Outcomes of BCP-ALL with hypodiploidy or BCR::ABL1 fusion in children undergoing allogeneic HSCT: results from the FORUM study

Hypodiploid (Hypo) and BCR::ABL1-positive (BCR-ABL+) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) confer a high risk of disease relapse. We investigated post-hematopoietic stem cell transplantation (HSCT) outcomes within the prospective FORUM trial, comparing these genetic subgroups to patients without these lesions. The use of pre- and post-HSCT add-on treatments, including tyrosine-kinase inhibitors (TKIs) and immunotherapies, was also assessed. Multivariate analysis evaluated associations with overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR). The FORUM trial enrolled 741 patients ≥4 years of age with BCP-ALL who underwent HSCT from HLA-matched donors (2013-2023). The 3-year OS (0.86 [95% CI, 0.76-0.92], 0.79 [0.65-0.87], and 0.79 [0.76-0.82]) and EFS (0.71 [0.59-0.80], 0.73 [0.59-0.83], and 0.67 [0.63-0.71]) did not differ significantly between BCR-ABL+, Hypo, and Neither patients, respectively. However, Hypo patients in second complete remission (CR2) showed inferior OS and EFS, driven by higher non-relapse mortality (NRM), which occurred exclusively in near-diploid cases. No NRM occurred in severe hypodiploid cases conditioned with TBI. MRD positivity at transplant predicted worse OS, EFS, and CIR in all genetic groups. Hypo patients were difficult to salvage post-relapse, even with CAR-T therapy. By contrast, BCR-ABL+ patients had favorable outcomes, even when MRD-positive prior HSCT. Prophylactic TKI use post-HSCT improved EFS and reduced CIR. BCR::ABL+ patients transplanted in CR2 had a 3-year OS of 96%. In conclusion, the standardized FORUM protocol yielded comparable outcomes across genetic subgroups. Post-transplant TKI maintenance improved outcomes in BCR-ABL+ BCP-ALL. EudraCT: 2012-0032-22; ClinicalTrials.gov: NCT01949129.