Meta‑analysis of the efficacy of venetoclax and azacitidine combination therapy and azacitidine monotherapy for treating acute myeloid leukemia
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- Published online on: February 26, 2024 https://doi.org/10.3892/etm.2024.12452
- Article Number: 164
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Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Acute myeloid leukemia (AML) is a malignant tumor of the hematopoietic system characterized by abnormal differentiation and excessive proliferation of hematopoietic stem cells, which may also be accompanied by invasion of the bone marrow, peripheral blood and extramedullary tissue (1). AML is the most common type of leukemia in adults, with a median age of 68 years at diagnosis, and its incidence increases with age (2). Compared with younger patients, older patients are more likely to have adverse cytogenetic risks, secondary AML, monosomal karyotypes and multidrug-resistant phenotypes, as well as more comorbidities and impaired organ function, thereby reducing their tolerance to intensive induction therapy and leading to higher rates of treatment-related mortality (3-6).
At present, the clinical treatment of AML mainly follows ‘3+7’ induction chemotherapy and high-dose cytarabine-based consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. However, in the actual treatment, the space to improve the clinical efficacy of the single application of conventional chemotherapy for AML is limited (7). In recent years, with the rise of molecular-targeted drugs for the treatment of leukemia, molecular-targeted therapy with novel targeted drugs, the combination of targeted drugs and their combination with intensive chemotherapy have attracted increasing attention. The BCL-2 protein is a key factor that regulates the mitochondrial apoptotic pathway, and the survival of leukemia stem cells depends on oxidative phosphorylation and BCL-2 upregulation (8). Notably, BCL-2 has recently become a target for leukemia treatment. Venetoclax is a powerful oral BCL-2 inhibitor, the efficacy and safety of which have been confirmed. The combination regimen of venetoclax with demethylated drugs (decitabine or azacytidine) was approved by the U.S. Food and Drug Administration in November 2018 for the clinical treatment of older adult patients (≥65 years old) with AML (9,10). Azacitidine, a recently developed demethylation drug, is a nucleoside metabolic inhibitor that can exert the dual effect of RNA and DNA demethylation and effectively inhibit the synthesis of proteins in tumor cells (11,12). Notably, it has been reported that venetoclax combined with azacytidine has good clinical value in patients with AML (13). Although the long-term benefits were not maintained in some patients, this regimen can significantly improve survival in patients who are not candidates for intensive chemotherapy. Most published studies are on a generally small size (14-17); therefore, the evidence for these findings is limited. To further optimize the formulation of chemotherapy regimens for patients with AML, exploration of the predictors of efficacy of combination regimens is necessary to guide clinical decision-making. Therefore, the present study focused on the efficacy of venetoclax combined with azacitidine and azacitidine monotherapy in patients with AML.
Materials and methods
Retrieval strategy
The Web of Science (https://www.webofscience.com/wos), PubMed (https://pubmed.ncbi.nlm.nih.gov/), Embase (https://www.embase.com), Cochrane Library (https://www.cochranelibrary.com/), Weipu Database (http://www.cqvip.com), Wanfang Digital Periodicals (https://www.wanfangdata.com.cn), Sinomed (http://www.sinomed.ac.cn), China National Knowledge Infrastructure (https://www.cnki.net/), ProQuest Dissertations and Theses (http://pqdtopen.proquest.com/) and Cumulative Index to Nursing and Allied Health Literature (https://www.ebsco.com/products/research-databases/cinahl-database) were searched for relevant literature. The search was carried out from the establishment of the database to May 2023, with two researchers independently conducting literature searches. The search keywords were (‘Venetoclax’ OR ‘ABT-199’ OR ‘Venclexta’ OR ‘RG7601’ OR ‘RG-7601’ OR ‘GDC-0199’, ‘leukemia, myeloid, acute’ OR ‘acute myeloid leukemia’ OR ‘AML’ OR ‘acute nonlymphocytic leukemia’).
Inclusion and exclusion criteria
The inclusion criteria were as follows: i) Research participants: Adult patients diagnosed with AML; ii) intervention measure: Experimental group (venetoclax combined with azacitidine), control group (azacitidine monotherapy); iii) outcome index: Complete remission (CR), partial remission (PR), no remission (NR) and adverse events (AEs); iv) Study design types: Controlled clinical trial. The exclusion criteria were as follows: i) Age <18 years, patients with non-AML; ii) reviews, systematic reviews, case reports, letters and republished studies; iii) non-case control studies; iv) incomplete or irrelevant treatment outcome reports.
Data extraction
Two independent researchers extracted data separately according to Cochrane systematic review methodology, and when there was a disagreement, it was resolved through discussion or joint evaluation with more senior researchers until a consensus was reached. The literature was scored according to the Newcastle-Ottawa scale (18). In the outcome measurement items, the follow-up time was defined as ≥1 year, the loss rate was ≤15%, and the scores were divided into low, medium and high as follows: <5, 5-8 and 8-9 points, respectively.
Statistical analysis
All extracted data were analyzed using Review Manager 5.4 (https://tech.cochrane.org/revman). Binary variables were represented according to the odds ratio (OR) and 95% confidence interval (CI) of the results. A random-effects model was used for summary analysis when I² was ≤50% between the study groups. When heterogeneity could not be completely eliminated, a random-effects model was adopted. A funnel plot was constructed to assess publication bias by removing studies with high heterogeneity for the sensitivity analysis. P<0.05 was considered to indicate a statistically significant difference.
Results
Search result
According to the search strategy of the present study, 5,271 relevant articles were retrieved from major databases. The inclusion and exclusion criteria were strictly implemented and 10 studies (14-17,19-24) were included.
Information included from the literature
A total of 1,988 patients were included, with 1,323 treated with venetoclax combined with azacitidine and 665 treated with azacitidine monotherapy. The included studies reported six hematological, five gastrointestinal, nine infectious and four serious AEs, as well as two studies each of hypokalemia, decreased appetite and hepatic insufficiency. CR was observed in eight studies, PR in seven studies and NR in eight studies. The literature screening process and results are shown in Fig. 1, and the basic characteristics of the included studies are listed in Table I.
Quality evaluation of the included literature
A total of 10 studies, including six prospective and four retrospective studies, were included. The Newcastle-Ottawa scale was used for quality evaluation, among which two studies scored 9 points, five studies scored 8 points, two studies scored 6 points, and one study scored 5 points. Seven studies were of high quality and three were of medium quality.
Meta-analysis results. Comparison of CR
Eight studies compared CR events between venetoclax combined with azacitidine and azacitidine monotherapy. The heterogeneity test (I2=0%) indicated no significant heterogeneity among the studies, and a random-effects model was used for classification. The results showed that CR events in patients with AML treated with azacitidine monotherapy were significantly lower than those in patients with AML treated with venetoclax combined with azacitidine (95% CI=2.30, 4.34; P<0.00001; Fig. 2).
Comparison of PR. Seven studies compared PR events between venetoclax combined with azacitidine and azacitidine monotherapy. Heterogeneity was observed among the studies (I2=38%); therefore, a random-effects model was used for classification. The results revealed no significant difference in PR events between the venetoclax combined with azacitidine group and the azacitidine monotherapy group (95% CI=1.01, 3.54; P=0.05; Fig. 3).
Comparison of NR. Eight articles compared NR events between venetoclax combined with azacitidine and azacitidine monotherapy. The heterogeneity test (I2=0%) indicated no significant heterogeneity among the studies, and the random-effects model was used for classification. The results showed that NR events in patients with AML treated with venetoclax combined with azacitidine were significantly lower than in patients with AML treated with azacitidine monotherapy (95% CI=0.15, 0.27; P<0.00001; Fig. 4).
Comparison of AEs. Hematological, gastrointestinal, infectious and serious AEs, as well as hypokalemia, decreased appetite and hepatic insufficiency, were included (Fig. 5). Six studies compared hematological AEs between venetoclax combined with azacitidine and azacitidine monotherapy for AML. The heterogeneity test (I2=0%) indicated no significant heterogeneity among the studies and a random-effects model was used for classification. The results showed that hematological AEs in the treatment of AML were significantly lower in patients treated with azacitidine monotherapy than those treated with venetoclax combined with azacitidine (95% CI=1.45, 2.65; P<0.0001).
Five studies compared gastrointestinal AEs in the treatment of AML between venetoclax combined with azacitidine and azacitidine monotherapy. The heterogeneity test (I2=0%) indicated no significant heterogeneity among the studies and a random-effects model was used for classification. The results showed that in the treatment of AML, the incidence of gastrointestinal AEs in response to azacitidine alone was lower than that in response to venetoclax combined with azacitidine, and the difference was statistically significant (95% CI=1.27, 2.72; P=0.001).
Two studies compared the decreased appetite events between venetoclax combined with azacitidine and azacitidine monotherapy in patients with AML. The heterogeneity test (I2=0%) indicated no significant heterogeneity among the studies and a random-effects model was used for classification. The results showed that in the treatment of AML, the incidence of decreased appetite in response to azacitidine alone was lower than that in response to venetoclax combined with azacitidine, and the difference was statistically significant (95% CI=1.06, 2.77; P=0.03).
In addition, no significant differences were observed regarding infectious AEs, serious AEs, hypokalemia or hepatic insufficiency between the two groups [(95% CI=0.86, 2.26; P=0.17), (95% CI=0.98, 2.62; P=0.06), (95% CI=0.64, 1.51; P=0.94), (95% CI=0.21, 8.27; P=0.77), respectively].
Publication bias and sensitivity analysis. Review Manager 5.4 statistical software was used to analyze publication bias for four outcome indicators: CR, PR, NR and AEs. References were individually excluded for sensitivity analysis, and the results were stable. The data were also considered stable and reliable after the sensitivity analysis. The results showed that the funnel plots were symmetric, suggesting no significant publication bias (Fig. 6).
Discussion
AML is a hematological disease with a relatively high incidence, which is characterized by rapid onset and progression. Most patients have several notable symptoms after the onset of the disease, which can have a serious impact on the life and health of patients if not treated in a timely manner (25). AML is characterized by clonal proliferation of malignant bone marrow stem cells, and is often accompanied by infection, anemia and bleeding (26). Currently, combination chemotherapy is the preferred treatment for clinically naïve patients with AML. However, conventional chemotherapy regimens may lead to drug resistance, whereas high-dose chemotherapy leads to severe myelosuppression (27). In recent years, the emergence of novel targeted drugs has provided innovative options for patients with AML not eligible for intensive induction chemotherapy, effectively improving the response and survival rates.
BCL-2 is a key molecule in the regulation of apoptosis of tumor cells and is a novel target for the treatment of leukemia (28). The BCL-2 protein family is an important regulator of endogenous apoptotic pathways. Notably, BCL-2 is upregulated in AML and its stem cells, thereby mediating the survival of AML cells, and their resistance to chemotherapy and targeted therapies (29,30). Venetoclax was the first marketed BCL-2 inhibitor (1); this drug induces the apoptosis of tumor cells and improves AML treatment sensitivity by targeting BCL-2. It has previously been shown that a combination of venetoclax and hypomethylating agents can delay the development of drug resistance, and improve the remission and survival rates of patients with AML (31). Azacitidine, a recently developed demethylation drug, is a nucleoside metabolic inhibitor that can exert the dual effect of RNA and DNA demethylation and effectively inhibit the synthesis of proteins in tumor cells (31,32). Relevant clinical trials have shown that compared with the traditional treatment regimen, azacitidine can effectively optimize the treatment effect and prolong the survival of patients with AML (33). Moreover, azacitidine is an effective and low-toxicity alternative for patients with AML who have lost the opportunity for transplantation and have difficulty tolerating traditional chemotherapy regimens (33,34). However, in untreated patients with AML aged ≥65 years, azacitidine monotherapy has a response rate of ≤30% and results in survival time of <1 year (35). Preclinical studies (11,36,37) have shown that azacitidine enhances the antitumor effect of venetoclax by activating the transcription of the pro-apoptotic protein NOXA, and that the combination of azacitidine and venetoclax induces deep and long-lasting anti-leukemia effects by blocking the energy metabolism of leukemia stem cells.
To evaluate the therapeutic effect of venetoclax combined with azacitidine, and provide more evidence for the selection of clinical treatment plans, the present study conducted a meta-analysis using venetoclax combined with azacitidine as the observation group and azacitidine alone as the control group. The aim was to observe the effects of these two treatment regimens on clinical efficacy and the AEs of patients with AML. Through data analysis, the present meta-analysis confirmed that azacitidine + venetoclax combination therapy exhibited a significant advantage in improving the CR rate of patients with AML (95% CI=2.30, 4.34; P<0.00001). Significant heterogeneity was not observed (I2=0%). DiNardo et al (19) reported that the composite CR rate of patients in the azacitidine + venetoclax group was 66.4%, which was significantly higher than that of patients in the azacitidine monotherapy group. The results of Cui et al (14) also showed that the total effective rate of the azacitidine + venetoclax group (86.67%) was significantly higher than that of the azacitidine group (46.67%) (P<0.05).
In the present study, no statistically significant difference was observed between the azacitidine + venetoclax combination treatment and azacitidine monotherapy groups regarding the occurrence of PR events in patients with AML (95% CI=1.01, 3.54; P=0.05). However, there was a statistically significant difference between the venetoclax + azacitidine combination treatment and azacitidine monotherapy groups regarding the occurrence of NR events (95% CI=0.15, 0.27; P<0.00001), with no significant heterogeneity (I2=0%), suggesting that venetoclax combined with azacitidine resulted in a lower incidence of NR events than azacitidine monotherapy in the treatment of AML. Therefore, it was concluded that azacitidine + venetoclax combination therapy may be superior to azacitidine monotherapy, and that combination therapy can significantly improve the incidence of CR in patients with AML. The present results are consistent with those of previous clinical studies (14-17,20-22,24) and practical experience, supporting the clinical feasibility and effectiveness of this treatment regimen. In addition, it is worth noting that the present meta-analysis observed that the overall incidence of AEs in patients with AML treated with venetoclax combined with azacitidine was significantly higher than those in patients treated with azacitidine monotherapy (95% CI=1.33, 1.91; P<0.000001); however, there was heterogeneity (I2=29%). The studies by Xia et al (16) and Yang et al (24) showed a significant impact on the incidence of AEs. Moreover, the most common AEs in both groups were hematological (pooled OR=1.96; 95% Cl=1.45, 2.65; P<0.0001) and gastrointestinal (pooled OR=1.86; 95% Cl=1.27, 2.72; P=0.001). These findings are consistent with those of previous studies (17,23).
Compared with previous similar studies, such as those by Du et al (38) and Bewersdorf et al (39), the present study has several advantages. First, few randomized controlled trials were included in the previous studies, and there was a lack of prospective studies that could affect the reliability of the results. The present meta-analysis included six randomized controlled trials, including prospective studies, which increased the reliability of the results. Second, more than half of the participants in previous studies were from the U.S.; therefore, there is insufficient evidence on whether the results of previous studies can be generalized to other populations. The present study included research on Chinese patients and patients from other countries, further demonstrating the efficacy and safety of azacitidine + venetoclax for treating patients with AML from different countries. Third, the data in previous meta-analyses were highly heterogeneous, and it was difficult to determine the cause of the heterogeneity. However, the current study showed low heterogeneity in the statistical data, demonstrating the reliability of the results.
Although the results of the present meta-analysis showed the advantages of azacitidine + venetoclax in AML treatment, some limitations should be noted. First, because the data sources were mainly clinical trials and literature reports, there may have been selective reporting and publication bias. Second, the dose and course of treatment used in the different studies may have produced some heterogeneity, affecting the reliability of the results. Based on the findings of the present study, we recommend that azacitidine + venetoclax combination therapy for AML be further promoted in clinical practice. However, more large-scale multicenter clinical studies are needed to better evaluate the efficacy and safety of this treatment regimen. We encourage further exploration of other potential combination treatment options to improve the survival and quality of life of patients with AML.
In conclusion, the present study observed that, despite some adverse reactions, the combination regimen of azacitidine and venetoclax did not lead to a deterioration in the prognosis of patients with AML, which is of great significance for the long-term treatment and quality of life of patients. Notably, azacitidine monotherapy is often associated with relapse and a series of side effects and AEs, such as bone marrow suppression and liver function abnormalities (35). Therefore, the addition of venetoclax serves a positive role in delaying disease recurrence and alleviating adverse reactions in patients. In summary, azacitidine + venetoclax has significant efficacy in AML treatment and can improve the overall response rate of patients with high safety.
Acknowledgements
Not applicable.
Funding
Funding: The present study was funded by the Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (grant no. 2021L353) and the Natural Science Foundation for Young Scientists of Shanxi Province (grant no. 20210302124089).
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
YQX and XQW were responsible for the design of the current study, and both performed the statistical analysis. YQX and XQW confirm the authenticity of all the raw data. WWW and CSL were responsible for the acquisition and sorting of data. PFH and YHY performed the interpretation of the data. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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