Increments in DNA-thioguanine level during thiopurine-enhanced maintenance therapy of acute lymphoblastic leukemia

Larsen, Rasmus; Rank, Cecilie Utke; Grell, Kathrine; Möller, Luciana M.; Overgaard, Ulrik Malthe; Kampmann, Peter; Nersting, Jacob; Degn, Matilda; Nielsen, Stine Nygaard; Holst, Helle; Albertsen, Birgitte Klug; Wehner, Peder Skov; Callesen, Michael; Kanerva, Jukka; Frandsen, Thomas Leth; Als‐Nielsen, Bodil; Hjalgrim, Lisa Lyngsie; Schmiegelow, Kjeld

doi:10.3324/haematol.2020.278166

Cited by 16 publications

(23 citation statements)

References 36 publications

(56 reference statements)

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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%

“…It has recently been shown that significant DNA-TG increments can be obtained by adding a very low dose (2.5–12.5 mg/m 2 /day) of the thiopurine 6-thioguanine (6TG) to the MTX/6MP backbone of maintenance therapy [ 23 ]. The cytotoxicity of 6TG is also exerted through DNA-TG.…”

Section: Introductionmentioning

confidence: 99%

“…The feasibility and safety of the TEAM strategy has been tested in a pilot study of 34 patients [ 23 ]. The backbone of 6MP (starting dose of 50 mg/m 2 /day) and MTX (starting dose of 20 mg/m 2 /week) was supplemented with 6TG at an initial dose of 2.5 mg/m 2 /day, which was then increased in steps of 2.5 mg/m 2 /day at 2 weeks intervals up to a maximum dose of 12.5 mg/m 2 /day.…”

Section: Introductionmentioning

confidence: 99%

“…The backbone of 6MP (starting dose of 50 mg/m 2 /day) and MTX (starting dose of 20 mg/m 2 /week) was supplemented with 6TG at an initial dose of 2.5 mg/m 2 /day, which was then increased in steps of 2.5 mg/m 2 /day at 2 weeks intervals up to a maximum dose of 12.5 mg/m 2 /day. The patients did not experience increased myelotoxicity or hepatotoxicity compared with historical controls from the NOPHO ALL2008 cohort, and it led to significantly higher DNA-TG levels when compared to historical data from the NOPHO ALL2008 maintenance sub-study (median DNA-TG on TEAM therapy: 764 fmol/μg vs 492 fmol/μg in NOPHO ALL2008 patients; p < 0.0001) [ 23 ]. Based on the Cox regression model from the NOPHO ALL2008 maintenance sub-study, this corresponds to a theoretical reduction in relapse hazard of 59% [ 20 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…The patients did not experience increased myelotoxicity or hepatotoxicity compared with historical controls from the NOPHO ALL2008 cohort, and it led to significantly higher DNA-TG levels when compared to historical data from the NOPHO ALL2008 maintenance sub-study (median DNA-TG on TEAM therapy: 764 fmol/μg vs 492 fmol/μg in NOPHO ALL2008 patients; p < 0.0001) [ 23 ]. Based on the Cox regression model from the NOPHO ALL2008 maintenance sub-study, this corresponds to a theoretical reduction in relapse hazard of 59% [ 20 , 23 ].…”

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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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Density functional study of transition metal (Fe,Co,Ni)‐doped C60 fullerenes as 6‐thioguanine delivery system

Liang

et al. 2023

Applied Organom Chemis

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The aim of this work is to investigate the adsorption and release mechanism of 6-thioguanine (6TG) on transition metal (Fe,Co,Ni)-doped C60 and C60 fullerene nanomaterials by density functional theory (DFT) and time-dependent density functional theory (TD-DFT) to better understand the targeted drug delivery performance of fullerene to 6TG anticancer drug. The adsorption energy, solvation energy, and related chemical properties were calculated.According to thermodynamic analysis, the interaction between 6TG drug and fullerene nanocarriers is exothermic and spontaneous. Density of state (DOS) and natural bonding orbital (NBO) analyses showed that during the adsorption process of 6TG drug on the surface of fullerene, 6TG was the charge donor and fullerene was the charge acceptor. Atoms in molecule (AIM) and independent gradient model based on Hirshfeld partition (IGMH) analyses revealed Van der Waals and hydrogen bond interactions between the 6TG drug and fullerenes. In addition, fullerenes doped with transition metals can increase the solvation effect of the 6TG drug and shorten its release time from fullerenes. These results indicate that transition metal (Fe,Co,Ni)-doped C60 fullerene can be the promising anticancer drug delivery system for 6TG.

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Comment on: Desensitization using PEGasparaginase in the era of commercially available Erwinia: A single‐institution report on efficacy, cost, and resource utilization

Tong

2024

Pediatric Blood & Cancer

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The article of Feldman et al. 1 reported 11 patients who had 33 attempts of desensitizations to both PEGasparaginase preparations (PEGasparaginase, Oncaspar 2 and calaspargase pegol-mknl, Asparlas 3 ). Feldman et al. found that zero patients experienced an allergy to or silent inactivation (SI) of PEGasparaginase preparations resulting in cessation of further asparaginase therapy. Of note, no rescue medications like clemastine or hydrocortisone were needed.The trough activity levels were above the prespecified thresholds of 100 U/L or greater. These authors only mentioned the success of desensitizations; however, these approaches are not without any risks.Recently, Swanson et al. confirmed the feasibility of drug sensitization in patients with persistent antidrug antibody levels (ADA). 4 Patients who were rechallenged with PEGasparaginase without desensitization, angioedema, and gastrointestinal (GI) symptoms during the initial reaction, as like pre-rechallenge ADA positivity, were still associated with rechallenge failure (RF). 5 Swanson et al. concluded therefore, desensitizing patients with detectable asparaginase antibodies and previous occurrence of angioedema with GI symptoms should be done with caution. 4 These patients are at high risk for RF either due to

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Increments in DNA-thioguanine level during thiopurine-enhanced maintenance therapy of acute lymphoblastic leukemia

Cited by 16 publications

References 36 publications

Density functional study of transition metal (Fe,Co,Ni)‐doped C60 fullerenes as 6‐thioguanine delivery system

Comment on: Desensitization using PEGasparaginase in the era of commercially available Erwinia: A single‐institution report on efficacy, cost, and resource utilization

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