Total body irradiation regimen superior to chemotherapy conditioning in pediatric ALL
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Total body irradiation plus etoposide improved OS and appeared to reduce risk for relapse among children with high-risk acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant, study results showed.
Researchers observed the benefit compared with chemotherapy conditioning among this patient population, according to the results, published in Journal of Clinical Oncology.
“ALL, for most children, has become a curable disease with contemporary chemotherapy. However, patients with refractory or relapsed ALL need additional treatment options,” Christina Peters, MD, PhD, professor of pediatrics in the department of stem cell transplantation at St. Anna Children’s Hospital in Vienna, told Healio. “Allogeneic HSCT is the most commonly applied method in such a situation. Total body irradiation in combination with chemotherapy is widely used to eradicate both leukemic cells and host immunity.”
For the international, randomized, open-label, phase 3 FORUM study, Peters and colleagues assessed and compared the OS benefit of total body irradiation plus etoposide vs. chemotherapy conditioning among 413 children and young adults (65% male; 34% aged 6 years to 10 years) with high-risk ALL in complete remission prior to HSCT. Researchers randomly assigned 201 patients to a chemotherapy-based conditioning regimen that consisted of udarabine, thiotepa and either busulfan or treosulfan. The other 212 patients received fractionated 12 Gy total body irradiation with etoposide (n = 212).
Median follow-up was 2.1 years.
Results showed a 2-year OS probability of 0.91 (95% CI, 0.86-0.95) after total body irradiation compared with 0.75 (95% CI, 0.67-0.81) after chemotherapy conditioning (P < .0001).
Researchers also observed higher 2-year EFS with total body irradiation (0.86; 95% CI, 0.79-0.9 vs. 0.58; 95% CI, 0.5-0.66; P < .0001), as well as lower 2-year cumulative incidence of relapse (0.12; 95% CI, 0.08-0.17 vs. 0.33; 95% CI, 0.25-0.4; P < .0001) and 2-year treatment-related mortality (0.02; 95% CI, 0.01-0.05 vs. 0.09, 95% CI, 0.05-0.14; P = .0268).
The study was stopped early after a planned interim analysis revealed the inferiority of the chemotherapy conditioning regimen compared with the total body irradiation regimen.
“Although used for decades, pediatric transplanters have no clear scientific background on whether total body irradiation is necessary today. Thus, an international consortium asked the question of whether modern chemotherapy combinations could substitute total body irradiation and reduce especially late effects like gonadal dysfunctions, secondary malignancies and some organ toxicities,” Peters said. “We demonstrated with this largest-ever randomized trial that the combination of total body irradiation plus etoposide is significantly better than chemo-conditioning and recommend this combination as standard of care for all patients older than 4 years with an HLA-matched related or unrelated donor. Future research may investigate modifications in irradiation dose, targeted chemotherapy, posttransplant immunomodulation, bispecific antibodies and chimeric antigen receptor T cells.”
Although total body irradiation remains the preferred approach, the search continues for alternatives to radiation-containing conditioning regimens, according to an editorial accompanying the study by Michael A. Pulsipher, MD, head of the section of blood and marrow transplantation at the Cancer and Blood Disease Institute of Children’s Hospital in Los Angeles.
“The [study] shows that for now, total body irradiation-based regimens are the best way to cure patients requiring [HSCT],” Pulsipher wrote. “However, in our new world of CAR T cells and immunotherapies, surely we can find safer paths to success.”
References:
Peters C, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.02529.
Pulsipher MA, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03261.
For more information:
Christina Peters, MD, PhD, can be reached at St. Anna Children’s Hospital, Stem Cell Transplant Unit, Kinderspitalgasse 6, A-1090, Vienna, Austria; email: christina.peters@stanna.at.
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