Distinct prognosis and transplant timing in core-binding factor Acute Myeloid Leukemia

Abstract Introduction: Core binding factor acute myeloid leukemia (CBF-AML), defined by t(8;21)/RUNX1::RUNX1T1 or inv (16)/CBFβ::-MYH11, is categorized as favorable-risk due to its high remission rate and better relapse-free survival. We aimed to delineate the similarities and differences in treatment response and prognosis between AML patients with RUNX1::RUNX1T1 and CBFβ::MYH11 fusions. Methods: 779 de novo CBF-AML patients (511 RUNX1::RUNX1T1, 225 CBFβ::MYH11) were enrolled. Measurable residual disease (MRD) was assessed via multi-parameter flow cytometry (MFC-MRD) and quantitative polymerase chain reaction (Mol-MRD) during/after treatment. Responders are defined as achieving MRD negativity (MFC-MRD 0.01% aberrant cells and Mol-MRD > 3-log reduction) after the second consolidation cycle (C2). Otherwise, it is considered positive. Survival analyses employed Kaplan-Meier and landmark methods (3-month cutoff [corresponding to the median time of C2 completion] for immortal time bias). Treatment response comparisons used time-dependent Cox models, while relapse risks were evaluated via the Prentice, Williams and Peterson (total times) (PWP-TT) modeling. Logistics regression models were used to develop the predictive model for the responses after C2. Results: With a median follow-up of 34.6 months (range: 3.9-106.2), early mortality by C2 was lower in RUNX1::RUNX1T1 (4.7%, n=25) versus CBFβ::MYH11 (7.1%, n=18, P = 0.042) patients. The 3-year overall survival (OS) was significantly better in patients with CBFβ::MYH11 compared to RUNX1::RUNX1T1 (90.2% vs 80.6%, P = 0.011). 695 patients were evaluable for C2 assessment, with 42.5% with RUNX1::RUNX1T1(n = 206) and 33.2% with CBFβ::MYH11 fusions (n = 74) as responders. Landmark analysis showed superior 3-year OS for RUNX1::RUNX1T1responders vs. non-responders (86.3% vs. 76.5%, P = 0.008), however, responders and non-responders have comparable survival outcomes in patients with CBFβ::MYH11 (95.1% vs. 88.1%, P= 0.49). Multivariable Cox model further identified Mol-MRD positivity (HR [95%CI]: 1.96[1.08–3.54], P = 0.026) and/or MFC-MRD positivity (2.79[1.61–4.85], P<0.001) at C2 as significant risk factors for RUNX1::RUNX1T1 survival, with no associations in CBFβ::MYH11. PWP-TT model showed that non-responders at C2 were related to more relapses in the RUNX1::RUNX1T1 patients (Mol-MRD positivity: 2.126[1.181-3.828], P = 0.012; MFC-MRD positivity: 2.855[1.733-4.704], P < 0.001), but not in patients with CBFβ::MYH11 fusion. Allogeneic hematopoietic stem cell transplantation (allo-HCT) was a protective factor for long-term survival (HR [95%CI]: 0.391 [0.206-0.740], P = 0.004) with the multivariable Cox model and relapse (HR [95%CI]: 0.565 [0.386-0.828], P = 0.003) with the PWP-TT model in RUNX1::RUNX1T1 patients, but not for CBFβ::MYH11 patients. Integration of landmark analysis and time-dependent cohort allocation, we found that for RUNX1::RUNX1T1 non-responders, allo-HCT provided a superior 3-year OS compared with chemotherapy (81.9% vs. 56.4%, P < 0.001), which was different from non-responders with CBFβ::MYH11. Responders with RUNX1::RUNX1T1 or CBFβ::MYH11 had comparable outcomes when consolidated with allo-HCT or chemotherapy. Transplant in first CR provided better outcomes for RUNX1::RUNX1T1 (3-year OS: CR1-HCT 85.8% vs. non-CR1-HCT 71.4%, P < 0.001; relapses: CR1-HCT 8.3% vs. non-CR1 18.9%, P = 0.024). Consolidation therapies did not show significant impacts on long-term outcomes in CBFβ::MYH11 patients (3-year OS: Chemotherapy vs. non-CR1-HCTvs. CR1-HCT: 89.9% vs. 90.7% vs. 92,2%, P = 0.871). At last, we developed a comprehensive predictive model for C2 response incorporating clinical factors: (age < 40y [1 score], initial white blood count [<50 × 109/L: 1 score; 50-100: 2 score; > 100: 3 scores]; hemoglobin < 100 g/L [1 score]), mutational profiling (KIT D816/D822 variants [3 scores], other KIT mutations [1 score], FLT3-ITD [1 score]), as well as initial RUNX1::RUNX1T1/ABL value (<500%[4 scores], 500-1000%[3 scores], 1000-1500%[2 scores], ≥1500%[1 score]). A score ≥8 predicted non-response with 78.3% specificity and 57.4% sensitivity, effectively identifying high-riskRUNX1::RUNX1T1 AML cases needing urgent transplant evaluation. Conclusion: For CBFβ::MYH11 AML, C2 assessment offers minimal clinical significance, with allo-HCT reserved for CR2. In contrast, RUNX1::RUNX1T1 patients with post-C2 MRD positivity should receive allo-HCT at CR1.