The Efficacy of Venetoclax + LDAC and CPX-351 over Traditional Regimen in Older Patients with AML Not Eligible for Intensive Therapy: A Meta-Analysis and Systematic Review
Authors: Wang Kai , Pokima Ngowari , Keesari Praneeth Reddy , El-gharib Khalil , Widjaja Michael , El-Sayegh Suzanne 
Published: December 2024

Background: Acute myeloid leukemia (AML) is the second most common type of leukemia and an aggressive hematological malignancy whereby both differentiation failure and over-proliferation of stem cells in the bone marrow cause an accumulation of immature myeloblasts. Treatment of AML with curative intent is typically reserved for patients younger and healthier. However, given the complexity of the disease and poorer outcomes in the elderly, a significant portion of patients are considered not fit for standard treatment. For a long time, low-dose Cytarabine (LDAC) was the go-to chemotherapy agent as a less-intensive approach to treatment albeit with varied response rates. When combined with an anthracycline in the 7+3 regimen, it showed an improvement in efficacy and became a standard for AML induction therapy. In recent years, B-cell leukemia/lymphoma-2 (BCL-2) inhibitor Venetoclax has been studied alone and in combination with other agents and has shown significant response improvement in hematological malignancies. Moreover, CPX-351 (VYXEOS; Jazz Pharmaceuticals, Palo Alto, CA), a dual-drug encapsulation with 5:1 ratio of cytarabine + anthracycline, has also shown great promise in initial studies against the traditional 7+3 regimen. This systematic review and meta-analysis aim to synthesize current trials on the efficacy of traditional vs newer treatments of AML.

Methods: A systematic review search was conducted on PubMed to identify studies examining the efficacy of AML treatment. Studies were included if they tested for the efficacy of treatments using LDAC +/- Venetoclax, 7+3 regimen, or CPX-351 in patients not eligible for standard intensive chemotherapy against a matched sample of controls (matched on age, comorbidities, and AML diagnosis criteria). Controls were either treated with LDAC alone or with the 7+3 regimen. From 16 records initially found in the database, only 5 were eligible and included in this meta-analysis. The outcomes studied were overall survival (OS) and complete remission rate (CR) in each treatment group. We used the random effects method to pool weighted mean differences in outcomes. Heterogeneity was assessed with I2. The parameters of the effect size used a confidence interval of 95% and a statistical significance with p-value &lt; 0.05.

Results: The meta-analysis included 5 studies and a total of 493 patients. Patients receiving Venetoclax+LDAC have a significantly higher OS (pooled mean different = 4.05, 95% CI 3.27-4.84, p&lt;0.01) and a higher CR (pooled mean difference = 26.57, 95% CI 13.54-39.61, p&lt;0.01) when compared to LDAC alone. Patients who received the CPX-351 formulation also had a significantly higher OS (pooled mean difference = 2.55, 95% CI 1.27-3.83, p&lt;0.01) and CR (pooled mean difference = 13.63, 95% CI 10.94-16.31, p&lt;0.01) when compared to the traditional 7+3 regimen. The Venetoclax/LDAC group showed a low heterogeneity index ( I2=47%), further reinforcing the validity of the results in this group.

Conclusions: This systematic review and meta-analysis demonstrate that newer combination therapies (Venetoclax + LDAC) or formulations (CPX-351) have superior efficacy than traditional therapies such as LDAC alone or the 7+3 regimen. While the sample size in this analysis is relatively small, there is a clear positive trend in favor of the newer combination therapies that can increase survival in patient groups that would otherwise have a very poor prognosis. On the other hand, the results seen in this meta-analysis also bring interest to other combination therapies (such as Venetoclax + hypomethylating agents, targeted therapies, gilteritinib, CAR-T therapy, etc) that may also be more efficacious than traditional therapies. Further, more research can be conducted to explore the tolerance and adverse effects of these newer combination therapies to bring a more complete understanding of treating older patients with AML. Overall, the results in this meta-analysis have important implications in clinical counseling and therapy decisions in AML and elucidate important future research interests for the treatment of AML in older patients.

Keywords: Acute myeloid leukemia, ventoclax, LDAC, CPX-351, 7+3 regimen, combination therapy, Meta-analysis, Systematic Review