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Eliminating total body irradiation (TBI) from conditioning regimens yielded efficacy outcomes comparable with established benchmarks for pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL), according to results from the phase 2 EndRAD trial (NCT03509961). The findings, presented at the 2025 ASH Annual Meeting and Exposition showed that TBI-free conditioning maintained disease control without compromising treatment response.

The 2-year event-free survival (EFS) rate in the treatment arm 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%). These results showed that the primary end point of the trial of EFS was met.

“Based upon this data, pediatric and young adult patients who are bone marrow next-generation sequencing (NGS)-minimal residual disease (MRD)-negative may consider non-TBI approaches as they choose therapy,” Hisham Abdel-Azim, MD, chief of Transplant and Cellular Therapy at Loma Linda University Health, said during the presentation.

A total of 202 patients were enrolled in the trial. The treatment arm (n = 51) was designed to estimate survival after non-TBI myeloablative conditioning prior to allogeneic hematopoietic cell transplant (HCT) for NGS-MRD-negative B-ALL. A total of 86% of patients were given busulfan, fludarabine, and thiopeta. Other comparable therapies included fludarabine, melphalan, and thiopeta (6%), and fludarabine, melphalan, clofarabine, and thiopeta (6%). In the observational arm (n = 151), patients were given myeloablative HCT and were not eligible for the treatment arm.

Abdel-Azim stated he and his colleagues hypothesized that the 2-year EFS and OS rates in patients who are NGS MRD negative and receiving a non-TBI-based regimen would be around 75% and 80%, respectively. The study was conducted in 45 centers in North America between 2018 and 2025.

Infants were not allowed in the treatment arm, and young children who were not eligible and received non-TBI treatment were included in the observational arm. Additionally, the observational arm included those who were flow-negative but NGS-positive who received TBI.

In the treatment arm, patients were eligible for treatment if they were between 1 and 31 years old and had high-risk complete remission 1 (CR1) or CR2 status. Receipt of prior CAR T-cell therapy and blinatumomab (Blincyto) was allowed. Patients were excluded from the treatment arm but were eligible to enroll on the observational arm if they were less than 1 year old, CR2 with a history of central nervous system relapse, had T-cell ALL and mixed-phenotype acute leukemia, and had active CNS/extramedullary disease at HCT.

In the treatment arm, the median age was 13.5 years (range, 2.3-30.5), and 51% of patients were male. Additionally, 37% had HLA-matched sibling donors, 35% had mismatched/unrelated haploidentical donors, 20% had matched unrelated donors, and 8% had unrelated cord blood donors. Bone marrow graft was given in 71% of patients, peripheral blood stem cell graft was given to 21% of patients, and 8% received an unrelated cord blood graft. Additionally, at HCT, 49% of patients had CR1 and 51% had CR2.

“OS and EFS in our phase 2 non-TBI treatment arm for NGS MRD-negative B-ALL matched our hypothesis and were comparable with outcomes of patients who are MRD-negative receiving TBI in previous studies,” Abdel-Azim concluded.

Abdel-Azim disclosures: Kite, consultancy; Novartis, consultancy; Adaptive, consultancy and research funding; Vertex, consultancy; and Johnson and Johnson, consultancy.

Reference

Abdel-Azim H, Quigg T, Kapoor N, et al. High event-free (EFS) and overall survival (OS) after non-total body irradiation (TBI) conditioning and allogeneic hematopoietic cell transplantation (HCT) in next-generation-sequencing minimal residual disease (NGS-MRD) negative B-acute lymphoblastic leukemia (B-ALL): Results from the EndRAD trial (PTCTC ONC1701). Blood. 2025;146(suppl 1):163. doi:10.1182/blood-2025-163

Measurable residual disease (MRD) following induction chemotherapy may robustly predict overall survival (OS) among patients with acute myeloid leukemia (AML), according to findings from a pooled analysis study presented in a press briefing at the 2025 American Society of Hematology Annual Meeting & Exposition (ASH).

Pooled data on 1858 patients undergoing treatment across 7 randomized trials showed that the achievement of MRD negativity correlated with a risk of death that was twice as low vs patients who had MRD-positive status (P <.0001). This association between MRD and OS occurred regardless of age, genetics, and treatment arm; outcomes were consistent across trials and the use of multiparameter flow cytometry (MFC) or qPCR for NPM1 in the evaluation of MRD. Overall, the data showed a strong patient-level link between survival and MRD status.

Across the evaluable trials, MRD responses showed a strong correlation with OS benefit (R² = 0.91; 95% CI, 0.56-1.00). As far as trial-level surrogacy was concerned, presenting author Jesse Tettero, MD, PhD, noted that the confidence interval for this finding fell below what is typically used in the FDA framework.

“The lower bound of the confidence interval was 0.56. The FDA requires the lower bound to be above 0.60, so there is some caution to be noted when interpreting these data,” Tettero, a postdoctoral associate at Fralin Biomedical Research Institute (FBRI) Cancer Research Center in Washington, DC, and a visiting hematology fellow at Amsterdam University Medical Center in the Netherlands, said in the presentation.

However, findings showed an even stronger relationship between MRD responses and survival among patients who did not undergo a transplant (R² = 0.99; 95% CI, 0.94-1.00). Tettero described how such agreement was rare for oncologic end points.

“We could identify effective therapies [with MRD] earlier than OS; that could be a benefit of 4 to 5 years. It therefore enables potential accelerated approval…only if the FDA truly regards MRD as a surrogate end point,” Tettero said. “When supported, it could lead to smarter and faster trials for [patients with] AML.”

Despite the advent of new treatment modalities such as FLT3 and IDH inhibitors, Tettero stated that AML remains a difficult-to-cure disease, as most patients will relapse following treatment. Additionally, he noted how the longer follow-up associated with OS end points in clinical trials may delay progress for therapeutic advances. Given that MRD is already used as a surrogate marker for approval in other blood cancers like acute lymphoblastic leukemia and multiple myeloma, Tettero and colleagues aimed to determine whether MRD could represent an earlier predictor of survival in AML.

As part of the largest collaboration to evaluate MRD as a surrogate end point in AML, investigators collected patient-level data from 7 randomized trials. These studies included 4 from European cooperative groups: the German-Austrian AML Study Group (AMLSG), the Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK), Study Alliance Leukemia (SAL), and the UK National Cancer Research Institute (UK-NCRI). The study compared MRD status with long-term OS based on FDA expectations.

Eligible studies were those that randomly assigned patients to experimental or placebo treatments in combination with standard intensive induction chemotherapy, with at least 20 patients on each arm and the inclusion of MRD subgroups.

Regarding study limitations, Tettero stated that the analysis only related to trials assessing intensive therapy in the EU, as less intensive regimens such as venetoclax (Venclexta) plus hypomethylating agents (VEN-HMA) were not represented, and the confidence intervals for trial-led surrogacy were wide, as the lower bound was below the 0.6 threshold typically used in regulatory framework. Additionally, the study did not fully standardize the use of MRD assays across clinical trials, which may have correlated with data heterogeneity. According to Tettero, several relevant MRD datasets were also inaccessible for the analysis.

Looking towards the future, Tettero and colleagues aim to expand analyses that account for modern, non-intensive treatment backbones and regimens like VEN-HMA and FLT3 or IDH inhibitors. The investigators also look to achieve global harmonization of MRD testing across these treatment modalities while promoting data sharing on an international level to expand the number of eligible trials.

Disclosures: Tettero had no relevant relationships to disclose.

Reference

Tettero J, Eric S, Freeman S, et al. Validation of measurable residual disease as a surrogate endpoint in acute myeloid leukemia: a HARMONY Alliance study of European randomized trials. Blood. 2025;146(supplement 1):343. doi:10.1182/blood-2025-343