Real-world outcomes of shortened venetoclax course plus decitabine in newly diagnosed acute myeloid leukemia Free

Introduction

The combination of hypomethylating agent (HMA) and 28 days of venetoclax (VEN) is a standard first-line treatment for elderly and unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). However, treatment-related cytopenias and infectious complications are frequent and have prompted real-world adaptations to dosing schedules. Real world data reported complete remission (CR) rates ranging from 22 to 89% in different risk groups. Recent studies have shown that reducing VEN duration does not compromise outcomes. However, the optimal duration of VEN remains uncertain. In this retrospective study, we evaluated the outcomes of patients with ND-AML receiving a reduced 10-days duration of VEN per cycle along with decitabine (DEC).

Methods

A total of 72 consecutive patients were treated between March 2024 and March 2025 at the University of Alabama at Birmingham with reduced VEN duration regimen (AMANDA regimen). The regimen consisted of DEC 20 mg/m² IV daily for 5 days and VEN 400 mg orally daily for 10 days per cycle (DEC5/VEN10) with a minimum of 4 weeks between cycles. Standard dose modifications were utilized for VEN in patients receiving concomitant CYP3A4 inhibitors. Composite CR rates (CRc) included CR and CR with incomplete hematologic recovery (CRi). Overall response rate (ORR) was defined as CR, CRi, and morphologic leukemia free state (MLFS). Minimal residual disease (MRD) was determined by flow cytometry per institutional standards. Event-free survival (EFS) was defined as the number of days from day 1 of cycle 1 to disease progression, treatment failure (failure to achieve CR or <5% bone marrow blasts after at least six cycles of treatment), confirmed relapse, or death.

Results

Median age was 72 (range, 41-90) years, with 30% being 75 or older. Forty-six (63%) patients were male, 54 (75%) were of white race, and 17 (23.6%) were black patients. Secondary AML was the indication for treatment in 23 (31.9%) patients. Our cohort was enriched with TP53 mutated AML representing 27 (37.5%) patients, and 24 (33.3%) had complex karyotype. IDH1 or IDH2 (IDH1/2) mutations were observed in 11 (15.2%) patients. Most patients had European LeukemiaNet (ELN) 2022 adverse-risk (n=61, 84.7%), followed by intermediate-risk (n=8, 11.1%), and favorable-risk (n=3, 4/2%) disease. ELN2024 groups were as follows: favorable (n=27, 37.5%), intermediate (n=18, 25%), adverse (n=27, 37.5%). Only 3 patients received VEN for <10 days during cycle 1 due to frailty or complications and were retained for analysis. A total of 16 patients were non-evaluable after cycle 1: 9 (12.5%) patients died before day 30, two were lost to follow-up, and 5 decided not to pursue further treatment. Of the remaining 56 patients, VEN was altered per physician discretion in 23 patients as follows in subsequent cycles: VEN duration reduced to 5 (n=12) or 7 (n=1) days, VEN duration increased to 28 days (n=8), VEN held (n=2). To date, 9 patients have proceeded to allogeneic hematopoietic transplantation in remission. The best CRc and ORR were 53% and 63%, respectively. Excluding patients who received VEN 28 days in subsequent cycles, best CRc and ORR remained similar at 52% and 61%, respectively. CRc with MRD negative disease was achieved in 25% of patients. Median number of cycles to CRc was 2 (range, 1-5) cycles. In the subgroup of pts with IDH1/2 and TP53 mutations, the CRc/ORR were 55%/73% and 46%/50%, respectively. CRc and ORR based on ELN2024 risks were 59% and 78% for favorable-risk, 50% and 56% for intermediate-risk, and 46% and 50% for adverse-risk. The median follow-up is 9 (1-15) months. The median overall survival was 8.44 (95%CI: 4.69-12.18) months and the median EFS of 6.18 (95%CI: 2.53-9.83) months. Twenty-one (35%) patients developed an infection, with ≥grade 3 observed in 19 (26%) patients.

Conclusions

This real-world study demonstrates that the DEC5/VEN10 regimen yielded comparable efficacy to published clinical trials and real-world data, even in adverse-risk subgroups. Notably, our study showed an apparent improved safety profile, as evidenced by a lower rate of infections. These findings underscore the feasibility of administering this regimen to older and frail patients. Continued long-term follow-up is underway to determine the durability of response and survival, and updated results will be presented at the meeting.