Real-world insights into venetoclax and/or hypomethylating agent discontinuation in patients with Acute Myeloid Leukemia

Abstract

Abstract Introduction. Hypomethylating agent (HMA) plus venetoclax (VEN) regimen, until disease progression or unacceptable toxicity, is the standard of care in patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Although the HMA-VEN regimen was developed as a continuous therapy, there is limited evidence on the impact of treatment discontinuation due to toxicity or patient´s decision on event-free survival (EFS) and overall survival (OS) in patients in remission. The primary objective of this study was to describe long-term outcomes in patients in remission who discontinued HMA and/or VEN regimen due to unacceptable toxicity or patient's decision. Methods. This is a retrospective, observational, multicenter, international study of patients with AML diagnosed between January 2020 and March 2025 from the CETLAM and PETHEMA Spanish cooperative groups. We included AML patients treated in the frontline setting with HMA-VEN who discontinued treatment (HMA, VEN, or both) at any time after achieving a response (complete response [CR], complete response with incomplete hematologic recovery [CRi], or morphologic leukemia-free state [MLFS]). A multicenter control cohort consisting of patients who did not discontinue treatment after achieving a response was used as a comparator. Statistical analysis was performed using Jamovi software. Results. A total of 65 patients from 25 centers in Spain, Portugal, and Argentina were included. Of these, 53.8% were male, with a median age of 76.3 years (range 53.6–88.2). Next generation sequencing (NGS) was available in 49 patients. 69.5% of patients were categorized as favorable risk, 16.3% as intermediate risk, and 14.2% as adverse risk according to the 2024 European Leukemia Net (ELN) classification. Median number of treatment cycles at discontinuation was 6 (range 1–26). Forty patients (61.6%) discontinued HMA and VEN, whereas 20 (30.8%) stopped VEN only and 5 (7.6%) HMA alone. Main reasons for discontinuation were hematologic toxicity (55.4%), infections (17%), and patient decision (17%). With respect to those patients who discontinued therapy due to hematologic toxicity, 92.5% did so because of grade 4 neutropenia and/or grade 4 thrombocytopenia. At discontinuation, 33 patients (50.8%) were in CR, 31 (47.7%) in CRi, and 1 patient (1.5%) in MFLS. 24 patients (36.9%) were measurable residual disease (MRD)-negative and 14 (21.5%) MRD-positive. Dose adjustments of HMA and/or VEN prior to discontinuation were indicated in 80% of patients. After a median follow-up of 18.7 months (range 2.4–47.7), median EFS and OS were 27.7 months (20.5–NR) and 29.2 months (23.3–NR), respectively. Twenty patients relapsed. Twenty-four patients died, 15 due to relapse, 3 because of infection and 6 for other causes. No differences in OS were observed between patients who discontinued HMA or VEN compared to those who discontinued both agents. The type of response at the time of discontinuation also had no significant impact on OS or EFS. In the multivariate analysis, protective factors for EFS and OS included the ELN 2024 favorable risk group (HR = 0.25, p = 0.042; HR = 0.23, p = 0.048, respectively), and having received at least six cycles of therapy (HR = 0.010, p = 0.008; HR = 0.01, p = 0.014, respectively). Conversely, having MRD positive at the time of treatment discontinuation was identified as a risk factor for both EFS (HR = 6.27, p = 0.017) and OS (HR = 34.72, p = 0.023). A group of 66 patients with AML treated with HMA-VEN as first-line therapy who did not discontinue treatment was used as a control group. The median follow-up was 14.6 months (range, 2.39–42.5), and the median number of cycles received was 8 (range, 2–43). There were no significant differences in patient characteristics between the two groups. No significant differences in OS were observed between patients who discontinued treatment (29.2 months) and those who did not (24.6 months), HR 0.59 (0.34 – 1.01, p=0.555). Conclusions. In our cohort, long median EFS and OS were observed in AML patients under remission who discontinued HMA and/or VEN after frontline HMA-VEN therapy. Patients classified as favorable risk according to ELN 2024, with MRD negativity at discontinuation, and those who had received at least 6 treatment cycles showed better EFS and OS. Prospective studies are needed to confirm these findings and to identify which patient subgroups may benefit from fixed-duration therapy.