Paper Details

ABSTRACT

Background  

The conventional “7+3” induction has been the standard for fit younger patients with newly diagnosed AML for decades, while venetoclax plus hypomethylating agents are approved only for older/unfit populations. Emerging data suggest this combination may benefit younger fit patients, yet the optimal integration of anthracycline in specific genetic subsets remains unclear. We therefore designed a risk-adapted strategy based on RUNX1::RUNX1T1 (ETO) status and evaluated its real-world efficacy and safety in 165 fit patients aged ≤65 years.

Methods

Eligible patients received azacitidine 75 mg/m² s.c. days 1–7 and venetoclax (100→400 mg orally days 1–21) in 28-day cycles. Those negative for RUNX1::RUNX1T1 received the standard VA regimen (venetoclax plus azacitidine); ETO-positive patients received the same VA backbone plus idarubicin 6 mg/m² on days 1–3. After remission, all received intermediate-dose cytarabine consolidation, and high-risk patients with donors proceeded to allogeneic transplantation. Genetic risk was classified per ELN 2022 and 2024 criteria.

Results  

Among 165 enrolled patients (median age 56 years, range 17–65), 140 were evaluable. The ETO-positive cohort (n=6, VA+IDA) achieved a composite complete remission (CRc) rate of 80% with a 50% MRD-negativity rate among responders, while the ETO-negative cohort (n=134, treated with the standard VA regimen alone) showed a CRc of 85.82% and an MRD-negative rate of 68.70%. In the ETO-negative group, efficacy remained robust across adverse-risk subsets, with CRc/MRD-negativity rates of 73.17%/53.33% per ELN 2022 and 68.75%/36.36% per ELN 2024; specific molecular subgroups also responded favorably, including NPM1-mutated (n=37, CRc 91.89%, MRD-negative 73.53%), FLT3-ITD (n=27, CRc 96.3%, MRD-negative 76.92%), CBFB::MYH11-positive (n=16, 93.75% and 66.67%), CEBPA bZIP-mutated (n=16, 100% and 81.25%), TP53-mutated (n=15, 66.67% and 40%), as well as ASXL1 (n=9, 77.78% and 71.43%), BCOR (n=8, 100% and 50%), and EZH2 (n=7, 100% and 42.86%). Thirty-four patients underwent allogeneic transplantation. Grade 3/4 haematological adverse events included neutropenia (85.7%), anaemia (80.7%) and thrombocytopenia (79.3%); common non-haematological events were liver dysfunction (46.4%), fatigue (32.9%), constipation (23.6%) and nausea/vomiting (22.1%), with no unexpected toxicity. The 30-day early mortality rate was only 1.21%. With a median follow-up, progression-free survival was 597 days and median overall survival was not reached.

Conclusions

This ETO-guided, risk-adapted induction—standard VA for ETO-negative and VA+IDA for ETO-positive fit patients—yields high remission rates, deep molecular responses, and promising survival, particularly in adverse-risk genetics, while maintaining a manageable safety profile. Our real-world findings support this strategy as an effective and safe alternative to conventional 7+3 for younger newly diagnosed AML patients. These findings require confirmation in prospective studies.