Historically, myeloablative conditioning prior to allogeneic hematopoietic cell transplantation (HCT) for patients with acute leukemia routinely included high-dose total body irradiation (TBI) with or without chemotherapy. Studies over time failed to demonstrate additional benefit of myeloablative TBI relative to non-TBI myeloablative chemotherapy for many adults with acute myeloid leukemia.1-3 Conversely, a paucity of rigorous randomized studies — and the notion that TBI was necessary in lymphoid malignancies to optimally address extramedullary disease and sanctuary sites — has encouraged the general practice of high-dose TBI-based conditioning for patients with acute lymphoblastic leukemia (ALL) undergoing HCT.4 Myeloablative doses of TBI technically include >5 Gy (non-fractionated) or >8 Gy (fractionated); however, in the modern era of HCT, myeloablative TBI is typically administered as fractionated doses of 12 to 16 Gy combined with cytotoxic or lymphodepleting chemotherapy.5 Relative to chemotherapy, several studies have shown that high-dose TBI is associated with more frequent short- and long-term adverse effects following HCT, including pulmonary, endocrine, and ocular complications,6,7 and an increased risk of secondary malignancies.8,9 Efforts to minimize these toxicities through the omission of TBI for patients with ALL have been explored, although results are limited to retrospective comparisons and have drawn varying conclusions.10-14 Thus, the question remains: Do patients with ALL undergoing myeloablative HCT require TBI-based conditioning?
To address this gap, Zhang and colleagues conducted a randomized, phase III, noninferiority study of 550 adolescents and adults (aged 14-65 years) with cytogenetically standard-risk B-ALL undergoing human leukocyte antigen (HLA)-matched HCT in first complete remission (CR1) across 13 hospitals in China.15 Patients were randomly assigned 1:1 to receive a TBI/cyclophosphamide (TBI/Cy) regimen (TBI 9 Gy delivered as 2 daily doses of 4.5 Gy and cyclophosphamide 60 mg/kg on days -3 and -2) or a non-TBI regimen of intravenous busulfan/Cy (Bu/Cy; busulfan 0.8 mg/kg 4 times per day on days -7 to -4 and cyclophosphamide 60 mg/kg on days -3 and -2). The study was powered for a 10% noninferiority margin based on an estimated two-year overall survival (OS) of 70% following TBI/Cy. With a median follow-up of 42 months, the study met its primary endpoint: Two-year OS was noninferior following Bu/Cy conditioning (76.6%; 95% CI, 71.7-81.8) relative to TBI/Cy conditioning (79.4%; 95% CI, 74.7-84.4; p = 0.457). Additionally, there were no differences in disease-free survival, relapse, nonrelapse mortality, regimen-related toxicities, or the development of graft-versus-host disease in patients treated with TBI/Cy and Bu/Cy. Exploratory post-hoc analyses did not reveal any patient subgroups with greater benefit from TBI/Cy.
In Brief
So, has this well-done clinical trial definitively put an end to high-dose TBI in myeloablative HCT for ALL? We suspect not. Arguments may be made that the TBI dose used in this study (9 Gy) is lower than more commonly used myeloablative TBI dosing regimens. The authors also raise an important point that the patient cohort treated in this study were adolescents and adults with cytogenetically standard-risk ALL in CR1, which is a more favorable-risk population for whom we are less frequently offering consolidative HCT. Strikingly, a recent randomized phase III noninferiority trial of 417 children with high-risk B-ALL (in CR1 or CR2+) undergoing myeloablative HCT was terminated early due to inferior outcomes observed with chemotherapy-only conditioning compared to TBI-based conditioning, suggesting that non-TBI conditioning strategies may not be acceptable alternatives in higher-risk disease.16 The role of measurable residual disease (MRD) is also evolving and whether consolidative HCT can be safely de-intensified (or even omitted) in patients who achieve deep MRD-negativity after induction/consolidation therapy, regardless of their pretreatment cytogenetic risk, is yet to be determined. To this end, the Pediatric Transplantation and Cellular Therapy Consortium 1701 EndRAD trial (ClinicalTrials.gov Identifier: NCT03509961) is actively accruing patients with high-risk ALL to evaluate the necessity of TBI-based myeloablative conditioning according to pre-HCT MRD status. Recently presented preliminary results demonstrated that patients with MRD-negative disease by next-generation sequencing had excellent relapse-free survival without the use of high-dose TBI.17
Despite the evolving practices and advances in ALL treatment, Dr. Zhang and the study team should be commended for completing a much-needed randomized controlled trial in this space, and for convincingly demonstrating that Bu/Cy may be safely and effectively substituted for high-dose TBI in patients with standard-risk ALL undergoing HCT in CR1.
Competing Interests
Dr. Jackson and Dr. Muffly indicated no relevant conflicts of interest.
