Venetoclax with decitabine or azacitidine in the first‐line treatment of acute myeloid leukemia

Abstract

Treatment paradigms for acute myeloid leukemia (AML) have evolved at a rapid pace in recent years. The combination of venetoclax with a hypomethylating agent prolonged survival in clinical trials when compared to hypomethylating agent monotherapy. However, little is known about the performance of venetoclax‐based regimens outside of clinical trials, given conflicting safety and efficacy data. Even less is known about the impact of the hypomethylating agent backbone. In this study, we demonstrate that decitabine‐venetoclax is associated with a significantly higher rate of grade three or higher thrombocytopenia, but lower rates of lymphocytopenia compared to azacitidine‐venetoclax. There was no difference in response or survival across ELN 2017 cytogenetic risk categories in the overall cohort. Significantly more patients succumb to relapsed or refractory disease than death from any other cause. We demonstrated that a Charlson comorbidity index score threshold of seven identifies exceptionally high‐risk patients, providing evidence for clinical use to reduce the risk of early treatment‐related mortality. Lastly, we provide evidence that measurable residual disease negativity and an IDH mutation predict a significant survival benefit outside clinical trials. Taken together, these data illuminate the real‐world performance of venetoclax and decitabine or azacitidine in the treatment of AML.

Real-Life Multicenter Experience of Venetoclax in Combination with Hypomethylating Agents in Previously Untreated Adult Patients with Acute Myeloid Leukemia in Greece

“…Regarding toxicity, neutropenia was the most common side effect in both treatment groups and was observed in the vast majority (90%) of our patients receiving HMAvenetoclax, in accordance with previously reported real-world data [24]. Anemia and thrombocytopenia were also very common, at a rate of 85% and 67.5%, respectively, slightly less than some previous real-world reports [24], but higher than notified in VIALE-A [7]. Although retrospectively documenting real-life data is less accurate than randomized trials, partially contributing to these differences, it is obvious from our and previous data that hematologic toxicity is one of the main handling issues during HMA-venetoclax treatment in AML.…”

“…Regarding toxicity, neutropenia was the most common side effect in both treatment groups and was observed in the vast majority (90%) of our patients receiving HMAvenetoclax, in accordance with previously reported real-world data [24]. Anemia and thrombocytopenia were also very common, at a rate of 85% and 67.5%, respectively, slightly less than some previous real-world reports [24], but higher than notified in VIALE-A [7].…”

“…Comparing toxicity in patients treated with HMA monotherapy, even though patients treated with the HMA-venetoclax combination presented neutropenia more commonly (p = 0.020), infection rate and febrile neutropenia were similar in the two groups (p = 0.501 and p = 0.322, respectively). Febrile neutropenia was observed in 67.5% of patients in a HMA-venetoclax treatment setting, a higher percentage than previously notified [7,8,24]. GCSF was commonly used, especially with HMA-venetoclax, even in patients who were not in CR, despite conflicting data in the literature [15,17].…”

Venetoclax with Decitabine or Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia

“…Second, the CCI score provides a convenient and clinically meaningful parameter to assess treatment candidates. We previously reported that a CCI score threshold of 7 identified high-risk patients treated with venetoclax and a hypomethylating agent in the front-line setting [7]. We hypothesized that a lower score threshold would apply to the relapsed or refractory setting due to the burden and complications of multiple treatment courses.…”

“…However, outcomes need to be clarified in the context of lower-intensity venetoclax-based strategies. Our group, among others, reported significant survival differences in unique molecular cohorts unaccounted for in ELN 2022, such as AML with mutated IDH1 or IDH2 [4][5][6][7]. Additionally, preclinical studies and updated analyses of clinical trials have suggested that signaling mutations are implicated in primary refractoriness or adaptive resistance to venetoclaxincluding mutations in FLT3, PI3K, and RAS, as shown in Figure 1 [5,[8][9][10].…”