Clinical outcomes and novel therapeutic strategies in adult patients with MLL-rearranged acute lymphoblastic leukemia: A monocentric retrospective analysis

Abstract Introduction: Adults with MLL-rearranged b-cell acute lymphoblastic leukemia (MLL-r B-ALL) face dismal outcomes due to intrinsic chemo-resistance (historical median OS <12 months). While the efficacy of blinatumomab and CAR-T therapy has been established in relapsed/refractory B-ALL, clinical studies in adult patients with newly diagnosed MLL-r B-ALL remained limited. This study analyzed real-world data to evaluate therapeutic efficacy and prognostic factors. Methods: Patients diagnosed as MLL-r B-ALL by quantitative polymerase chain reaction (qPCR) and next-generation sequencing (NGS) were enrolled from December 2015 to January 2025 in Union Hospital. Frontline regimens consist of chemotherapy ± blinatumomab ± allogeneic hematopoietic stem cell transplantation (allo-HSCT); consolidation immunotherapy escalation consist of blinatumomab or chimeric antigen receptor T-cell therapy (CAR-T) for patients with bone marrow morphology in remission but MRD ≥0.01% by flow cytometry or persistent MLL transcript expression; and salvage therapy consist of CAR-T or allo-HSCT for patients relapsed (blast ≥5%). Data encompassed induction response (ELN 2022 criteria), MRD/MLL kinetics (qPCR), and survival. Result： A retrospective cohort study of 22 consecutive adult MLL-r ALL patients were analyzed. The median age was 48.5 years (range: 18-71). The MLL-AF4 subtype was predominant (86%, n=19), while MLL-ENL and MLL-ELL were diagnosed in two and one patient(s), respectively. At diagnosis, the median white blood cell (WBC) count was 123.32 × 10⁹/L (range: 7.5–440 × 10⁹/L; WBC > 30 × 10⁹/L: n=15; WBC > 100 × 10⁹/L: n=11). Following induction therapy, 73% (n=16/22) of patients achieved complete hematologic remission (CR), while only 36% (n=8/22) attained deep molecular remission (MLL-negative status). Among patients receiving immunotherapy: nine patients received allo-HSCT (frontline: n=5; relapsed/refractory [R/R] B-ALL: n=4). Three patients relapsed post-HSCT; Four patients (R/R B-ALL: n=2; CR with persistent MLL-positivity: n=2) received CAR-T therapy, achieving a 100% CR rate.Six patients received blinatumomab (frontline: n=2, 100% CR; salvage: n=4, 25% CR). No lineage switch events occurred in patients receiving immunotherapy. At a median follow-up of 16.3 months (range: 3–110 months), overall cohort mortality was 45.5% (n=10/22). Median overall survival (OS) was 16.2 months (95% CI: 9.1–Not Reached), and the landmark 2-year OS rate for the entire cohort was 54.5%. Landmark analysis demonstrated significant associations between molecular remission status and survival: Patients achieving MLL-negative status after induction (n=8): 100% 2-year OS; Patients achieving MLL fusion transcript clearance during consolidation (n=5): 80% 2-year OS. Patients with persistent MLL-positivity (n=9): 11.1% 2-year OS. All patients with primary refractory disease (n=3) had 100% mortality. Multivariate analysis identified both minimal residual disease (MRD) positivity (Hazard Ratio [HR] = 6.82, 95% CI: 1.98–23.5) and failure to achieve CR post-induction (HR = 7.46, 95% CI: 2.31–24.1) as significant independent predictors of inferior overall survival.. Conclusion: Dynamic MRD-directed sequential immunotherapy overcame chemo-resistance in MLL-r B-ALL, achieved molecular responses and long-term survival . MLL transcript clearance is a critical biomarker for cure, validating this paradigm as a new standard of care.