Two-year event-free survival rates were above 75% for children, adolescent, and young adult patients with B-cell acute lymphocytic leukemia (B-ALL) who had negative measurable residual disease (MRD) by next-generation sequencing prior to hematopoietic cell transplantation and who received a non–total body irradiation conditioning regimen and allogeneic transplantation, according to findings from the EndRAD trial (PTCTC ONC1701). These rates were comparable to those achieved with total body irradiation–based conditioning regimens, reported investigators at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 163).
“We used [MRD by next-generation sequencing]—a very sensitive method to identify any residual leukemia cells in the patient—to categorize patients who are at very low risk for relapse and pilot the use of non–total body irradiation–based conditioning vs the standard total body irradiation conditioning,” said lead study author Hisham Abdel-Azim, MD, MS, Division Chief for Transplant/Cell Therapy and Hematological Malignancies and Professor of Pediatrics, Medicine, and Basic Sciences at Loma Linda University School of Medicine in California. “Using our approach, we were able to save a significant portion of patients who were MRD-negative before transplant from having to receive total body irradiation without compromising their outcome.”
The study authors noted in their abstract that the results indicate that MRD by next-generation sequencing can be used to determine the choice of myeloablative conditioning regimen in young patients with B-ALL undergoing allogeneic hematopoietic cell transplantation.
Background and Study Methods
Total body irradiation has typically been included as a part of conditioning for hematopoietic cell transplantation for children, adolescent, and young adult patients with high-risk or relapsed B-ALL, as it has been shown to lead to superior outcomes to conditioning without total body irradiation; however, total body irradiation conditioning is associated with significant late adverse effects.
Researchers hypothesized that using a non–total body irradiation regimen in patients with high-risk/relapsed B-ALL who have negative MRD by next-generation sequencing of IgH B-cell receptor arrangements (prior to transplantation) could lead to 2-year event-free survival rates comparable with a total body irradiation–based regimen.
Investigators from the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) conducted the phase II prospective EndRAD trial across 45 centers in North America to explore outcomes of myeloablative non–total body irradiation conditioning regimens for allogeneic hematopoietic cell transplantation in patients with B-ALL at lower risk for relapse, as defined by the absence of IgH B-cell receptor arrangements (Clonoseq) prior to transplantation. The study was conducted between 2018 and 2025.
Patient Population
Eligible patients (n = 51) with B-ALL were between the ages of 1 and 31 years old, in first or second complete remission, and had no isolated or combined central nervous system disease at relapse; all underwent hematopoietic cell transplantation. Prior treatment with blinatumomab, inotuzumab ozogamicin, or chimeric antigen receptor (CAR) T-cell therapy treatments were allowed. All sources of grafts were allowed as well, and prophylaxis for graft-vs-host disease was given according to the graft source and institutional standards. All patients received myeloablative non–total body irradiation conditioning treatment prior to transplantation.
Fifty-one percent of patients were male and in second complete remission. The median age at the time of transplantation was 13.5 years. Thirty-seven percent of patients were Hispanic, 33% were White, 12% were Black or African American, and 18% were another race. Fifty-five percent of patients had previously received blinatumomab, 2% had received inotuzumab, 21% had received CAR T-cell therapy, 14% had received two prior immunotherapies, and 8% had not received any prior immunotherapies.
Eighty-six percent of patients received the non–total body irradiation conditioning regimen of busulfan, fludarabine, and thiotepa that was chosen by the study of. Two comparable regimens were also allowed: fludarabine, melphalan, and thiotepa (received by 6%) or melphalan, fludarabine, clofarabine, and thiotepa (received by 8%). Donors included human leukocyte antigen–matched siblings for 41% of patients, mismatched related/haploidentical donors for 33%, matched unrelated for 18%, or unrelated cord blood donors for 8%. Related and unrelated donor graft sources included bone marrow for 71% of patients and peripheral blood stem cells for 21%. Transplant-related mortality within the first 100 days of transplantation occurred in 2% of patients.
Key Findings
Patients were followed for a median of 2.3 years (range = 0.2–6.0 years). The 2-year event-free survival rate was 76.3% (95% confidence interval [CI] = 61.1%–86.1%) and the 2-year overall survival rate was 82% (95% CI = 67.1%–90.6%).
Five patients who had negative MRD prior to transplantation had detectable T-cell receptor sequences, but all five were still alive and relapse free at the time of the analysis.
The nonrelapse mortality rate was 12%, for a range of 0.1 to 2.9 years from the time of transplantation; this occurred mostly in children aged 14 years or older.
Six children experienced relapse, and four of these underwent hematopoietic cell transplantation in second complete remission. Four of the six relapses occurred after matched sibling donor transplantation.
Acute graft-vs-host disease occurred in 39% of patients, with 25% being grade 3 or 4; chronic graft-vs-host disease occurred in 25% of patients, with 85% of these patients requiring systemic immunosuppressive treatment.
“This study really sets a new standard of care for those patients,” said Dr. Abdel-Azim. “Using this guided approach, patients who are NGS-MRD negative prior to transplant could be getting [non–total body irradiation] based conditioning.”
Disclosure: The study was funded by the Gateway for Cancer Research. Dr. Abdel-Azim reported a consultancy, including expert testimony, relationship with Kite, Novartis, Adaptive, Vertex, and J&J as well as research funding from Adaptive. For full disclosures of the study authors, visit hematology.org.
