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Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study

C. Peters, JH. Dalle, F. Locatelli, U. Poetschger, P. Sedlacek, J. Buechner, PJ. Shaw, R. Staciuk, M. Ifversen, H. Pichler, K. Vettenranta, P. Svec, O. Aleinikova, J. Stein, T. Güngör, J. Toporski, TH. Truong, C. Diaz-de-Heredia, M. Bierings, H....

. 2021 ; 39 (4) : 295-307. [pub] 20201217

Language English Country United States

Document type Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21026126

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 IRCCS Ospedale Pediatrico Bambino Gesù Sapienza University of Rome Rome Italy

Department of Pediatric Hematology and Oncology Motol University Hospital Prague Czech Republic

Department of Pediatric Hematology and Oncology Oslo University Hospital Oslo Norway

Division of Pediatric Stem Cell Therapy Department of Pediatric Oncology Hematology and Clinical Immunology Medical Faculty Heinrich Heine University Duesseldorf Germany

Geneva University Hospital Geneva Switzerland

Goethe University University Hospital Frankfurt Department for Children and Adolescents Division for Stem Cell Transplantation Immunology and Intensive Care Medicine Frankfurt am Main Germany

Hôpital Robert Debré GH APHP Nord Université de Paris Paris France

Hospital de Pediatría Buenos Aires Argentina

Hospital Universitari Vall d'Hebron Barcelona Spain

King Abdullah Specialist Children's Hospital King Abdullah International Medical Research Center King Saud Bin Abdulaziz University for Health Sciences Riyadh Saudi Arabia

National Institute of Children's Diseases Bratislava Slovakia

Princess Máxima Center for Pediatric Oncology Bilthoven the Netherlands

Schneider Children's Medical Center of Israel Sackler Faculty of Medicine Tel Aviv University Petach Tikva Israel

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

University of Malaya Kuala Lumpur Malaysia

Willem Alexander Children's Hospital Leiden the Netherlands

References provided by Crossref.org

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