Total-Body Irradiation/Etoposide vs Chemotherapy Conditioning Before Stem Cell Transplant for Pediatric Patients With ALL

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As reported in the Journal of Clinical Oncology by Peters et al, the phase III FORUM trial showed superior overall survival with total-body irradiation plus etoposide vs combination chemoconditioning in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation.

As stated by the investigators, “Total-body irradiation before allogeneic hematopoietic stem cell transplantation in pediatric patients with ALL is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace total-body irradiation in such patients.”

Study Details

In the open-label noninferiority trial, 417 patients from sites in 21 countries were randomly assigned between April 2013 and December 2018 to receive total-body irradiation (n = 212) or chemoconditioning (n = 201). Patients were aged ≤ 18 years at diagnosis and aged 4–21 years at hematopoietic stem cell transplantation; had incomplete remission pre–hematopoietic stem cell transplantation; and had a human leukocyte antigen–compatible related or unrelated donor. The total-body irradiation group received 12 Gy in six fractions over 3 days plus etoposide at 60 mg/kg once on day 3 before hematopoietic stem cell transplantation. The chemoconditioning group received fludarabine at 30 mg/m2 once daily over 5 days, thiotepa at 5 mg/kg twice daily for 1 day, and either treosulfan at 14 g/m2 once a day for 3 days or busulfan over 4 days. The primary endpoint was overall survival in the intention-to-treat population, with a noninferiority margin for chemoconditioning vs total body irradiation of 8%. The protocol specified a futility stopping rule that would stop random assignment if chemoconditioning was significantly inferior to total body irradiation.

Overall Survival


  • Total body irradiation plus etoposide was associated with significantly better overall survival vs combination chemoconditioning.
  • Overall survival at 2 years was 91% vs 75%.

The futility stopping rule was applied in March 2019. Median follow-up was 2.1 years. Probability of survival at 2 years was 91% in the total-body irradiation group vs 75% in the chemoconditioning group (P < .0001). The probability of event-free survival at 2 years was 86% vs 58% (P < .0001). At 2 years, the cumulative incidence of relapse was 12% vs 33% (P < .0001) and the cumulative incidence of treatment-related mortality was 2% vs 9% (P = .0269).

In the modified as-treated population, 2-year overall survival was 91% among 194 patients in the total-body irradiation group vs 77% among 96 patients who received busulfan in the chemoconditioning group (P = .0009) and 77% among 90 patients who received treosulfan (P = .0041).

Adverse Events

No significant differences were observed between the total-body irradiation vs chemoconditioning groups in grade 3 or 4 acute graft-vs-host disease (12% vs 9%, P = .339) or 2-year cumulative incidence of any-grade chronic graft-vs-host disease (16% vs 11%, P = .146).

As stated by the investigators, “There were no suspected unexpected serious adverse reactions. Regimens were associated with substantial degrees of reported toxicity, as expected.”

The most common grade 3 or 4 adverse events at day 100 in both groups were cytopenia, mucositis, nausea, and infection.

The investigators concluded: “Improved overall survival and lower relapse risk were observed following total-body irradiation plus etoposide compared with chemoconditioning. We therefore recommend total-body irradiation plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic hematopoietic stem cell transplantation.”

Christina Peters, MD, of St. Anna Children's Hospital, Children's Cancer Research Institute, University Vienna, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Amgen, Jazz Pharmaceuticals, Neovii, Medac, Riemser, and Children’s Cancer Research Institute (Austria). For full disclosures of the study authors, visit

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