Low-dose 10-day decitabine plus venetoclax induced rapid MRD negativity and durable remission in de novo AML and high-risk MDS

Abstract Background The combination of hypomethylating agents (HMAs) and venetoclax (VEN) have emerged as a new standard of care in older or unfit patients with acute myeloid leukemia (AML). In the VIALE-A study, VEN plus azacitidine (AZA) achieved a composite complete remission (CRc) rate of 66.4%. It was reported that VEN combined with decitabine (DEC) has shown better efficacy than VEN-AZA, achieving a CRc rate of 83%. However, standard DEC-VEN presented toxicity challenges in elderly patients. In this study, we explored the efficacy and safety of low-dose 10-day DEC plus VEN (lowDEC-VEN). Methods We performed a retrospective analysis of 41 patients with AML and high risk MDS who were ineligible for intensive chemotherapy. Patients received decitabine 6mg/m2 for 10 days and venetoclax (100mg d1, 200mg d2, 400mg d3-14 or -21). Seven patients subsequently underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Overall survival (OS) and event-free survival (EFS) were analyzed using Kaplan-Meier analysis, with follow-up concluding in May 2025. Results The median age was 66 years. The CRc was observed in 33/41 patients (80.5%), with 8/9 (88.9%) in favorable group and 21/28 (75.0%) in intermediate/adverse group according to ELN-2022 risk stratification. Notably, 30/41 (73.2%) patients achieved CRc after the first cycle of lowDEC-VEN regimen, accounting for 87.9% of all patients who achieved CRc throughout the entire treatment process. The MRD negative rate after the first cycle was 26/41 (63.4%). Among patients with CR/CRi, 26/30 (86.7%) patients attained MRD negativity after the first cycle. The median time to first CRc was 1.43 months. With a median follow-up of 39.2 months, the median duration of response (DOR) for CR was 21.3 months and median OS remained 36.1 months. The 12-month, 24-month and 36-month OS rates were 68.3%, 56.0% and 49.1%. For patients who underwent allo-HSCT, the 36-month OS rate was 80.0%; in patients aged ≥60 years, this rate was 47.2%. The 12-month, 24-month and 36-month EFS rates were 60.3%, 47.5% and 36.0% , respectively. Among allo-HSCT recipients, the 36-month EFS rate was 68.6%; in patients aged ≥60 years, it was 41.2%. For the ELN-2022 intermediate/adverse-risk group, 36-month OS and EFS rates were 38.3% and 28.1%, respectively. All patients with baseline neutropenia(grades ≤2) developed grade 4 neutropenia during the first cycle. The multivariate analysis shows that patients with ECOG≥3 and complex karyotype had significantly poorer OS. Compared with the VIALE-A study, our cohort demonstrated superior CRc rates, MRD negativity rates, and OS; however, validation in larger cohorts is warranted. Conclusion The regimen of low-dose 10-day decitabine combined with venetoclax induced rapid MRD negativity with good tolerability in patients who are not eligible for intensive therapy. Extended follow-up confirms high long-term survival rates and prolonged DOR, supporting its potential as a treatment option in this population.