Comparison of Myeloablative Conditioning with a Total Body Irradiation-Based Regimen Versus a Chemotherapy-Based Regimen in Adult Patients Undergoing Umbilical Cord Blood Stem Cell Transplant for Ph-Negative Acute Lymphoblastic Leukemia

Background: Myeloablative conditioning with high dose total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute lymphoblastic leukemia (ALL) is effective, but short-term toxicities may negatively impact long-term survival. As an attempt to reduce toxicity, myeloablative chemotherapy-based regimens have been developed as alternatives to TBI-based regimens. For pediatric ALL patients undergoing HSCT from HLA-matched donors, survival outcomes are superior with TBI-based conditioning compared to chemotherapy-based conditioning due to reduced relapse. Less is known about the relative benefit of high-dose TBI in adult ALL patients, particularly in the setting of HLA-mismatched umbilical cord blood transplant. We sought to compare outcomes of adult patients with ALL who underwent cord blood transplant with a high dose TBI-based regimen versus a myeloablative chemotherapy-based regimen.

Methods: Adult patients with Philadelphia chromosome (Ph) negative ALL who underwent cord-blood HSCT with myeloablative conditioning (MAC) between May 2016 and November 2023 at University of Colorado Hospital were included in this analysis. No patients with Ph-positive ALL underwent HSCT with high-dose TBI during this period. Patients in the high dose TBI-based conditioning regimen group received 12Gy TBI with 75 mg/m2 fludarabine and 120 mg/kg cyclophosphamide (TBI-MAC). Patients in the chemotherapy-based group received a regimen consisting of 10 mg/kg thiotepa, 150 mg/m² fludarabine, 50 mg/kg cyclophosphamide, and 4Gy TBI (chemo-MAC). Patients were transplanted with two cord blood units (dual cord) or a single cord blood unit combined with CD34-selected PBSCs from a haploidentical donor (haplo-cord).

Results: A total of 36 patients were included in this study, with 17 patients conditioned with TBI-MAC and 19 patients with chemo-MAC. The TBI-MAC group was younger (median age 27 years vs. 39 years, p=0.019), included fewer patients with B-ALL (41% vs. 74%, p=0.027) compared to T-ALL, and more frequently were transplanted between 2020-2023 compared to the chemo-MAC group (88% vs. 42%, p=0.033). There were no differences in proportion of patients transplanted in CR1 (58% vs 47%, p=0.54) versus CR2/CR3, MRD status by flow pre-SCT (MRD-negative 84% vs. 82%, p=1.0), proportion of patients who underwent dual cord (35% vs. 42%, p=0.8) versus haplo-cord SCT, or comorbidity scores (ECOG 0-1 94% vs. 100%, p=0.96). Cumulative incidence of relapse and non-relapse mortality (NRM) in the TBI-MAC vs. chemo-MAC groups was 0% vs 25% (p=0.11) and 6% vs 21% (p=0.4), respectively. 100-day cumulative incidence of any acute graft-versus-host-disease (aGVHD) (53% vs. 63%, p=0.6) and of grade ≥3 aGVHD (6% vs. 11%, p=1.0) did not differ, nor did cumulative incidence of chronic GVHD (18% vs. 11%, p=0.5). With median follow-up of 11.3 months and 32.0 months in the TBI-MAC and chemo-MAC groups respectively, estimated one-year relapse free survival (RFS) was 94% with TBI-MAC vs 66% with chemo-MAC (p=0.047). Estimated one-year overall survival (OS) was 94% with TBI-MAC vs 78% with chemo-MAC (p=0.058).

Conclusion: In adults with Ph-negative ALL undergoing cord blood transplant with myeloablative conditioning, high dose TBI was associated with significantly improved RFS compared to chemotherapy-based myeloablative conditioning. The combination of high dose TBI-based conditioning and strong graft-versus-leukemia effects mediated by HLA-mismatched cord blood may have contributed to the favorable outcomes seen in this group. Along with no difference in treatment-related mortality or GVHD, our results suggest that TBI-based conditioning regimens prior to HSCT with umbilical cord blood for ALL remains the most efficacious option for myeloablation, with a similar safety profile to chemotherapy-based regimens.

Amaya:Bristol Myers Squibb: Honoraria. McMahon:Syndax Pharmaceuticals, Inc.: Research Funding; Syros Pharmaceuticals: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees. Pollyea:Sanofi: Honoraria; Gilead: Honoraria; Qihan: Honoraria; Seres: Honoraria; Karyopharm: Honoraria, Research Funding; MEI: Honoraria; Syndax: Honoraria; Syros: Honoraria; Novartis: Honoraria; Sumitomo: Honoraria; Adicet: Honoraria; Aptevo: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Oncoverity: Honoraria; Rigel: Honoraria; Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; LINK: Honoraria; Abbvie: Honoraria, Research Funding; Medivir: Honoraria; Hibercell: Honoraria; Beigene: Honoraria; Ryvu: Honoraria.