Venetoclax/Azacitidine Shows Promise for Relapse Prevention in High-Risk MDS and AML

Venetoclax and azacitidine prophylactic maintenance can be safely administered for patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT), according to a study published in Blood Advances.

In patients with MDS and AML who undergo allo-SCT, who are mainly older patients with higher risk disease features, relapse is the leading cause of death. Adverse risk disease features and persistent measurable residual disease (MRD) can increase the risk of relapse, and are attributed with shortened survival rates, the investigators wrote.

A previous study investigated the addition of venetoclax to fludarabine and busulfan conditioning for allo-SCT, with the results indicating a safe regimen without impacts on donor engraftment or increased infectious complications, according to the study authors. Despite its safety, it did not achieve the early eradication of MRD in half of the patients.

Myelodysplastic syndromes | Image credit: Sviatlana-stock.adobe.com

Additionally, studies of preemptive azacitidine maintenance therapy after transplant demonstrated a delay in hematologic relapse but did not show a survival benefit in a randomized setting. The investigators aimed to determine whether reduced doses of maintenance venetoclax plus azacitidine could be safely administered and effective for patients with high-risk MDS/AML after venetoclax with fludarabine and busulfanas conditioning for allo-SCT.

Between 2020 and 2022, 27 patients (17 males and 10 females) were enrolled and included in the primary analysis of venetoclax with fludarabine and busulfan conditioning followed by allo-SCT, then venetoclax-azacitidine maintenance therapy. The median time to the beginning of treatment was 57 days (range, 42-103).

The investigators found that venetoclax-azacitidine maintenance was well tolerated among the study participants, and there were no unexpected adverse effects (AEs) observed. The most common grade 3 or 4 AEs thatemerged during treatment were leukopenia (95.5%, n = 21), neutropenia (81.8%, n = 18), thrombocytopenia (77.3%, n = 17), and anemia (45.5%, n = 10). In addition, infections were uncommon, with 4 total noted by the investigators.

Grade 2 to 4 acute graft-versus-host disease (GVHD) incidence at 6 months was cumulatively 22% (95% CI, 9%-29%) for the entire cohort. At 1 year, the cumulative GVHD incidence was 23% (95% CI, 8%-42%); at 2 years, it was 30% (95% CI, 0.3%-18%). The study authors noted that the overall frequency of GVHD events were similar tothe results in their previously published study.

The median duration of venetoclax-azacitidine maintenance therapy was 33.9 weeks (range 4-56.2 weeks), while the median number of cycles received in the 42-day and 28-day cycles were 3 of 8 (range, 1-8) and 5.5 of 12 (range, 1-12), respectively, the investigators found. Dose reductions for tolerability of the treatment or toxicity were only done in 2 of 22 (9.1%) patients.

Notably, treatment efficacy was not significantly high. At a median follow-up of 24 months among survivors and regardless of maintenance (range, 17-35 months), the 2-year overall survival (OS) was 58% (95% CI, 35%-75%) and progression-free survival (PFS) was 52% (95% CI, 32%-69%), according to the investigators. Cumulative incidence of relapse (CIR) over 2 years was 48% (95% CI, 28%-66%) and non-relapse mortality was 0%.

Patients who received venetoclax-azacitidine maintenance did not reach the median OS at a median follow-up of 25 months (range, 17-35 months). However, the 2-year OS was 67% (95% CI, 43%-83%) and PFS was 59% (95% CI, 36%-76%), while the 2-year CIR was 41% (95% CI, 20%-61%), the investigators found.

Although the data was encouraging in this specific cohort of patients with high-risk MDS/AML, the investigators raised the question of whether maintenance added any benefit to transplant and in which patients it should be considered.

The investigators discussed the need for further randomized trials to evaluate the efficacy of this treatment, but recommended consideration of prophylactic maintenance for patients at exceedingly high riskfor relapse, including those with pretransplant molecular MRD.

Reference

Garcia J S, Kim H T, Murdock M, et al. Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML. Blood Adv. 2024;(8)4:978-990. doi:10.1182/bloodadvances.2023012120