Comparable Outcome after Busulfan- or Treosulfan-Based Conditioning Regimen in Children Above 4 Years of Age with ALL Undergoing Allogeneic HSCT. Results from the Prospective International Forum-Trial

Purpose: Total body irradiation (TBI) has proved to be the “gold standard” as part of the conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL). Its superiority over chemo-based conditioning was recently demonstrated in the prospective, international, randomized phase III study, which enrolled 417 patients beyond the age of 4 years transplanted for ALL in complete morphological remission (CR) from either matched sibling (MSD) or matched unrelated donor (MD) (Peters et al, JCO 2021, FORUM study; EudraCT: 2012-003032-22;ClinicalTrials.gov: NCT01949129). The use of either of the two protocol-prespecified chemo-conditioning regimens resulted in significantly worse EFS. Given the unavailability of TBI in some regions/centres and contraindications to TBI in individual patients, we here compare the outcomes of patients who received busulfan (BU) - based regimen vs of those who were given a treosulfan (TREO) - based conditioning in FORUM centres in both randomizing and non-randomizing countries in the years 2013-2018.

Patients and methods: Patients ≤ 18 years at diagnosis (median age at HSCT 9.9 years, range 4-19.5), in CR pre-HSCT and with an MSD or MUD were assigned to myeloablative conditioning with fludarabine (FLU), thiotepa (THIO) and either BU or TREO according to country preference. Children transplanted from MSDs received cyclosporine A only as graft-versus-host disease (GvHD) prophylaxis, whereas recipients of MUD HSCT also received short-term methotrexate and anti-thymocyte globulin (ATG). Further details of the transplant procedure have been previously described (Peters C, et al. J Clin Oncol 2021).

Results:In addition to the 193 patients from the randomizing countries, the FORUM trial included 115 additional children enrolled in countries where randomization could not occur (for legal or technical reasons). Overall, 180 vs. 128 patients received BU/THIO/FLU vs TREO/THIO/FLU, respectively. There were no differences about the patients' gender, age, and remission status and slight differences regarding donor, stem cell source and MRD status pre-transplant between the two cohorts of patients (see Table 1 for details). Patient's outcomes were updated as of February 20 ^th, 2023, and median follow-up was 4.2 years (range 0.3 - 9.1). There were neither differences between the 3-year overall survival (OS) (0.71±0.03 for BU/THIO/FLU vs 0.72±0.04 for TREO/THIO/FLU) nor event-free survival (EFS) (0.61±0.04 for BU/THIO/FLU vs 0.55±0.04 for TREO/THIO/FLU, p=NS). Three-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 0.31±0.03 and 0.08±0.02 following BU/THIO/FLU and 0.36±0.04 and 0.09±0.03 following TREO/THIO/FLU, respectively (p=NS). Only one case of secondary malignancy was observed in the TREO cohort and one case of fatal liver veno-occlusive disease (VOD) in the BU group. No statistical differences were observed regarding the cumulative incidence of both aGvHD and cGvHD between the two groups; 3-year GFRS was almost identical (0.42± 0.04 in the BU/THIO/FLU group and 0.43±0.04 in the TREO/THIO/FLU cohort). There were no differences in OS, EFS, CIR, NRM and GFRS in either CR1 or CR2 patients between the two conditioning regimens. Furthermore, there were no differences in outcomes between countries. Patients given BU/THIO/FLU had a faster leucocyte, neutrophil and platelet recovery as compared to those prepared with TREO/THIO/FLU.

Conclusion: Comparable long-term outcomes were observed after BU/THIO/FLU or TREO/THIO/FLU in children with ALL undergoing allogeneic HSCT included in the FORUM trial. Therefore, either of the 2 regimens may be effectively and safely used worldwide in patients > 4 years having a contraindication to or treated in centres/countries unable to deliver TBI.