Dose of Venetoclax in Combination with Hypomethylating Agents and Outcomes of Patients with Acute Myeloid Leukemia: A Retrospective Study

Introduction:

Historically, acute myeloid leukemia (AML) in elderly or unfit patients has been considered an incurable disease with only palliative treatment options available. The introduction of venetoclax in combination with a hypomethylating agent (HMA) has improved the outcomes and became a widely accepted new standard of care. The dose of venetoclax is commonly reduced in cases of therapy-related toxicities or with concomitant administration of a CYP3A4 inhibitor such as fluconazole and posaconazole. We sought to investigate the safety and efficacy of a reduced dose of venetoclax in combination with HMA for the treatment of patients with AML.

Methods:

We retrospectively reviewed the electronic health records of patients with a diagnosis of AML who were evaluated at Atlantic Health System and who received any dose of venetoclax for induction between 2019 and 2023. SPSS (version 29) software was used for all statistical analyses. Categorical variables were compared between the two venetoclax dose groups defined below using chi-squared tests. Continuous variables were compared using Mann-Whitney tests. Survival analysis was performed using Kaplan-Meier estimators, and log-rank tests were used to compare survival curves.

Results:

The analysis included 121 patients, with a median age at diagnosis of 77 years [range 34-93], including 78 (65%) males and 103 (85%) Caucasian. About 94% of these patients resided in New Jersey. ECOG score was documented for 70 (58%) patients, of whom 57 (47%) had an ECOG of 0-1, and 13 (11%) had a score of 2-3. Risk stratification by cytogenetic abnormalities included adverse, intermediate and favorable categories in 82 (68%), 13 (11%) and 20 (17%) patients respectively. Induction therapy consisted of venetoclax in combination with HMA: azacitidine in 78 (65%) patients, and decitabine in 40 (33%). The median dose of venetoclax was 100 mg [range 70-400]. We define low dose group as patients receiving 100 mg or less of venetoclax, and high dose as those receiving greater than 100 mg. There was no statistically significant difference in median overall survival (OS) between the low dose (17 months) and high dose (18 months) groups. Similarly, there was no difference in complete remission (CR/CRi) between the two groups (77% vs. 64%). Of note, the rates of infections including bacteremia within 30 days of induction were higher in the low dose compared to the high dose group (Infections: 57% vs. 34% p=0.02; and bacteremia: 25% vs. 8.5% p= 0.03). Looking at the subgroup of patients who received venetoclax + HMA as a first line treatment, i.e. newly diagnosed AML, no significant difference was noted for median OS, CR/CRi, nor difference in rates of infections or bacteremia within 30 days from date of induction. There was no statistically significant difference between the nadir of platelet count in the first 30 days after induction nor the median number of days with absolute neutrophil count (ANC)<1000 or ANC<500 between the two groups either.

Conclusions:

Our analysis showed that reduced dose of venetoclax in combination with HMA yields similar outcomes to higher dose in terms of survival and achieving remission in patients with AML, and similar rates of infection, bacteremia and cytopenia when used as a first line treatment. We acknowledge as limitations the inclusion of patients who might have had a prematurely interrupted course of venetoclax due to infections or hospitalization, and the inability to capture outpatient administration of venetoclax beyond cycle 1 of induction. Nonetheless, our results highlight the possibility of reducing the dose of venetoclax without affecting the outcome. Future studies to investigate the difference in treatment-related costs with dose reduction of venetoclax are needed, especially in settings with limited resources. Further studies may also be undertaken to elucidate the outcomes of dose reduction on other areas in the real-world such as patient-reported quality of life, length of hospital stay and resource utilization.