A recent study published in Nature investigated the efficacy and safety of venetoclax-based induction regimens in pediatric patients with acute myeloid leukemia (AML). The study, conducted between December 2021 and September 2023, enrolled 45 untreated AML patients and found that venetoclax-based therapies achieved high remission rates, although with notable hematological toxicities.
Study Design and Patient Characteristics
The study included 45 pediatric AML patients (27 boys and 18 girls) with a median age of 9.3 years (range 0.9–15.8). Among them, 19 were diagnosed with low- or middle-risk AML, and 26 were diagnosed with high-risk AML. The most common morphological type was M2, accounting for 40.0% of cases. Genetic analysis revealed that FLT3 mutations were the most prevalent (26.7%), followed by AML1-ETO (22.2%), MLL rearrangement (20%), and WT1 mutations (17.8%).
The most common treatment approach was a combination therapy of venetoclax, homoharringtonine, and cytarabine (V+HA), which constituted 60.0% of the cases. The median duration of venetoclax dosing was 18 days (range 9–28).
Efficacy of Venetoclax Combinations
The overall complete remission (CR) rate was 86.7% (n=39), and the MRD-negative rate was 44.4% (n=20) on day 28 of venetoclax application. In the low/middle-risk group, the CR rate and MRD-negative rate were 94.7% and 52.6%, respectively. For the high-risk group, these figures were 80.8% and 38.5%, respectively. The differences in CR and MRD-negative rates between risk groups were not statistically significant (P=0.359 and 0.345, respectively).
Specifically, the CR rates in the V+HMAs, V+LDAC, and V+HA therapy groups were 75.0%, 83.3%, and 92.6%, respectively, on day 28. The MRD-negative rates in these groups were 58.3%, 50.0%, and 37.0%, respectively. Again, these differences were not statistically significant (P=0.309 and 0.641).
Safety Profile and Toxicity
Venetoclax-based combination therapy was generally well-tolerated. However, 35.6% of patients received venetoclax for the full 28-day cycle, while others discontinued due to drug-related hematotoxicity. All patients experienced grade 4 neutropenia, and febrile neutropenia was reported in 97.8% of cases. Infections were also common, affecting 97.8% of patients, with pneumonia being the predominant type (22.2%). Tumor lysis syndrome occurred in 24.4% of cases, and mucositis was also frequently observed.
Notably, no grade 5 adverse events were reported in this study.
Impact of CYP3A Inhibitors on Venetoclax Concentration
Plasma concentrations of venetoclax were measured in 37 patients on day 5 of full-dose venetoclax treatment. The trough and peak concentrations of venetoclax averaged 1007.2 ng/ml and 2004.6 ng/ml, respectively. Concurrent use of azoles, potent CYP3A inhibitors, significantly increased venetoclax trough concentrations (p=0.000). However, peak concentrations did not differ significantly between patients using or not using azoles (p=0.986). Despite the increased trough concentrations, there was no significant association between the use of CYP3A inhibitors and achieving CR (p=1.000) or MRD negativity (p=0.092).
Clinical Implications
The study suggests that venetoclax-based induction regimens are effective in achieving high remission rates in pediatric AML patients. The combination of venetoclax with homoharringtonine and cytarabine (V+HA) showed particularly promising results. While hematological toxicities are common, they are generally manageable. The impact of CYP3A inhibitors on venetoclax concentrations warrants consideration, although it did not significantly affect treatment outcomes in this study.
