TY - JOUR
T1 - Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL
T2 - A Multinational, Randomized, Noninferiority Phase III Study
AU - Peters, Christina
AU - Dalle, Jean-Hugues
AU - Locatelli, Franco
AU - Poetschger, Ulrike
AU - Sedlacek, Petr
AU - Buechner, Jochen
AU - Shaw, Peter J
AU - Staciuk, Raquel
AU - Ifversen, Marianne
AU - Pichler, Herbert
AU - Vettenranta, Kim
AU - Svec, Peter
AU - Aleinikova, Olga
AU - Stein, Jerry
AU - Güngör, Tayfun
AU - Toporski, Jacek
AU - Truong, Tony H
AU - Diaz-de-Heredia, Cristina
AU - Bierings, Marc
AU - Ariffin, Hany
AU - Essa, Mohammed
AU - Burkhardt, Birgit
AU - Schultz, Kirk
AU - Meisel, Roland
AU - Lankester, Arjan
AU - Ansari, Marc
AU - Schrappe, Martin
AU - von Stackelberg, Arend
AU - Balduzzi, Adriana
AU - Corbacioglu, Selim
AU - Bader, Peter
AU - IBFM Study Group;
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - Adolescent
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Busulfan/administration & dosage
KW - Chemoradiotherapy/mortality
KW - Child
KW - Child, Preschool
KW - Equivalence Trials as Topic
KW - Etoposide/administration & dosage
KW - Female
KW - Follow-Up Studies
KW - Humans
KW - International Agencies
KW - Male
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
KW - Prognosis
KW - Survival Rate
KW - Thiotepa/administration & dosage
KW - Vidarabine/administration & dosage
KW - Whole-Body Irradiation/mortality
UR - http://www.scopus.com/inward/record.url?scp=85101058557&partnerID=8YFLogxK
U2 - 10.1200/JCO.20.02529
DO - 10.1200/JCO.20.02529
M3 - Journal article
C2 - 33332189
SN - 0732-183X
VL - 39
SP - 295
EP - 307
JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
IS - 4
ER -