Venetoclax, an orally administered B-cell lymphoma (BCL-2) inhibitor plays a crucial role in regulating cell survival by inhibiting apoptosis. Overexpression of BCL-2 in cancer cells can promote the survival and proliferation of such cells (1–4). Venetoclax selectively binds to BCL-2, restoring the apoptotic process within cancer cells and inhibiting tumor growth (5). Studies have demonstrated the notable therapeutic efficacy of venetoclax in various malignancies, including acute myeloid leukemia (AML), chronic lymphocytic leukemia, multiple myeloma and mantle cell lymphoma (6–20).

In hematological-oncological treatment, antifungal agents are commonly used either for therapeutic or prophylactic purposes alongside anticancer medications (21). Specific antifungal agents, such as posaconazole and voriconazole, act as cytochrome P450 inhibitors (22,23), and since venetoclax is metabolized through cytochrome P450, their co-administration can result in drug interactions, necessitating a reduction in venetoclax dosage to prevent potential adverse effects (24).

The literature emphasizes the need for dose adjustments when combining venetoclax with cytochrome P450 inhibitors in patients with AML. However, drug interactions affecting venetoclax blood concentrations are non-linear (25,26). Currently, research on clinical outcomes in patients with AML receiving reduced venetoclax doses due to such interactions is limited. Furthermore, venetoclax has a restricted duration of coverage under Taiwan's National Health Insurance system. Therefore, to alleviate the financial burden or extend treatment duration, combining venetoclax with antifungal agents may be a viable option for patients with AML who cannot tolerate intensive chemotherapy.

This single-center study retrospectively investigated progression-free survival (PFS), overall survival (OS) and drug-related adverse events (AEs) in patients with AML who received adjusted venetoclax doses in combination with antifungal agents compared with those receiving standard treatment.

This retrospective observational single-center study included patients who had been treated within a 7-year period between January 2015 and December 2021, and who met the following inclusion criteria: i) Age >20 years; ii) diagnosis of non-M3 AML classified according to the French-American-British classification system (27); iii) AML treatment with venetoclax and a cytochrome P450 inhibitor (posaconazole or voriconazole); iv) induction therapy with idarubicin + cytarabine and high-dose cytarabine consolidation therapy; and v) treatment with low-dose cytarabine (LDAC). Patient demographic and clinical characteristics, namely age, sex, Eastern Cooperative Oncology Group (ECOG) performance status (28), cytogenetic risk category (29), somatic mutations, bone marrow blast count, PFS, OS and optimal treatment response dose, were collected retrospectively. Ethical approval was granted by the Chi-Mei Medical Center Institutional Review Board (approval no. 11107-L01) on August 2, 2022, and the study commenced on August 8, 2022, and was conducted in accordance with the Helsinki Declaration. The requirement for informed patient consent was exempted by the Institutional Review Board. Patients were enrolled from the Division of Hematology-Oncology, Department of Internal Medicine, Chi-Mei Medical Center (Tainan, Taiwan). To ensure patient confidentiality, all data were anonymized and were accessible only through unique codes. In accordance with legal regulations, only the principal investigator was authorized access and allowed to manage the complete dataset.

The primary outcomes of the study were OS (defined as the time from the start of drug treatment to death) and PFS (defined as the time from treatment initiation to disease progression or treatment change). For patients alive at the study endpoint, data were based on the most recent confirmation of survival date.

Secondary outcomes included the evaluation of treatment-related grade 3/4 AEs, based on the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0 (30), and treatment response rates, based on the criteria outlined by Döhner et al (31).

AML treatment regimens included induction therapy with idarubicin and cytarabine (12 mg/m² idarubicin on days 1–3 + 100 mg/m² cytarabine on days 1–7 or 12 mg/m² idarubicin on days 1–2 + 100 mg/m² cytarabine on days 1–5). Consolidation therapy involved 1–2 g/m² cytarabine on days 1, 3 and 5. Venetoclax-based regimens included 100 mg venetoclax on days 1–28 + 300 mg posaconazole on days 1–28 + 100 mg azacitidine on days 1–7 (28 days per cycle) or 100 mg venetoclax on days 1–28 + 300 mg posaconazole on days 1–28 or 20 mg/m² LDAC on days 1–10 + 100 mg venetoclax on days 1–28 + 300 mg posaconazole on days 1–28 or 200 mg voriconazole twice daily on days 1–28 (28 days per cycle). The cytarabine-based regimen involved 20 mg/m² LDAC on days 1–10 (28 days per cycle). Treatment continued until disease progression or until the patient could no longer tolerate drug side effects.

For elderly patients with AML or those unfit for intensive chemotherapy, venetoclax combined with hypomethylating agents or LDAC has become the gold-standard treatment in numerous clinical settings (13,15). However, in Taiwan, financial constraints and limited health insurance coverage restrict the widespread clinical application of this treatment approach. During the period covered by the present study, venetoclax was not reimbursed under Taiwan's National Health Insurance system. According to current regulations, its coverage is restricted to frail patients and limited to a maximum of four cycles. As a result, patients requiring venetoclax must bear a portion of the medication cost themselves. Considering that not all patients have the financial capacity to afford the treatment, a potential solution to this issue is using a reduced dosage of venetoclax in conjunction with antifungal agents, which can lower medication costs while maintaining efficacy and safety. This approach aims to optimize treatment outcomes while alleviating the financial burden on patients.

Elderly patients with AML often have reduced tolerance to intensive chemotherapy and face an increased risk of complications. Consequently, low-intensity treatment regimens are advisable to balance efficacy and tolerability. Previous research has highlighted that advanced age is associated with a poorer prognosis in AML, emphasizing the need to consider physiological age and overall health when making treatment decisions (32). Although no statistically significant differences were observed in the cytogenetic risk categories (P=0.80) and somatic mutations (P=0.12) across treatment groups in our study (which may reflect the small sample size or patient heterogeneity), these factors remain important prognostic markers in AML (33) and should be considered in future studies that aim to tailor treatment strategies more effectively.

The present study uniquely focused on the efficacy and safety of reduced-dose venetoclax (primarily 100 mg daily) combined with antifungal agents such as voriconazole and posaconazole. In this retrospective analysis, the I3A7 group demonstrated superior OS and PFS times compared with the venetoclax, LDAC and I2A5 groups, consistent with current AML treatment guidelines (34). Additionally, among the patients receiving venetoclax combined with antifungal agents, those treated with azacitidine exhibited numerically longer median OS and PFS times compared with those treated with LDAC. While this trend suggests a potential benefit of combining azacitidine with venetoclax over LDAC, the differences were not statistically significant. The I3A7 group also demonstrated a numerically longer median RFS time compared with the venetoclax plus antifungal agents group, although this analysis was limited to patients achieving complete remission (8 in the I3A7 group and 1 in the venetoclax group), reducing the statistical power and with a lack of statistically significant differences, thereby limiting the generalizability of the findings. Larger studies are needed to validate these results and explore venetoclax-based regimens in AML treatment. While the venetoclax group exhibited slightly lower OS and PFS times than the I3A7 group, patients also experienced fewer hematological and infection-related AEs. Additionally, despite poorer survival outcomes compared with the more intensive I3A7 chemotherapy regimen, venetoclax achieved more favorable outcomes than traditional treatments such as LDAC and I2A5, particularly when combined with hypomethylating agents. Patients in the venetoclax group also exhibited a lower risk of infection compared with the I3A7 and I2A5 groups, and patients who were treated with hypomethylating agents showed better survival outcomes than those treated with the LDAC regimen. Accordingly, venetoclax-based combination regimens should be considered a superior treatment option to LDAC or I2A5, particularly for elderly or frail AML patients.

Regarding antifungal prophylaxis, 3 patients in the I3A7 group and 7 patients in the LDAC group did not receive prophylactic antifungal therapy. However, no cases of fungal infections were observed in any treatment group throughout the study. This aligns with recent findings (35) that suggest a low incidence of invasive fungal infections among patients with AML treated with venetoclax and hypomethylating agents, even without routine antifungal prophylaxis. This study (35) and others, suggest that while antifungal prophylaxis can be beneficial, its necessity should be determined based on individual patient risk factors and specific treatment regimens. Similarly, another previous study (36) found that antifungal prophylaxis did not significantly reduce fungal infections in patients receiving azacitidine alone, further indicating that routine prophylaxis may not be necessary for all patients. These findings imply that the risk of fungal infections in certain AML treatment regimens may be lower than expected, and the decision to implement antifungal prophylaxis should be tailored to the specific treatment context and patient risk profile. The present clinical observations, supported by the extant literature, suggest that the absence of antifungal prophylaxis in specific patient groups, including the LDAC group, did not lead to an increased incidence of fungal infections. In the venetoclax group, antifungal agents were, in fact, primarily administered to increase drug concentration not to prevent infections.

The observed statistical difference in overall response rate (P<0.05) in the present study provides valuable insights into the clinical implications of the treatment regimens. This finding suggests that certain regimens may have better efficacy, but their safety profiles should still be carefully evaluated to ensure a favorable risk-benefit balance. By contrast, no statistically significant differences in AEs were observed among the groups. However, common hematological toxicities, including anemia, neutropenia and thrombocytopenia, remain critical concerns in AML treatment and necessitate careful monitoring and supportive care, such as transfusions when required. Similarly, infection-related events, including fever and sepsis, should be actively managed through early detection and prophylactic strategies to mitigate potential complications. While hepatic and renal toxicities did not differ significantly between groups, routine liver and kidney function assessments remain essential in clinical practice. While no statistically significant differences in AEs were found, continued monitoring remains essential to ensure patient safety and optimize treatment outcomes.

Notably, in the venetoclax group, two grade 3 or higher cardiovascular AEs were identified. Literature regarding venetoclax-related cardiovascular reactions is limited (12,14,20), with only one such publication suggesting a potential mechanism where venetoclax induces cardiovascular toxicity through the NF-κB and BCL-2 pathways, which regulate oxidative stress-mediated cardiac inflammation and apoptosis (37). However, further analysis is needed to better understand the origins of these adverse cardiovascular reactions.

Another grade 3 or higher adverse reaction identified in the present study was TLS, with incidence rates comparable to those reported in previous clinical trials (11,12,20). Venetoclax is metabolized by the liver enzyme cytochrome P450 3A4 (24), therefore the present study conducted a subgroup analysis in the venetoclax group to assess the combined effects of multiple cytochrome P450 (CYP) inhibitors and chemotherapy drugs on OS and PFS time. However, the analysis concluded that this did not significantly influence OS or PFS time, which suggests that a 75% reduction in venetoclax dosage with CYP inhibitors may not affect treatment efficacy (24). This dose reduction could potentially lower medication costs and reduce adverse reactions compared with normal doses of venetoclax. Previous studies have shown that strong CYP inhibitors such as ritonavir (38), ketoconazole (39), itraconazole (26,40,41) and posaconazole (25,42) can significantly increase venetoclax levels in the bloodstream.

The unique aspect of the present study was the use of low-dose venetoclax in combination with potent CYP inhibitors. Compared with standard chemotherapy, the venetoclax plus antifungal agents regimen resulted in lower PFS time, OS time and overall response rate. However, it also had a lower infection risk and reduced drug costs, offering potential savings for patients.

The present study also had several limitations primarily stemming from its retrospective design, which may have resulted in small sample sizes in certain groups, potentially introducing statistical bias. For instance, the venetoclax plus azacitidine and antifungal agents group was not represented separately in Fig. 1, Fig. 2, Fig. 3, 4 due to the small sample size, which limited the statistical power for meaningful comparisons. However, aggregated data for this subgroup showed promising trends in terms of efficacy and safety. While these findings are encouraging, they should be interpreted with caution, and further studies with larger sample sizes are necessary to validate these observations. Moreover, venetoclax blood concentrations were not monitored during the study period, although it has previously been suggested that body surface area is negatively correlated with venetoclax levels, implying that monitoring these blood concentrations could improve personalized treatment strategies (43). A final limitation of the present study is the absence of patients with relapsed AML and those receiving standard venetoclax therapy, which is a key area for future research.

In conclusion, the present study suggests that low-dose venetoclax combined with antifungal agents may be inferior to standard chemotherapy treatment, but more effective than regimens involving LDAC or I2A5. In addition, venetoclax demonstrated a relatively low risk of infection, but vigilant monitoring for adverse cardiovascular events and TLS, particularly in patients with relevant medical histories, is crucial. Further studies are necessary to validate these findings.