Venetoclax-based combination therapies for AML in patients ineligible for intensive chemotherapy

Treatment for patients with acute myeloid leukemia (AML) typically consists of intensive chemotherapy; however, many patients are ineligible for intensive chemotherapy due to toxicity.¹ Treatment in these patients typically includes lower-intensity regimens, such as hypomethylating agents, low-dose cytarabine, or supportive care.

The use of venetoclax, a B-cell lymphoma 2 inhibitor has been extensively covered by the AML Hub. In addition, the VIALE-A (NCT02993523) and VIALE-C (NCT03069352) trials have demonstrated the efficacy of venetoclax in combination with azacitidine or low-dose cytarabine, respectively, in patients with AML who are ineligible for intensive chemotherapy.¹

To date, there have been no head-to-head randomized controlled trials comparing the efficacy of venetoclax-based combinations with conventional treatment options in patients with AML who are ineligible for intensive chemotherapy.¹ Li et al. recently published a network meta-analysis assessing the efficacy of venetoclax-based combinations compared with conventional treatment options in Value Health. Here, we summarize the key points.

Methods¹

In October 2020, a systematic literature review was performed to identify phase III randomized controlled trials for network meta-analyses. Eligible trials compared complete remission (CR) + CR with incomplete count recovery (CRi) and overall survival (OS) for ≥2 treatments of interest in adult patients with AML who were ineligible for intensive chemotherapy.

Two separate network meta-analyses were conducted for CR + CRi and OS. Relative rankings for each treatment were estimated based on surface area under the cumulative ranking curve (SUCRA) value, with a higher SUCRA indicating the treatment was more likely to be efficacious in the network.

In total, five randomized controlled trials were included in this analysis (Figure 1).

Figure 1. Randomized controlled trials included in the venetoclax network meta-analysis*

CR, complete remission; CRi, CR with incomplete count recovery.
*Data from Li et al.^1
†The AZA-001 trial was not included in the CR + CRi analysis.

Results¹

Responses

Patients treated with venetoclax + azacitidine or venetoclax + low-dose cytarabine were more likely to achieve CR + CRi than patients receiving azacitidine, low-dose cytarabine, or best supportive care (Table 1). Patients who received venetoclax-based combinations were numerically more likely to achieve CR + CRi than patients treated with decitabine, but this did not reach statistical significance.

Table 1. Pairwise treatment comparison of CR + CRi*

Based on cumulative treatment rankings, venetoclax-based combinations were the highest-ranked, followed by decitabine, azacitidine, low-dose cytarabine, and best supportive care (Figure 2).

Figure 2. SUCRA values for CR + CRi* 

AZA, azacitidine; BSC, best supportive care; CR, complete remission; CRi, CR with incomplete count recovery; DEC, decitabine; LDAC, low-dose cytarabine; SUCRA, surface area under the cumulative ranking curve; VEN, venetoclax.
*Data from Li, et al.¹

Survival

Patients treated with venetoclax + azacitidine had a lower risk of death compared with patients treated with azacitidine, low-dose cytarabine, and best supportive care (Table 2). Treatment with venetoclax + low-dose cytarabine was also associated with a lower risk of death compared with low-dose cytarabine + best supportive care (Table 2). Patients treated had a numerically lower risk of death with venetoclax-based treatment compared with patients treated with decitabine; however, this was not significant.

Table 2. Pairwise treatment comparison of OS*

Venetoclax-based treatments were the highest-ranked treatments for OS, followed by decitabine, azacitidine, low-dose cytarabine, and best supportive care (Figure 3).

Figure 3. SUCRA values for OS* 

AZA, azacitidine; BSC, best supportive care; DEC, decitabine; LDAC, low-dose cytarabine; OS, overall survival; SUCRA, surface area under the cumulative ranking curve; VEN, venetoclax.
*Data from Li, et al.¹

Conclusion

The findings from this analysis suggest that venetoclax-based combinations are associated with improved response rates and survival outcomes when compared with azacitidine, low-dose cytarabine, and best supportive care alone.

While this network meta-analysis provides an indirect comparison of venetoclax-based treatments and other lower-intensity treatments in the absence of phase III randomized controlled trials, there are several limitations; the results may be influenced by the heterogeneity of patient populations across the included trials. Additionally, not all treatment options were captured, particularly venetoclax + decitabine.

Despite these limitations, results suggest that venetoclax-based treatments have the potential to improve outcomes in patients with AML who are ineligible for intensive chemotherapy, a patient population with historically poor outcomes.