Total body irradiation (TBI)-based conditioning has historically been the standard approach prior to allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL), supported by randomized data demonstrating superior survival outcomes, particularly in minimal residual disease (MRD)-negative patients.¹ However, TBI is associated with substantial late morbidity, including metabolic, endocrine, growth-related, and secondary malignancy risks, with greater long-term impact in younger patients.¹ At the ASH Annual Meeting 2025, Dr. Hisham Abdel-Azim from Loma Linda University School of Medicine, Cancer Center, Children’s Hospital and Medical Center in the United States, presented results from the EndRAD trial, evaluating outcomes with non-TBI-based myeloablative conditioning in NGS-MRD-negative B-cell ALL (B-ALL) undergoing allogeneic HCT.¹

Next-generation sequencing (NGS)-based MRD assessment offers substantially greater sensitivity than conventional flow cytometry, with reported detection thresholds of 10^-6 to 10^-7 and utility in the majority of patients.¹ Prior comparative analyses also demonstrated superior discrimination for relapse and survival risk using NGS-MRD.¹ Based on favorable outcomes observed in NGS-MRD-negative patients treated with TBI, the EndRAD study was designed to assess whether omission of TBI in this molecularly defined population could maintain favorable survival outcomes without compromising efficacy.¹

EndRAD is an investigator-initiated, phase 2, multicenter, prospective trial conducted across 45 centers in North America between 2018 and 2025.¹ A total of 202 patients were enrolled, including a treatment arm (n=51) and an observational arm (n=151).¹ The treatment arm included NGS-MRD-negative patients in first or second complete remission (CR1/CR2) receiving non-TBI myeloablative conditioning prior to allogeneic HCT.¹ The recommended conditioning regimen was busulfan/fludarabine/thiotepa (86%), with additional comparable regimens permitted.¹ The observational arm comprised patients who were not eligible for or did not consent to the treatment arm and received conditioning per institutional standard of care, including both TBI- and non-TBI-based approaches.¹

Patients in the treatment arm had a median age of 13.5 years (range: 2.3-30.5), with 51% male.¹ Donor sources included HLA-matched sibling (37%), mismatched related or haploidentical (35%), matched unrelated (20%), and unrelated cord blood (8%), with bone marrow used in 71% of transplants.¹ Complete remission status at HCT was evenly split between CR1 (49%) and CR2 (51%).¹

In the treatment arm, the 2-year event-free survival (EFS) rate was 76.3% (95% CI: 61.1-86.1), and the 2-year overall survival (OS) rate was 82.0% (95% CI: 67.1-90.6).¹ Analyses evaluating the effect of age demonstrated that patients older than 10 years at the time of HCT had a lower risk of relapse compared with younger patients (HR=0.10; 95% CI: 0.01-0.50; p=0.001).¹ A similar association was observed for age older than 10 years at diagnosis (HR=0.10; 95% CI: 0.01-0.94; p=0.011).¹ Molecular risk group was not statistically significant in these analyses.¹

In the combined study population, comparisons by TBI exposure showed no statistically significant differences in EFS (p=0.511) or OS (p=0.603).¹ Analyses by pre-HCT NGS-MRD status in bone marrow demonstrated a trend toward separation for EFS (p=0.067) and a statistically significant difference for OS (p=0.005).¹

Landmark analyses assessing post-HCT NGS-MRD status at day 100 demonstrated strong associations with relapse-free survival and non-relapse mortality.¹ Positive NGS-MRD in the bone marrow (HR=7.4; 95% CI: 2.68-20.34; p<0.001) and peripheral blood (HR=9.8; 95% CI: 3.65-26.14; p<0.001) was associated with increased risk of relapse.¹ Patients with concurrent NGS-MRD positivity in both blood and bone marrow exhibited the highest risk (HR=18.9; 95% CI: 5.24-67.97), with similar patterns observed for time to non-relapse mortality.¹

In conclusion, outcomes observed in the EndRAD treatment arm were comparable to published registry data and to results from MRD-negative patients receiving TBI-based conditioning.¹ The 2-year EFS and OS achieved with non-TBI conditioning aligned with the study hypothesis and compared favorably with non-TBI outcomes reported in the FORUM trial.¹ These findings suggest that pediatric and young adult patients with B-ALL who are bone marrow NGS-MRD negative prior to HCT may be candidates for non-TBI conditioning approaches, while post-HCT NGS-MRD status remains strongly associated with outcomes, especially if both bone marrow and peripheral blood NGS were positive.¹