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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 |
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| Author: | Toksvang, Linea Natalie1; Als-Nielsen, Bodil1; Bacon, Christopher2; |
| Organizations: |
1Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark 2St. James Hospital, Dublin, Ireland 3Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania
4Instituto Português de Oncologia Lisboa Francisco Gentil Departamento de Pediatria, Lisbon, Portugal
5University Medical Center Hamburg-Eppendorf, Hamburg, Germany 6Landspitali University Hospital, Reykjavik, Iceland 7Oslo University Hospital, Oslo, Norway 8Örebro University Hospital, Örebro, Sweden 9Drottning Silvias Barnsjukhus, Gothenburg, Sweden 10Tallinn Children’s Hospital, Tallinn, Estonia 11Oulu University Hospital and PEDEGRO Research Unit, University of Oulu, Oulu, Finland 12Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark 13Tartu University Hospital, Tartu, Estonia 14Helsinki University Central Hospital, Helsinki, Finland 15Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium 16Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands 17Our Lady’s Children Hospital, Dublin, Ireland 18Université de Paris, hôpital universitaire Robert-Debré (APHP), Paris, France 19Center for Pediatric Oncology and Hematology, Vilnius University, Vilnius, Lithuania 20Karolinska Institutet, Stockholm, Sweden 21Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden 22University of Copenhagen, Copenhagen, Denmark |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 1.2 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2022092960474 |
| Language: | English |
| Published: |
Springer Nature,
2022
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| Publish Date: | 2022-09-29 |
| Description: |
AbstractBackground: 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, see all
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| Series: |
BMC cancer |
| ISSN: | 1471-2407 |
| ISSN-E: | 1471-2407 |
| ISSN-L: | 1471-2407 |
| Volume: | 22 |
| Issue: | 1 |
| Article number: | 483 |
| DOI: | 10.1186/s12885-022-09522-3 |
| OADOI: | https://oadoi.org/10.1186/s12885-022-09522-3 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3122 Cancers |
| Subjects: | |
| Funding: |
The Novo Nordisk Foundation (grant no: NNF19OC0056458); the Danish Cancer Society (grant no: R231-A14071-B34); the Danish Childhood Cancer Foundation (grant no: 2017–2034; 2018–3705); the Swedish Childhood Cancer Foundation (grant no: KP2018–0008). This work is part of Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and supported by Danish Cancer Society (R-257-A14720) and the Danish Childhood Cancer Foundation (2019–5934). The study has undergone full external peer review as part of the funding process. The funding bodies had no influence on study design, data collection, analysis, or interpretation of data, nor writing the manuscript. |
| Copyright information: |
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visithttp://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
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https://creativecommons.org/licenses/by/4.0/ |