Abstract
Introduction Patients (pts) with core-binding factor (CBF) AML (defined by inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11 or t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 gene fusions) are considered to have favorable risk disease when treated with intensive chemotherapy regimens. However, since these pts were excluded from pivotal trials evaluating venetoclax in combination with hypomethylating agents (HMA/Ven) or low-dose cytarabine (LDAC/Ven), little is known about the efficacy of these regimens in CBF AML pts ineligible for intensive treatment. Case series suggest that pts with CBFB::MYH11 respond well to HMA/Ven, whereas those with RUNX1::RUNX1T1 may be less responsive (Zhang et al., 2023, Shen et al., 2025). Given the lack of approved and effective therapies for older or frail pts with CBF AML besides HMA/Ven, this study aimed to assess its efficacy in this specific patient population.
Methods Based on data from seven European study group registries (PETHEMA, DATAML, CELL, ALFA, NCRI, PALG, and SAL), we retrospectively analyzed adult pts with newly diagnosed CBF AML treated with HMA/Ven. CBF fusions were identified using conventional karyotyping, FISH, PCR and/or NGS. For response evaluation, ELN 2022 criteria were used, and best response within six HMA/Ven cycles is reported. The median overall survival (mOS) was estimated using the Kaplan-Meier method. Statistical analyses were performed using GraphPad Prism v.10.5.0.
Results We identified 53 pts with newly diagnosed CBF AML (27 (51%) with CBFB::MYH11 and 26 (49%) with RUNX1::RUNX1T1) treated with HMA/Ven between September 2019 and July 2025. The median age of the entire cohort was 76 years (range, 30-86), and 21 pts (40%) were female. ECOG performance status was ≥2 in 17 pts (35%). Eight pts (20%) had AML post-cytotoxic therapy. According to the European LeukemiaNet (ELN) 2024 risk classification, 70%, 28%, and 2% of pts had favorable, intermediate, and adverse risk disease, respectively. The most common secondary genetic alterations were mutations in NRAS (31%), TET2 (30%), KIT (29%), KRAS (23%) and DNMT3A (14%). Except for a higher KRAS mutation prevalence in pts with CBFB::MYH11 (44% vs. 5%; p=0.051), there were no significant differences in baseline characteristics between CBFB::MYH11 or RUNX1::RUNX1T1 subgroups.
None of the pts had previously been exposed to HMA or Ven, and most pts (95%) received Ven in combination with azacitidine. The median planned Ven schedule (cycle one) was 21 days (range, 7-28), and the median number of administered HMA/Ven cycles was 4 (range, 1-24). Two pts underwent subsequent allogeneic hemopoietic cell transplantation.
The composite complete remission rate (CRc, CR + CRi) of the entire cohort was 69%, and was similar for pts with CBFB::MYH11 orRUNX1::RUNX1T1 fusions(67% vs. 72%,p=0.564). Pts with ELN 2024 intermediate risk mutations (i.e., FLT3-ITD, NRAS and/or KRAS) had a CRc rate similar to those without any of these variants (68% vs. 73%,p=0.752). Also, the CRc rate of pts with KIT mutations was comparable to wild-type pts (68% vs 79%,p=0.29). The 60-day mortality rate was 8%.
After a median follow-up of 14 months, the mOS of the entire cohort was 13 months, with corresponding 12-month and 24-month OS rates of 54% and 39%, respectively. The mOS of pts with RUNX1::RUNX1T1 was similar to those with CBFB::MYH11 (12 months vs. 14 months, p=0.447). As compared to the corresponding wild-type pts, neither ELN 2024 intermediate risk variants nor KIT mutations adversely impacted mOS (FLT3-ITD/NRAS/KRAS, 11 months vs. NR, p=0.191; KIT, 14 months vs. 12 months, p=0.681).
Conclusions Based on our analysis in a larger cohort of international pts, treatment with HMA/Ven seems to be a valuable treatment option for CBF AML pts ineligible for intensive chemotherapy. In contrast to previous studies in mostly Chinese cohorts, we did not observe a significant difference in response or survival between pts with AML with CBFB::MYH11 and those with RUNX1::RUNX1T1. With a mOS of around 12 months, outcomes of HMA/Ven treated CBF AML pts appear less favorable than those previously reported for pts with ELN 2024 favorable risk disease, and similar to those observed in ELN 2024 intermediate risk non-CBF AML pts, irrespective of FLT3-ITD, NRAS and/or KRAS mutations. Therefore, we propose that all pts with CBF AML treated with HMA/Ven should be provisionally classified as having ELN 2024 intermediate risk disease.
