; Hjalgrim, Lisa Lyngsie; Schmiegelow, Kjeld

doi:10.1016/s1470-2045(17)30154-7

Cited by 78 publications

(98 citation statements)

References 39 publications

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“…The levels of DNA-TG were quantified using LC-MS/MS, as described in previous reports [16, 18–20]. DNA-TG stability was evaluated and we observed no significant variation within the 72 h window.…”

Section: Introductionmentioning

confidence: 75%

“…When thiopurine dosing is adjusted based on TPMT genotype, the premise is to decrease thiopurine dose for patients with TPMT deficiency such that they are exposed to a TGN level comparable to that in patients with wild-type alleles who receive the standard thiopurine dose. Although we hypothesized that this principle could be adopted for MP dose reduction in patients with NUDT15 risk alleles [12, 16], it remains unclear which MP metabolites should be monitored to direct dose modification. Herein, as a part of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL B-12 protocol, we simultaneously determined TGN and DNA-TG during MP therapy, and evaluate the effects of NUDT15 genotype on these metabolites.…”

Section: Introductionmentioning

confidence: 99%

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The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

Moriyama¹,

Nishii

Lin³

et al. 2017

Pharmacogenetics and Genomics

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Thiopurines (e.g., mercaptopurine [MP]) are widely used chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia (ALL) with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with ALL, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely due to toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P = 4.0 × 10−9). Cytosolic TGN and nuclear DNA-TG were positively correlated with each other across genotype groups (P = 6.5 × 10−4), but the ratio of DNA-TG to TGN was significantly higher in NUDT15 deficient patients (P = 3.6 × 10−9), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.

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Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

Moriyama¹,

Nishii

Lin³

et al. 2017

Pharmacogenetics and Genomics

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“…Our data regarding the effect on 6-MP metabolism in presence of MTX are interesting and encourage further research to elucidate all the effects of the successful combination treatment. Why the decrease in TGN is beneficial to the treatment remains to be explained and it seems to be in conflict with reports of low levels of TGN in patients being connected to worse outcomes in ALL treatment [55,76,200,201]. Individuals with low TPMT enzyme activity due to heterozygosity have lower rates of relapse than TPMT wildtype individuals, and are shown to have higher intracellular TGN levels and lower risk of positive MRD after the consolidation phase of the treatment [202].…”

Section: Drug Interaction -Methotrexate and 6-mpmentioning

confidence: 98%

“…Since these [75]. In addition, the lack of endogenous nucleotides increases the proportion of incorporated TGN [72,76].…”

Section: Metabolism and Clinical Action Of Thiopurinesmentioning

confidence: 99%

Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism

Zimdahl

2020

Linköping University Medical Dissertations

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“…Thus, MTXpg in mature erythrocytes reflect exposure at the bone marrow precursor stage, and MTX accumulation is delayed approximately 2 weeks corresponding to their maturation and migration into peripheral blood [7]. We have recently shown that cytosolic thiopurine and total MTXpg2-6 synergize in DNA-TG formation and that DNA-TG is associated with relapse risk independent of on-therapy WBC [8].…”

Section: Introductionmentioning

confidence: 99%

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

Nersting

Nielsen

Grell

et al. 2018

Cancer Chemother Pharmacol

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Purpose Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing. Methods and results Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/ mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were r s = 0.68 and r s = 0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all r s ≥ 0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset. Conclusions Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

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DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial

Cited by 78 publications

References 39 publications

The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

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