Veneclat and azacitidine show promise in preventing relapse of high-risk MDS and acute myeloid leukemia

Venetoclax/Venetoclax and azacitidine prophylactic maintenance can be safely used in patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) undergoing low-intensity allogeneic stem cell transplantation (allo-SCT), according to the results of a published study. Among MDS and AML patients undergoing allo-SCT, primarily older patients with higher-risk disease characteristics, relapse is the leading cause of death. Adverse risk disease characteristics and persistent measurable residual disease (MRD) increase the risk of recurrence and lead to shortened survival.

A previous study investigated the addition of venetoclax to fludarabine and busulfan pretreatment and showed that it was a safe regimen that did not interfere with donor engraftment or increase infectious complications. Although it is safe, it does not achieve early eradication of MRD in half of patients. Furthermore, studies of upfront azacitidine maintenance therapy after transplantation have shown a delay in hematological disease recurrence but no survival benefit in a randomized setting. We aimed to determine whether maintenance therapy with reduced-dose venetoclax plus azacitidine after allo-SCT conditioning with fludarabine and busulfan is safe and effective in patients with high-risk MDS/AML.

Between 2020 and 2022, 27 patients (17 men and 10 women) were included in the primary analysis of fludarabine and busulfan followed by allo-SCT followed by venetoclax-azacitidine maintenance therapy. The median time to treatment initiation was 57 days (range, 42-103 days). Maintenance venetoclax-azacitidine was well tolerated among study participants, and no unexpected adverse effects (AEs) were observed. The most common grade 3 or 4 AEs that occurred during treatment were leukopenia (95.5%, n=21), neutropenia (81.8%, n=18), thrombocytopenia (77.3%, n=17), and anemia (45.5%, n=10). Additionally, infections were uncommon, with the researchers noting four cases in total.

Entire QueueThe cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) at 6 months was 22% (95% CI, 9%-29%). The cumulative incidence of GVHD was 23% (95% CI, 8%-42%) at 1 year and 30% (95% CI, 0.3%-18%) at 2 years. The study authors noted that the overall frequency of GVHD events was similar to their previously published findings. The median duration of venetoclax-azacitidine maintenance therapy was 33.9 weeks (range, 4-56.2 weeks), and the median number of cycles for 42-day and 28-day cycles was 3 of 8 cycles (range, 1-8) and 5.5 of 12 cycles (range, 1-12), respectively. Only 2 of 22 patients (9.1%) had dose reductions due to treatment intolerance or toxicity.

It is worth noting that the treatment effect was not significant. According to the researchers, the median follow-up of survivors was 24 months, and regardless of maintenance duration (range, 17-35 months), the 2-year overall survival rate was 58% (95% CI, 35%-75%), and the progression-free survival rate was 52% (95% CI, 32%-69%). The cumulative recurrence rate (CIR) over 2 years was 48% (95% CI, 28%-66%), and the non-relapse mortality rate was 0%. Patients receiving venetoclax-azacitidine maintenance therapy did not reach median OS at a median follow-up of 25 months (range, 17-35 months). However, the researchers found that the two-year OS was 67% (95% CI, 43%-83%), the PFS was 59% (95% CI, 36%-76%), and the two-year CIR was 41% (95% CI, 20%-61%).

Although the data are encouraging in a specific cohort of high-risk MDS/AML patients, the study raises the question of whether maintenance therapy provides any benefit to transplantation and which patients should be considered. Researchers may discuss the need for further randomized trials to evaluate the efficacy of this treatment, but recommend that prophylactic maintenance therapy be considered in patients at extremely high risk of relapse, including patients with pretransplant molecular MRD.