DNA-TG and risk of sinusoidal obstruction syndrome in childhood acute lymphoblastic leukemia

Toksvang, Linea Natalie; Grell, Kathrine; Nielsen, Stine Nygaard; Nersting, Jacob; Murdy, Daniel; Moorman, Anthony V.; Vora, Ajay; Schmiegelow, Kjeld

doi:10.1038/s41375-021-01420-0

Cited by 5 publications

(8 citation statements)

References 16 publications

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“…TEAM is a novel approach for maintenance therapy, that is based on a line of supportive studies relating to anticipated toxicity [ 25 , 32 ], a large observational study on the association between DNA-TG and relapse risk [ 20 ], and a pilot study on feasibility and efficacy (with respect to DNA-TG) of the TEAM drug combination [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…The risk of SOS and NRH is anticipated to be low, due to the low dose of 6TG used [ 32 ]. Furthermore, SOS has not been associated with DNA-TG [ 25 ]. SMN has been associated with higher doses and longer duration of 6MP therapy in previous retrospective studies [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…This conclusion is further supported by a retrospective study including 11 patients receiving 6TG who developed SOS and 121 who did not. In this study, SOS was not associatied with DNA-TG (hazard ratio = 0.91 [95% CI 0.76–1.09%; p = 0.30] per 100 fmol/μg increase in DNA-TG in a simple Cox regression) [ 25 ]. Furthermore, studies have shown angioprotective functions of 6MP possibly through the enhanced activity of the transcriptional factors Nur77 [ 33 ] and hypoxia-inducible factor-1α [ 34 ], and decreased expression of vascular adhesion molecules PECAM-1 and VLA-4 [ 35 ].…”

Section: Introductionmentioning

confidence: 94%

“…The cytotoxicity of 6TG is also exerted through DNA-TG. However, 6TG is more extensively converted into TGN than 6MP, leading to 7-times higher erythrocyte TGN levels [ 24 ]; but as MeMP is lacking, a 6TG dose of 40 mg/m 2 in combination with MTX does not cause profound myelosuppression [ 24 ], and it does not provide higher DNA-TG levels [ 25 ]. We therefore hypothesized that significant, but tolerable, DNA-TG increments can be obtained by adding a very low dose of 6TG to the conventional MTX/6MP maintenance therapy, which we hereby name the Thiopurine Enhanced ALL Maintenance (TEAM) strategy.…”

Section: Introductionmentioning

confidence: 99%

“…The replacement of 6MP with 6TG did not result in an overall improvement of EFS [ 31 ]. Since replacing 6MP with 6TG also eliminates MeMP this will lead to less inhibition of purine de novo synthesis, which explains why DNA-TG levels do not increase even though cytosol TGN levels are higher with 6TG therapy [ 25 ]. This may also explain the lack of efficacy improvement in these trials.…”

Section: Introductionmentioning

confidence: 99%

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Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0–45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol

et al. 2022

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Background A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance. Methods TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0–45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5–12.5 mg/m2/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m2/day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients. Discussion TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms. Trial registration EudraCT, 2018–001795-38. Registered 2020-05-15, Clinicaltrials.gov, NCT04307576. Registered 2020-03-13, https://clinicaltrials.gov/ct2/show/NCT04307576

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0–45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol

et al. 2022

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Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy

Bayoumy,

Ansari,

Mulder

et al. 2024

Clin Pharmacokinet

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Background and Objective Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography–tandem mass spectrometry (LC–MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants. Methods A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword “DNA-TG” with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher’s z -transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle–Ottowa quality assessment scale. Results In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL ( n = 16) or IBD ( n = 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78–184.35), P ...

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Erythrocyte-incorporated 6-mercaptopurine metabolite levels are not affected by recent drug administration during maintenance therapy for childhood acute lymphoblastic leukemia

Aukstikalne,

Klejus,

Thastrup

et al. 2023

EJC Paediatric Oncology

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DNA-TG and risk of sinusoidal obstruction syndrome in childhood acute lymphoblastic leukemia

Cited by 5 publications

References 16 publications

Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy

Erythrocyte-incorporated 6-mercaptopurine metabolite levels are not affected by recent drug administration during maintenance therapy for childhood acute lymphoblastic leukemia

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