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

Peters C 1 , Dalle JH 2 , Locatelli F 3 , Poetschger U 4 , Sedlacek P 5 , Buechner J 6 Show all authors , Shaw PJ 7 , Staciuk R 8 , Ifversen M 9 , Pichler H 1 , Vettenranta K 10 , Svec P 11 , Aleinikova O 12 , Stein J 13 , Güngör T 14 , Toporski J 15 , Truong TH 16 , Diaz-de-Heredia C 17 , Bierings M 18 , Ariffin H 19 , Essa M 20 , Burkhardt B 21 , Schultz K 22 , Meisel R 23 , Lankester A 24 , Ansari M 25 , Schrappe M 26 , IBFM Study Group; , von Stackelberg A 27 , IntReALL Study Group , Balduzzi A 28 , I-BFM SCT Study Group , Corbacioglu S 29 , EBMT Paediatric Diseases Working Party , Bader P 30

Affiliations 

  • 1 St. Anna Children's Hospital, Children's Cancer Research Institute, University Vienna, Vienna, Austria
  • 2 Hôpital Robert Debré, GH APHP-Nord Université de Paris, Paris, France
  • 3 Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Sapienza University of Rome, Rome, Italy
  • 4 Children's Cancer Research Institute, Vienna, Austria
  • 5 Department of Pediatric Hematology and Oncology, Motol University Hospital, Prague, Czech Republic
  • 6 Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway
  • 7 The Children`s Hospital at Westmead, Sydney, Australia
  • 8 Hospital de Pediatría, Buenos Aires, Argentina
  • 9 Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
  • 10 Children's Hospital, University of Helsinki, Helsinki, Finland
  • 11 National Institute of Children's Diseases, Bratislava, Slovakia
  • 12 Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Borovlyani, Belarus
  • 13 Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Petach-Tikva, Israel
  • 14 Universitäts-Kinderspital, Zurich, Switzerland
  • 15 Skåne University Hospital, Lund, Sweden
  • 16 Alberta Children's Hospital Calgary, Calgary, Alberta, Canada
  • 17 Hospital Universitari Vall d'Hebron, Barcelona, Spain
  • 18 Princess Máxima Center for Pediatric Oncology, Bilthoven, the Netherlands
  • 19 University of Malaya, Kuala Lumpur, Malaysia
  • 20 King Abdullah Specialist Children's Hospital, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
  • 21 Children's University Hospital Münster, Münster, Germany
  • 22 University of British Columbia, Vancouver, British Columbia, Canada
  • 23 Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany
  • 24 Willem-Alexander Children's Hospital, Leiden, the Netherlands
  • 25 Geneva University Hospital, Geneva, Switzerland
  • 26 Universitätsklinikum Schleswig-Holstein, Kiel, Germany
  • 27 Charité University Hospital Berlin, Berlin, Germany
  • 28 Università degli Studi di Milano-Fondazione MBBM, Monza, Italy
  • 29 Universitätsklinikum Regensburg, Regensburg, Germany
  • 30 Goethe University, University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Frankfurt am Main, Germany
J Clin Oncol, 2021 02 01;39(4):295-307.
PMID: 33332189 DOI: 10.1200/JCO.20.02529

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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