Prognostic Associations of Molecular MRD and Genomic Features in ZNF384-Rearranged B-ALL Undergoing Allo-HSCT

ZNF384-rearranged (ZNF384-r) B-cell acute lymphoblastic leukemia (B-ALL) is a rare subtype in which the prognostic significance of persistent molecular measurable residual disease (MRD), particularly isolated ZNF384 transcript positivity with negative multiparameter flow cytometric (MFC) MRD, before allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively analyzed 60 patients with ZNF384-r B-ALL who underwent allo-HSCT in complete remission (CR) between April 2020 and December 2024. Pre-transplant MRD was assessed by MFC and RT-qPCR targeting ZNF384 fusion transcripts. The most common fusion partners were EP300::ZNF384 (43.3%) and TCF3::ZNF384 (31.7%); 58.3% of patients harbored kinase/RAS pathway mutations. Diagnostic immunophenotyping confirmed the characteristic ZNF384-r phenotype, with more frequent uniform CD33 expression in EP300::ZNF384 and other fusion subgroups than in TCF3::ZNF384 (P<0.05). After a median follow-up of 28.2 months, the 3-year overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) were 81.9%, 78.7%, 10.0%, and 11.3%, respectively. Molecular MRD remained detectable in 12 patients (20.0%), including 9 (15.0%) with discordant MFC-negative/molecular-positive (MFC-/Mol+) MRD. All nine discordant cases were alive at last follow-up, with 3-year OS and LFS of 100% and 80.0%, respectively. Molecular MRD positivity was not associated with inferior OS (83.3% vs 81.8%; P = 0.806), LFS (66.7% vs 80.5%; P = 0.516), or CIR (25.0% vs 7.3%; P = 0.255). Similarly, recurrent genomic alterations, including kinase/RAS pathway, IKZF1, ETV6, and KMT2A/D abnormalities, were not significantly associated with post-transplant survival (all P>0.05). Among patients who achieved CR and proceeded to allo-HSCT, favorable outcomes were observed across molecular MRD and genomic subgroups. In particular, isolated pre-transplant ZNF384 transcript positivity with MFC-MRD negativity was not significantly associated with inferior post-transplant outcomes, although these findings are exploratory and require validation in larger, preferably multicenter cohorts.