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

Christina Peters, Jean-Hugues Dalle, Franco Locatelli, Ulrike Poetschger, Petr Sedlacek, Jochen Buechner, Peter J Shaw, Raquel Staciuk, Marianne Ifversen, Herbert Pichler, Kim Vettenranta, Peter Svec, Olga Aleinikova, Jerry Stein, Tayfun Güngör, Jacek Toporski, Tony H Truong, Cristina Diaz-de-Heredia, Marc Bierings, Hany AriffinMohammed Essa, Birgit Burkhardt, Kirk Schultz, Roland Meisel, Arjan Lankester, Marc Ansari, Martin Schrappe, Arend von Stackelberg, Adriana Balduzzi, Selim Corbacioglu, Peter Bader, IBFM Study Group;

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.

OriginalsprogEngelsk
TidsskriftJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol/bind39
Udgave nummer4
Sider (fra-til)295-307
Antal sider13
ISSN0732-183X
DOI
StatusUdgivet - 1 feb. 2021

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