Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu klinické zkoušky, fáze III, časopisecké články, multicentrická studie, randomizované kontrolované studie, práce podpořená grantem
PubMed
33332189
PubMed Central
PMC8078415
DOI
10.1200/jco.20.02529
Knihovny.cz E-zdroje
- MeSH
- akutní lymfatická leukemie patologie terapie MeSH
- busulfan aplikace a dávkování analogy a deriváty MeSH
- celotělové ozáření mortalita MeSH
- chemoradioterapie mortalita MeSH
- dítě MeSH
- etoposid aplikace a dávkování MeSH
- hodnocení ekvivalence jako téma MeSH
- lidé MeSH
- mezinárodní agentury MeSH
- míra přežití MeSH
- mladiství MeSH
- následné studie MeSH
- předškolní dítě MeSH
- prognóza MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- thiotepa aplikace a dávkování MeSH
- vidarabin aplikace a dávkování analogy a deriváty MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- busulfan MeSH
- etoposid MeSH
- fludarabine MeSH Prohlížeč
- thiotepa MeSH
- treosulfan MeSH Prohlížeč
- vidarabin MeSH
PURPOSE: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Alberta Children's Hospital Calgary Calgary Alberta Canada
Belarusian Research Center for Pediatric Oncology Hematology and Immunology Borovlyani Belarus
Charité University Hospital Berlin Berlin Germany
Children's Cancer Research Institute Vienna Austria
Children's Hospital University of Helsinki Helsinki Finland
Children's University Hospital Münster Münster Germany
Copenhagen University Hospital Rigshospitalet Copenhagen Denmark
Department of Pediatric Hematology and Oncology Motol University Hospital Prague Czech Republic
Department of Pediatric Hematology and Oncology Oslo University Hospital Oslo Norway
Geneva University Hospital Geneva Switzerland
Hôpital Robert Debré GH APHP Nord Université de Paris Paris France
Hospital de Pediatría Buenos Aires Argentina
Hospital Universitari Vall d'Hebron Barcelona Spain
National Institute of Children's Diseases Bratislava Slovakia
Princess Máxima Center for Pediatric Oncology Bilthoven the Netherlands
Skåne University Hospital Lund Sweden
St Anna Children's Hospital Children's Cancer Research Institute University Vienna Vienna Austria
The Children`s Hospital at Westmead Sydney Australia
Università degli Studi di Milano Fondazione MBBM Monza Italy
Universitäts Kinderspital Zurich Switzerland
Universitätsklinikum Regensburg Regensburg Germany
Universitätsklinikum Schleswig Holstein Kiel Germany
University of British Columbia Vancouver British Columbia Canada
Zobrazit více v PubMed
Friend BD Bailey-Olson M Melton A, et al. : The impact of total body irradiation-based regimens on outcomes in children and young adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation. Pediatr Blood Cancer 67:e28079, 2020 PubMed
Gao RW Dusenbery KE Cao Q, et al. : Augmenting total body irradiation with a cranial boost before stem cell transplantation protects against post-transplant central nervous system relapse in acute lymphoblastic leukemia. Biol Blood Marrow Transplant 24:501-506, 2018 PubMed PMC
Hill-Kayser CE Plastaras JP Tochner Z, et al. : TBI during BM and SCT: Review of the past, discussion of the present and consideration of future directions. Bone Marrow Transplant 46:475-484, 2011 PubMed
Balduzzi A Dalle JH Wachowiak J, et al. : Transplantation in children and adolescents with acute lymphoblastic leukemia from a matched donor versus an HLA-identical sibling: Is the outcome comparable? Results from the International BFM ALL SCT 2007 Study. Biol Blood Marrow Transplant 25:2197-2210, 2019 PubMed
Dopfer R Henze G Bender-Gotze C, et al. : Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: Results of the German Cooperative Study. Blood 78:2780-2784, 1991 PubMed
Ifversen M Turkiewicz D Marquart HV, et al. : Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience. Br J Haematol 184:982-993, 2019 PubMed
Peters C Schrappe M von Stackelberg A, et al. : Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol 33:1265-1274, 2015 PubMed
Dalle JH Balduzzi A Bader P, et al. : Allogeneic stem cell transplantation from HLA-mismatched donors for pediatric patients with acute lymphoblastic leukemia treated according to the 2003 BFM and 2007 International BFM Studies: Impact of disease risk on outcomes. Biol Blood Marrow Transplant 24:1848-1855, 2018 PubMed
Bunin N Aplenc R Kamani N, et al. : Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: A pediatric blood and marrow transplant consortium study. Bone Marrow Transplant 32:543-548, 2003 PubMed
Gupta T Kannan S Dantkale V, et al. : Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia: A systematic review and meta-analysis. Hematol Oncol Stem Cell Ther 4:17-29, 2011 PubMed
Baker KS Leisenring WM Goodman PJ, et al. : Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood 133:2790-2799, 2019 PubMed PMC
Lawitschka A, Peters C: Long-term effects of myeloablative allogeneic hematopoietic stem cell transplantation in pediatric patients with acute lymphoblastic leukemia. Curr Oncol Rep 20:74, 2018 PubMed
Saglio F Zecca M Pagliara D, et al. : Occurrence of long-term effects after hematopoietic stem cell transplantation in children affected by acute leukemia receiving either busulfan or total body irradiation: Results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study. Bone Marrow Transplant:55:1918-1927, 2020 PubMed
Ansari M Theoret Y Rezgui MA, et al. : Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation. Ther Drug Monit 36:93-99, 2014 PubMed
Boztug H Zecca M Sykora KW, et al. : Treosulfan-based conditioning regimens for allogeneic HSCT in children with acute lymphoblastic leukaemia. Ann Hematol 94:297-306, 2015 PubMed
Harris AC Boelens JJ Ahn KW, et al. : Comparison of pediatric allogeneic transplant outcomes using myeloablative busulfan with cyclophosphamide or fludarabine. Blood Adv 2:1198-1206, 2018 PubMed PMC
Lee JW Kang HJ Kim S, et al. : Favorable outcome of hematopoietic stem cell transplantation using a targeted once-daily intravenous busulfan-fludarabine-etoposide regimen in pediatric and infant acute lymphoblastic leukemia patients. Biol Blood Marrow Transplant 21:190-195, 2015 PubMed
Kato M Ishida H Koh K, et al. : Comparison of chemotherapeutic agents as a myeloablative conditioning with total body irradiation for pediatric acute lymphoblastic leukemia: A study from the pediatric ALL working group of the Japan Society for Hematopoietic Cell Transplantation. Pediatr Blood Cancer 62:1844-1850, 2015 PubMed
Zecca M Pession A Messina C, et al. : Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings. J Clin Oncol 17:1838-1846, 1999 PubMed
Glucksberg H Storb R Fefer A, et al. : Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18:295-304, 1974 PubMed
Kebriaei P Bassett R Lyons G, et al. : Clofarabine plus busulfan is an effective conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia: Long-term study results. Biol Blood Marrow Transplant 23:285-292, 2017 PubMed PMC
Willasch AM Peters C Sedlacek P, et al. : Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy? A multicenter EBMT-PDWP study. Bone Marrow Transplant 55:1540-1551, 2020 PubMed PMC
Bhatia S, Armenian SH, Landier W: How I monitor long-term and late effects after blood or marrow transplantation. Blood 130:1302-1314, 2017 PubMed
Shah NN Borowitz MJ Steinberg SM, et al. : Factors predictive of relapse of acute leukemia in children after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 20:1033-1039, 2014 PubMed PMC
Burke MJ Verneris MR Le Rademacher J, et al. : Transplant outcomes for children with T cell acute lymphoblastic leukemia in second remission: A report from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 21:2154-2159, 2015 PubMed PMC
Hamidieh AA Monzavi SM Kaboutari M, et al. : Outcome Analysis of pediatric patients with acute lymphoblastic leukemia treated with total body irradiation-free allogeneic hematopoietic stem cell transplantation: Comparison of patients with and without central nervous system involvement. Biol Blood Marrow Transplant 23:2110-2117, 2017 PubMed
Kalwak K Mielcarek M Patrick K, et al. : Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies. Bone Marrow Transplant 55:1996–2007, 2020 PubMed PMC
Page KM Labopin M Ruggeri A, et al. : Factors associated with long-term risk of relapse after unrelated cord blood transplantation in children with acute lymphoblastic leukemia in remission. Biol Blood Marrow Transplant 23:1350-1358, 2017 PubMed PMC
Mehta PA Zhang MJ Eapen M, et al. : Transplantation outcomes for children with hypodiploid acute lymphoblastic leukemia. Biol Blood Marrow Transplant 21:1273-1277, 2015 PubMed PMC
Yanir AD Martinez CA Sasa G, et al. : Current allogeneic hematopoietic stem cell transplantation for pediatric acute lymphocytic leukemia: Success, failure and future perspectives-a single-center experience, 2008 to 2016. Biol Blood Marrow Transplant 24:1424-1431, 2018 PubMed
Locatelli F, Moretta F, Rutella S: Management of relapsed acute lymphoblastic leukemia in childhood with conventional and innovative approaches. Curr Opin Oncol 25:707-715, 2013 PubMed
McNeer JL Devidas M Dai Y, et al. : Hematopoietic stem-cell transplantation does not improve the poor outcome of children with hypodiploid acute lymphoblastic leukemia: A report from Children's Oncology Group. J Clin Oncol 37:780-789, 2019 PubMed PMC
Schultz KR Bowman WP Aledo A, et al. : Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: A children's oncology group study. J Clin Oncol 27:5175-5181, 2009 PubMed PMC
Bader P Salzmann-Manrique E Balduzzi A, et al. : More precisely defining risk peri-HCT in pediatric ALL: Pre- vs post-MRD measures, serial positivity, and risk modeling. Blood Adv 3:3393-3405, 2019 PubMed PMC
Eckert C Henze G Seeger K, et al. : Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol 31:2736-2742, 2013 PubMed
Pulsipher MA Langholz B Wall DA, et al. : The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: A phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood 123:2017-2025, 2014 PubMed PMC
Bernard F Auquier P Herrmann I, et al. : Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: An LEA study. Bone Marrow Transplant 49:709-716, 2014 PubMed
Bresters D Emons JA Nuri N, et al. : Ovarian insufficiency and pubertal development after hematopoietic stem cell transplantation in childhood. Pediatr Blood Cancer 61:2048-2053, 2014 PubMed
Faraci M Diesch T Labopin M, et al. : Gonadal function after busulfan compared with treosulfan in children and adolescents undergoing allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant 25:1786-1791, 2019 PubMed
