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
Abstract 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...
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BMC
2022-05-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-022-09522-3 |
| _version_ | 1811308229634818048 |
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| author | Linea Natalie Toksvang Bodil Als-Nielsen Christopher Bacon Ruta Bertasiute Ximo Duarte Gabriele Escherich Elín Anna Helgadottir Inga Rinvoll Johannsdottir Ólafur G. Jónsson Piotr Kozlowski Cecilia Langenskjöld Kristi Lepik Riitta Niinimäki Ulrik Malthe Overgaard Mari Punab Riikka Räty Heidi Segers Inge van der Sluis Owen Patrick Smith Marion Strullu Goda Vaitkevičienė Hilde Skuterud Wik Mats Heyman Kjeld Schmiegelow |
| author_facet | Linea Natalie Toksvang Bodil Als-Nielsen Christopher Bacon Ruta Bertasiute Ximo Duarte Gabriele Escherich Elín Anna Helgadottir Inga Rinvoll Johannsdottir Ólafur G. Jónsson Piotr Kozlowski Cecilia Langenskjöld Kristi Lepik Riitta Niinimäki Ulrik Malthe Overgaard Mari Punab Riikka Räty Heidi Segers Inge van der Sluis Owen Patrick Smith Marion Strullu Goda Vaitkevičienė Hilde Skuterud Wik Mats Heyman Kjeld Schmiegelow |
| author_sort | Linea Natalie Toksvang |
| collection | DOAJ |
| description | Abstract 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 |
| first_indexed | 2024-04-13T09:18:23Z |
| format | Article |
| id | doaj.art-f64cd07c7c004a71a562cc8d487925a5 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-13T09:18:23Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-f64cd07c7c004a71a562cc8d487925a52022-12-22T02:52:41ZengBMCBMC Cancer1471-24072022-05-0122111910.1186/s12885-022-09522-3Thiopurine 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 protocolLinea Natalie Toksvang0Bodil Als-Nielsen1Christopher Bacon2Ruta Bertasiute3Ximo Duarte4Gabriele Escherich5Elín Anna Helgadottir6Inga Rinvoll Johannsdottir7Ólafur G. Jónsson8Piotr Kozlowski9Cecilia Langenskjöld10Kristi Lepik11Riitta Niinimäki12Ulrik Malthe Overgaard13Mari Punab14Riikka Räty15Heidi Segers16Inge van der Sluis17Owen Patrick Smith18Marion Strullu19Goda Vaitkevičienė20Hilde Skuterud Wik21Mats Heyman22Kjeld Schmiegelow23Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital RigshospitaletDepartment of Pediatrics and Adolescent Medicine, Copenhagen University Hospital RigshospitaletSt. James HospitalVilnius University Hospital Santariskiu KlinikosInstituto Português de Oncologia Lisboa Francisco Gentil Departamento de PediatriaUniversity Medical Center Hamburg-EppendorfLandspitali University HospitalOslo University HospitalLandspitali University HospitalÖrebro University HospitalDrottning Silvias BarnsjukhusTallinn Children’s HospitalOulu University Hospital and PEDEGRO Research Unit, University of OuluCopenhagen University Hospital RigshospitaletTartu University HospitalHelsinki University Central HospitalLeuvens Kanker Instituut (LKI), KU Leuven – UZ LeuvenPrincess Maxima Center for Pediatric OncologyOur Lady’s Children HospitalUniversité de Paris, hôpital universitaire Robert-Debré (APHP)Center for Pediatric Oncology and Hematology, Vilnius UniversityOslo University HospitalKarolinska InstitutetDepartment of Pediatrics and Adolescent Medicine, Copenhagen University Hospital RigshospitaletAbstract 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/NCT04307576https://doi.org/10.1186/s12885-022-09522-3Acute lymphoblastic leukemiaMaintenanceThiopurines6-mercaptopurineMethotrexate6-thioguanine |
| spellingShingle | Linea Natalie Toksvang Bodil Als-Nielsen Christopher Bacon Ruta Bertasiute Ximo Duarte Gabriele Escherich Elín Anna Helgadottir Inga Rinvoll Johannsdottir Ólafur G. Jónsson Piotr Kozlowski Cecilia Langenskjöld Kristi Lepik Riitta Niinimäki Ulrik Malthe Overgaard Mari Punab Riikka Räty Heidi Segers Inge van der Sluis Owen Patrick Smith Marion Strullu Goda Vaitkevičienė Hilde Skuterud Wik Mats Heyman Kjeld Schmiegelow 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 BMC Cancer Acute lymphoblastic leukemia Maintenance Thiopurines 6-mercaptopurine Methotrexate 6-thioguanine |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Acute lymphoblastic leukemia Maintenance Thiopurines 6-mercaptopurine Methotrexate 6-thioguanine |
| url | https://doi.org/10.1186/s12885-022-09522-3 |
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