DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis

Toksvang, Linea Natalie; Grell, Kathrine; Nersting, Jacob; Degn, Matilda; Nielsen, Stine Nygaard; Abrahamsson, Jonas; Lund, Bendik; Kanerva, Jukka; Jónsson, Òlafur G.; Lepik, Kristi; Vaitkevičienė, Goda; Griškevičius, Laimonas; Quist‐Paulsen, Petter; Vora, Ajay; Moorman, Anthony V.; Murdy, Daniel; Zimmermann, Martin; Möricke, Anja; Bostrom, Bruce; Joshi, Jaitri; Hjalgrim, Lisa Lyngsie; Dalhoff, Kim; Als‐Nielsen, Bodil; Schmiegelow, Kjeld

doi:10.1038/s41375-021-01182-9

Cited by 11 publications

(10 citation statements)

References 25 publications

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“…SMN has been associated with higher doses and longer duration of 6MP therapy in previous retrospective studies [ 36 ]. An IPD meta-analysis including 1910 patients, of which 14 developed a SMN, did not find an association between DNA-TG and SMN, although larger studies confirming this are warranted [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…As no significant associations were found between DNA-TG and 6MP dose, blood counts (neutrophils, lymphocytes, thrombocytes, hemoglobin), or aminotransferase levels during maintenance, these cannot replace DNA-TG measurements [ 20 ]. The association between DNA-TG and relapse hazard has been confirmed in a recent individual patient data (IPD) meta-analysis including the NOPHO ALL2008 pediatric cohort as well as five other international pediatric and adult ALL cohorts of patients aged 1–45 years [ 22 ]. Furthermore, DNA-TG was not associated with the hazard of developing a second malignant neoplasm (SMN) (hazard ratio = 0.88; 95% CI: 0.68–1.14; p = 0.34) [ 22 ].…”

Section: Introductionmentioning

confidence: 90%

“…The association between DNA-TG and relapse hazard has been confirmed in a recent individual patient data (IPD) meta-analysis including the NOPHO ALL2008 pediatric cohort as well as five other international pediatric and adult ALL cohorts of patients aged 1–45 years [ 22 ]. Furthermore, DNA-TG was not associated with the hazard of developing a second malignant neoplasm (SMN) (hazard ratio = 0.88; 95% CI: 0.68–1.14; p = 0.34) [ 22 ].…”

Section: Introductionmentioning

confidence: 90%

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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: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 90%

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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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“…TG·T mismatching is recognized by the mismatch repair (MMR) system, with MutS homolog 6 (MSH6) playing a key role; however, as the aberrant base is in the template strand, it ultimately leads to DNA strand breaks and apoptosis [ 13 ]. Higher levels of DNA-TG have been associated with a reduced relapse hazard [ 14 , 15 ]. There are many other intermediate thiopurine metabolites, some of which have also been linked to anti-leukemia effects.…”

Section: -Mercaptopurinementioning

confidence: 99%

“…At the time of diagnosis of ALL, the normal level for each patient is unknown; therefore, applying a common WBC/ANC target for MT dose adjustment result in differing treatment intensities across patients. Hence, new strategies are needed to guide MT, and one based on DNA-TG may be a useful candidate, because (i) DNA-TG is a downstream metabolite that integrates upstream thiopurine and MTX metabolites; (ii) it is readily manipulable [ 27 ]; (iii) it has been linked to relapse, especially in patients who are MRD positive at the end of induction therapy [ 14 , 15 ]; and (iv) monitoring of DNA-TG is feasible in multi-center studies, because it is very stable. Meanwhile, an optimal DNA-TG level that balance efficacy and toxicity has yet to be determined.…”

Section: Measures Of Treatment Intensity and Novel Biomarkers For The...mentioning

confidence: 99%

Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations

et al. 2022

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Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy—the addition of low-dose (2.5–12.5 mg/m2/day) 6-thioguanine to the 6-MP/MTX backbone—that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.

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Thiopurine Methyltransferase Intermediate Metabolizer Status and Thiopurine‐Associated Toxicity During Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia

Schwarz

Woldanski‐Travaglini

Swanston

et al. 2023

Clin Pharma and Therapeutics

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Mercaptopurine is a cornerstone of maintenance chemotherapy in childhood acute lymphoblastic leukemia (ALL). Its cytotoxic effects are mediated by 6‐thioguanine nucleotides (TGNs) incorporation into lymphocyte DNA. Thiopurine methyltransferase (TPMT) inactivates mercaptopurine, and deficiency resulting from genetic variants increases TGN exposure and hematopoietic toxicity. Although mercaptopurine‐dose reduction reduces toxicity risk without compromising relapse rate in patients with TPMT deficiency, dosing recommendations for those with moderately reduced activity (intermediate metabolizer (IM)) are less clear and their clinical impacts have yet to be established. This cohort study assessed the effect of TPMT IM status on mercaptopurine‐associated toxicity and TGN blood exposure in pediatric patients with ALL initiated on standard dose mercaptopurine. Of 88 patients studied (mean age 4.8 years), 10 (11.4%) were TPMT IM, and all had undergone ≥ 3 cycles of maintenance therapy (80% completed). A larger proportion of TPMT IM than normal metabolizers (NM) had febrile neutropenia (FN) during the first two cycles of maintenance, reaching significance in the second cycle (57% vs. 15%, respectively; odds ratio = 7.33, P < 0.05). Compared to NM, FN events occurred more frequently and with prolonged duration in IM in cycles 1 and 2 (adjusted P < 0.05). IM had a 2.46‐fold increased hazard ratio for FN, and about twofold higher TGN level than NM (P < 0.05). Myelotoxicity was more common in IM than NM (86% vs. 42%, respectively) during cycle 2 (odds ratio = 8.2, P < 0.05). TPMT IM initiated at a standard mercaptopurine dose are at greater risk for FN during early cycles of maintenance therapy, thus our findings support genotype‐guided dose adjustment to reduce toxicity.

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DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis

Cited by 11 publications

References 25 publications

Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations

Thiopurine Methyltransferase Intermediate Metabolizer Status and Thiopurine‐Associated Toxicity During Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia

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