The efficacy and safety of venetoclax combined with decitabine in elderly patients with acute myeloid leukemia: a systematic review and meta-analysis

Abstract

Acute Myeloid Leukemia (AML) carries a high mortality rate in elderly patients who often face limited treatment options and a poor overall prognosis. The combination of Venetoclax (VEN) and Decitabine (DEC) is recommended for treatment, yet there is insufficient evidence to fully support its efficacy. This study aims to perform a meta-analysis to evaluate the effectiveness and safety of the VEN + DEC regimen in treating elderly patients with AML. We systematically searched PubMed, EMBASE, the Cochrane Library, CNKI, and WanFang. Efficacy was evaluated using complete remission (CR), composite response rate, overall response rate, and median overall survival. Safety was assessed based on adverse events. The fixed/random effect model was employed to evaluate the effect sizes. Seven articles were included in this meta-analysis. VEN + DEC group (OR 1.90, 95%CI 1.36–2.67) could significantly improve CR among the elderly patients with AML, compared to the control group. VEN + DEC was associated with a significantly lower risk of death (HR 0.55, 95%CI 0.40–0.75). VEN (400 mg) + DEC group (OR 1.99, 95%CI 1.37–2.87) could significantly increase CR. Subgroup analysis reported that there were significant differences in both any grade (OR 1.99, 95%CI 1.18–3.35) and grade 3/4 febrile neutropenia (OR 1.99, 95%CI 1.18–3.35) between VEN + DEC group and the control group. Our findings demonstrated that the VEN + DEC regimen is both effective and safe for treating elderly patients with AML. Besides, the combination of VEN (400 mg) with DEC had relatively high rate of CR.

Trial registration We have registered out study on PROSPERO with the registration number CRD42024554185.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10238-025-01794-w.

Background

Acute Myeloid Leukemia (AML) is a malignant proliferative disease of the blood that results in an abnormal increase in the number of leukocytes in the peripheral blood and hematopoietic insufficiency, mainly through proliferation, cloning, and aberrant differentiation in the bone marrow, blood, and other tissues [1]. AML is the most common form of acute leukemia in adult [2]. AML predominantly affects adults, particularly those over 60 years of age. Epidemiological studies indicate that in many countries, the annual incidence of AML among adults is approximately 3–5 cases per 100,000 individuals [3–5], with a 5-year overall survival rate ranging from 40 to 50% [6]. Among individuals aged over 65, the incidence rises substantially to more than 10 cases per 100,000 population [6, 7]. The prognosis for elderly patients with AML remains dismal, with the majority succumbing to the disease within one year of diagnosis [8].

AML can be life-threatening, with a particularly high mortality rate in the elderly. Several factors contribute to the poor prognosis in older AML patients compared to younger AML patients. First, Advanced age is often accompanied by poor basal status, comorbidities, complications, and reduced tolerance to conventional chemotherapy regimens [9]. Second, older patients frequently present with adverse disease characteristics and an increased prevalence of primary drug resistance genes [10, 11], rendering standard chemotherapy regimens significantly less effective. Finally, recent studies suggest that low-intensity chemotherapy or supportive care may not adequately address this disease [12, 13]. All these factors make the treatment options for elderly AML patients, making them both controversial and challenging [14]. Consequently, there is an urgent need to identify optimal treatment strategies for elderly AML patients.

The occurrence of AML is related to the abnormal methylation of oncogenes such as Hypermethylated in Cancer 1 (HIC-1A), P15 and Estrogen Receptor (ER). When the oncogenes are abnormally methylated, the anticancer ability of the oncogenes will be weakened, which will lead to the further progression and differentiation of tumors, and reduce the efficacy of chemotherapeutic agents, especially in the context of poor tolerability and declining physical function [15]. Decitabine (DEC) is a DNA demethylating agent (HMA) that inhibits DNA methyltransferases and induces the re-expression of oncogenes associated with the pathogenesis of MDS or AML, promoting apoptosis in leukemia cells via the P53-mediated DNA damage repair pathway [16]. DEC in the treatment of MDS has been internationally recognized [17] and has also been introduced into the treatment of AML. Several studies have shown that DEC is effective in the elderly with AML and shows tolerable toxicity [16]. However, while DEC monotherapy shows some clinical value in treating AML, its efficacy remains limited [18]. Therefore, the efficacy of DEC is still unsatisfactory and needs to be combined with other drugs to further improve its efficacy.

Kwag et al. [19] reported that DEC + Venetoclax (VEN) has superior outcomes to DEC monotherapy for older adults with AML. B-cell lymphoma 2 (Bcl-2) plays a key role in apoptosis process of tumor cells and it is a new target for leukemia [20, 21]. The combination regimen of the Bcl-2 inhibitor VEN and hypomethylating agents for this target has been approved by the U.S. Food and Drug Administration (FDA) in November 2018 for the treatment of newly-diagnosed AML patients who are 75 years or older, or who have complications that are not suitable for high-intensive chemotherapy [22]. Several studies have confirmed that combination strategies of VEN and DEC have obtained positive results in the treatment of elderly patients with AML [19, 23]. However, there are only a few reports on the efficacy and safety of the combination therapy of VEN and DEC for the treatment of elderly patients with AML.

This study performed a meta-analysis to explore the efficacy and safety of the combination therapy of VEN and DEC in order to provide more evidence for the clinical treatment of elderly patients with AML.

Methods

Research design

The present meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement [24]. We have registered our study on PROSPERO with the registration number CRD42024554185.

Search strategy and data sources

The data sources include the following electronic databases: PubMed, EMBASE, the Cochrane Library, CNKI, and WanFang (up to 3 April 2024). We used the search terms, including “Acute Myeloid Leukemia,” “Decitabine,” and “Venetoclax”. The detailed search strategies were presented in Table S1.

Selection criteria

We established the inclusion criteria based on the Population, Intervention, Comparator, Outcomes, and Study designs (PICOS) framework. Specifically, studies were eligible for inclusion if they met the following criteria: (1) Population: Untreated AML patients aged 60 years or older who fulfilled established diagnostic criteria; (2) Intervention: VEN combined with DEC was used in the treatment regimen; (3) Outcomes: All studies had clear defied outcome measures, including complete remission (CR), composite response rate (CRR), overall response rate (ORR), median overall survival (OS), and adverse event (AE).

We excluded ineligible studies according to the following exclusion criteria: duplicate reports involving the same patient group, ineligible study design (e.g., animal experiments, reviews, and abstracts), and lack of essential data.

Outcome definition

The efficacy was assessed as the rates of objective response, including CR, CRR (CR + CR with incomplete blood count recovery [CRi]), and ORR (CR + CRi + partial remission [PR]), and median OS. The safety was assessed as the rates of adverse event.

Data extraction

Information was extracted from eligible studies by two authors independently. The included information are as follows: authors of the articles, published year, study location, study design, age of patients, sample size, covariates, and measured outcome (such as events occurred in each group and/or hazard ratios [HR] with 95% confidence interval [CI]). Any disagreements were resolved through discussion among all authors.

Risk of bias assessment

The revised Cochrane Risk of Bias (RoB) Assessment Tool 2.0 was adopted to assess the risk of bias in each eligible study across five domains. Each domain was classified as having “low risk,” “some concerns,” or “high risk” of bias. Any discrepancies were settled by consensus among the authors.

Statistical analysis

Revman 5.4 and Stata V.12.0 (StataCorp LP) were used for this study. Outcomes were presented as odds ratios (ORs) and HR with their 95% CI. The Cochrane Q and I² statistics were employed to assess heterogeneity among the studies, with substantial statistical heterogeneity indicated by P < 0.1 and I² ≥ 50%. When there is the presence of heterogeneity, random-effects model should be adopted to calculate the pooled estimated size and 95% CI. Otherwise, the fixed effects model was conducted. Subgroup analysis according to VEN dosage, study design and AE type. A sensitivity analysis was performed to evaluate the robustness of the pooled results by omitting each study one at a time to assess the stability of the conclusions. A probability value of less than 0.05 (two-tailed) was considered statistically significant.

Results

Search results

Initially, 10,488 articles were identified. Following the exclusion criteria, 6,859 articles were removed due to duplication and irrelevance, and an additional 3,617 articles were excluded based on study types (including animals’ trials, meeting abstracts, case reports, meta-analyses, reviews, dissertations, books, and protocols). According to the inclusion criteria, eight articles were further excluded due to insufficient data. As a result, seven articles [19, 23, 25–29] were included in this meta-analysis (Fig. 1).

Fig. 1.

Flow diagram of the search process and study selection

Study characteristics

Seven articles were included in this meta-analysis, comprising two radomized cotrolled trials (RCTs), two sing-arm non-RCTs, and three cohort studies. A total of 707 patients with AML were analyzed, with ages ranging from 61 to 90 years. Two articles investigated different VEN dose during the expansion phase to assess the efficacy and safety of VEN + DEC, including 400 mg, 800 mg, and 1200 mg. The control groups featured four different treatment regimens: VEN + azacitidine (AZA), DEC + Cytarabine + Adriamycin + Granulocyte Colony-Stimulating Factor (CAG), DEC monotherapy, and intensive chemotherapy. There were three studies in China, three in USA, and one in Korea. Detailed study characteristics are reported in Table 1.

Table 1.

Study characteristics of included studies

Study	Country	Study design	Intervention group					Control group					VEN dosage
			Treatment	Sample size	Median age	Male (%)	Median OS (months)	Treatment	Sample size	Median age	Male (%)	Median OS (Months)
DiNardo et al. 2019	USA	Single-arm non-RCT	VEN + DEC	73	73 (65–86)	30 (21)	14.2 (7.7-NR)	VEN + AZA	72	74 (65–86)	31 (62)	NR (9.0-NR)	400 mg, 800 mg, 1200 mg, qd
Pollyea et al. 2020	USA	Single-arm non-RCT	VEN + DEC	31	72 (65–86)	15 (48)	16.2 (9.1–27.8)	VEN + AZA	84	75 (61–90)	51 (61)	16.4 (11.3–24.5)	400 mg, 800 mg, 1200 mg, qd
Kwag et al. 2022	Korea	Cohort	VEN + DEC	74	71 (68–75)	32 (43.2)	13.4 (8.7-NR)	DEC	74	72 (70–76)	37 (50.0)	8.3 (5–10.5)	400 mg, qd
Maiti et al. 2022	USA	Cohort	VEN + DEC	85	72 (69–78)	45 (53)	12.4	Intensive chemotherapy	85	73 (67–76)	48 (56)	5	400 mg, qd
Chen et al. 2024	China	RCT	VEN + DEC	25	72.55 ± 3.53	14 (56)	NR	VEN + AZA	25	71.56 ± 3.50	16 (64)	NR	400 mg, qd
Zhang et al. 2022	China	Cohort	VEN + DEC	17	65 (63–70.5)	4 (23.53)	10.73	DEC + CAG	12	64 (61.25–66.75)	5 (41.67)	8.57	400 mg, qd
Ren et al. 2023	China	RCT	VEN + DEC	25	67.89 ± 4.39	18 (72)	NR	DEC	25	67.76 ± 4.46	17 (68)	NR	400 mg, qd

RCT randomized controlled trial, VEN venetoclax, DEC decitabine, AZA azacitidine, NR not reached

Study quality

Study quality was assessed using the ROB 2.0 tool in this meta-analysis. Overall, four studies exhibited some concerns regarding the risk of bias, two studies had a low risk, and one study was classified as having a high risk of bias (Figure S1).

Complete remission (CR)

Fixed effects model analysis showed that VEN + DEC group (OR 1.90, 95%CI 1.36–2.67) could significantly improve CR among the elderly patients with AML compared to the control group (Fig. 2A).

Fig. 2.

Forest plot of complete remission (A), composite response rate (B), overall response rate (C), median overall survival (D)

Subgroup analysis (Figure S2 and Table 2) revealed that the VEN (400 mg) + DEC group (OR 1.99, 95%CI 1.37–2.87) significantly increased CR among the elderly patients with AML (Figure S2 and Table 2), while the VEN (800 mg) + DEC group (OR 1.25, 95%CI 0.50–3.13) and VEN (1200 mg) + DEC group (OR 7.50, 95%CI 0.46–3.13) did not show significant improvements in CR. In addition, the studies evaluating CR included both RCTs and non-RCTs. To investigate the impact of study design on the results, we conducted a subgroup analysis. The findings revealed that in the RCT subgroup, there was no significant difference in CR between the VEN + DEC group and the control group (OR 1.11, 95% CI 0.45–2.73). However, in the non-RCT subgroup, the pooled results indicated that the VEN + DEC group (OR 2.08, 95% CI 1.44–3.00) was associated with a significantly higher CR rate among elderly patients with AML (Figure S3 and Table 2).

Table 2.

Subgroup analysis of complete remission (CR), composite response rate (CRR), overall response rate (ORR), and adverse events (AEs)

Stratified analysis	N	Pooled estimates (95%CI)	Heterogeneity
			I2 (%)	P-value
CR (any dose)
VEN 400 mg	6	1.99 (1.37, 2.87)	32.2	0.194
VEN 800 mg	1	1.25 (0.50, 3.13)	0.0	–
VEN 1200 mg	1	7.50 (0.46, 3.13)	0.0	–
CR (any study design)
RCT	2	1.11 (0.45, 2.73)	63	0.82
Non-RCT	6	2.08 (1.44, 3.00)	0.0	< 0.0001
CRR
VEN 400 mg	3	2.43 (0.60, 9.92)	79.3	0.008
VEN 800 mg	1	2.06 (0.78, 5.45)	0.0	–
VEN 1200 mg	1	1.50 (0.14, 5.45)	0.0	–
ORR
VEN 400 mg	3	2.16 (0.50, 9.38)	80.3	0.006
VEN 800 mg	1	2.12 (0.78, 5.75)	0.0	–
VEN 1200 mg	1	3.00 (0.25, 35.33)	0.0	–
AEs (any grade)
Febrile neutropenia	4	1.99 (1.18, 3.35)	0.0	0.462
Decreased WBC count	4	1.46 (0.85, 2.50)	0.0	0.462
Anemia	3	1.05 (0.50, 2.19)	15.8	0.305
Pneumonia	1	1.33 (0.57, 2.19)	0.0	–
AEs (grade 3/4)
Febrile neutropenia	4	1.99 (1.18, 3.35)	0.0	0.462
Decreased WBC count	3	1.34 (0.66, 2.70)	18.2	0.295
Anemia	4	0.87 (0.49, 1.55)	0.0	0.756
Pneumonia	1	1.01 (0.42, 2.43)	0.0	–

Composite response rate (CRR)

Random effects model analysis showed that VEN + DEC group could not improve CRR (OR 2.29, 95%CI 0.96–5.51) (Fig. 2B) compared to the control group. In addition, none of the dosage groups significantly increased CRR (400 mg: OR 2.43, 95%CI 0.60–9.92; 800 mg: OR 2.06, 95%CI 0.78–5.45; 1200 mg: OR 1.50, 95%CI 0.14–5.45) (Figure S4 and Table 2).

Overall response rate (ORR)

Random effects model analysis indicated that VEN + DEC group could not improve ORR (OR 2.31, 95%CI 0.95–5.63) (Fig. 2C) compared to the control group. Furthermore, none of the dosage groups demonstrated significant increases in ORR (400 mg: OR 2.16, 95%CI 0.50–9.38; 800 mg: OR 2.12, 95%CI 0.78–5.75; 1200 mg: OR 3.00, 95%CI 0.25–35.33) (Figure S5 and Table 2).

Median overall survival (OS)

Fixed effects model analysis showed that VEN + DEC (HR 0.55, 95%CI 0.40–0.75) (Fig. 2D) was associated with a significantly lower risk of death than the control group.

Any grade adverse events (AEs)

In the included studies, AEs mainly included febrile neutropenia, decreased white blood cell (WBC) count, anemia, and pneumonia. To visually present the occurrence of different AEs, a subgroup analysis was conducted. This analysis revealed a significant difference in any grade febrile neutropenia between the VEN + DEC group and the control group (OR 1.99, 95%CI 1.18–3.35). However, there was no significant difference in any grade decreased WBC count (OR 1.46, 95%CI 0.85–2.50), anemia (OR 1.05, 95%CI 0.50–2.19), or pneumonia (OR 1.33, 95%CI 0.57–3.14) (Fig. 3A and Table 2).

Fig. 3.

Forest plot of any grade adverse events (A) and grade 3/4 adverse events (B)

Grade 3/4 adverse events (AEs)

Regarding grade 3/4 AEs, subgroup analysis reported that there was a significant difference in grade 3/4 febrile neutropenia between the VEN + DEC group and the control group (OR 1.99, 95%CI 1.18–3.35). However, there was no significant difference in any grade decreased WBC count (OR 1.34, 95%CI 0.66–2.70), anemia (OR 0.87, 95%CI 0.49–1.55), or pneumonia (OR 1.01, 95%CI 0.42–2.43) (Fig. 3B and Table 2).

Sensitivity analysis

Sensitivity analysis showed that all the pooled CR, CRR, and ORR results were stable, indicating that our findings were reliable (Figure S56-S8).

Discussion

This study represents the first meta-analysis assessing the efficacy and safety of the VEN + DEC regimen for elderly patients with AML. VEN is a potent oral Bcl-2 selective inhibitor that binds to the BH3 structural domain of Bcl-2 family proteins, inhibiting Bcl-2 protein expression and activating the endogenous mitochondrial apoptotic pathway, which leads to rapid apoptosis of tumor cells [28]. Several studies have demonstrated the antitumor activity and tolerable safety profile of VEN in elderly AML patients who are not candidates for conventional chemotherapy [30–33]. Increasingly studies used VEN + DEC regimen, and got satisfactory outcomes for elderly patients with AML [19, 26]. Results of our meta-analysis further confirmed the efficacy and safety of VEN + DEC regimen.

Our findings indicated that VEN + DEC regimen was associated with a better CR than observed with the control groups in elderly patients with AML, which was in accordance with previous studies. A meta-analysis [34] reported that VEN combined with demethylating agents (e.g., DEC) had a good therapeutic effect in elderly patients with AML. Maiti et al. [26] reported that CR rate was significantly higher in the VEN + DEC group than in the intensive chemotherapy group (62.0% vs. 42.0%, P = 0.01). Studies have indicated that VEN in combination with demethylating drugs, could prevent the uptake of amino acids by leukemia cells, thereby interfering with the oxidative phosphorylation process in leukemia cells [35, 36]. In addition, our study found that VEN 400 mg + DEC group could significantly increase CR among the elderly patients with AML. However, similar results were not found in VEN 800 mg and 1200 mg group due to small sample size. This result indicated that the combination of VEN 400 mg with DEC demonstrated high rates of CR in elderly patients with AML, compared to VEN 800 mg or 1200 mg.

Furthermore, our results demonstrated that VEN + DEC regimen was associated with a significantly reduced risk of death in elderly patients with AML. Medeiros et al. [37] thought that OS is the gold standard adhered to by health regulators and is the most common primary endpoint in Phase III clinical trials when determining the clinical benefit of any new AML therapy. Kwag et al. [19] reported that OS was significantly longer in the VEN + DEC group than in the DEC group (62.0% vs. 42.0%, P < 0.05). These results further confirmed that VEN + DEC regimen offers superior outcomes in older patients with AML. Besides, CR + CRi is an important outcome in patients with AML and is increasingly used to assess the clinical efficacy of new therapies [38]. However, our results found that there were no significant differences in CRR and ORR due to small sample size.

Regarding the safety of VEN + DEC, our results reported that VEN + DEC regimen was more likely to occur febrile neutropenia compared to the control group, while similar frequencies of decreased WBC count, anemia, and pneumonia were not observed in both groups. WEI et al. [34] conducted a meta-analysis to evaluate the efficacy and adverse effects of VEN in combination with demethylating drugs (e.g., DEC) in elderly with AML, and reported that febrile neutropenia had the highest incidence of approximately 49% in VEN in combination with demethylating drugs. These AEs were tolerable and resolved with treatment. Therefore, VEN + DEC regimen had good safety for elderly patients with AML.

In this meta-analysis, the control groups included VEN + AZA, intensive chemotherapy, and decitabine monotherapy, each with distinct efficacy and safety profiles, which may introduce heterogeneity and affect the interpretation of our results. Compared to VEN + AZA, VEN + DEC demonstrated numerically higher response rates and overall survival [23]. However, these differences may be due to variations in study design, patient characteristics, and venetoclax dosing, with a lack of direct comparative data between the regimens. While intensive chemotherapy achieves higher CRR, it carries increased mortality risks and limited benefits for elderly or frail patients. In contrast, VEN + DEC has shown better tolerability and favorable outcomes in this population [26]. The response rates of decitabine monotherapy were consistently lower than those with VEN + DEC, highlighting the synergistic effect of the combination. However, monotherapy groups often included more advanced or relapsed patients, complicating direct comparisons [19, 28]. Due to the limited number of studies, we could not perform subgroup analyses based on control group types. Further high-quality, well-designed controlled studies are necessary to validate the efficacy and safety of the VEN + DEC regimen in elderly patients with AML.

Our findings are significant because the U.S. FDA approved the VEN + DEC regimen without data specifically supporting its use. They only compared the efficacy and safety of VEN + AZA and AZA monotherapy [39]. Thus, our findings provided strong evidence for FDA approval of the effectiveness of the VEN + DEC regimen. Our data further suggest that the VEN + DEC regimen is a clinically effective treatment option for elderly AML patients who are not candidates for intensive chemotherapy.

However, several limitations should be noted in the present meta-analysis. First, our meta-analysis only included seven studies and some of them did not adequately report key survival data. Hence, the number of the included studies and sample size of the included elderly patients with AML were relatively limited. In addition, there were some certain degree of heterogeneity. Second, some of the included studies were not randomized, blinded, and had unclear allocation concealment, which led to increased bias. Third, not all included studies reported relevant adverse events, and thus the synthesis of data on the incidence of adverse events was not sufficiently analyzed.

Conclusion

In summary, our findings demonstrated that the VEN + DEC regimen was effective and safe for treatment of elderly patients with AML. Results of subgroup analysis indicated that the combination of VEN 400 mg with DEC had relatively high rate of CR. A large-sample multicenter randomized controlled trial study is needed to further confirm the clinical efficacy of the therapy so that it can be rationally promoted and applied in clinical practice.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

AML

Acute Myeloid Leukemia

CR

Complete remission

CRR

Composite response rate

ORR

Overall response rate

OS

Median overall survival

MDS

Myelodysplastic syndrome

MPN

Myeloproliferative neoplasms

VEN

Venetoclax

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analysis

AE

Adverse event

ASD

Autism Spectrum Disorder

HR

Hazard risk

Author contributions

(I) Conception and design: Lina Xing. (II) Administrative support: Feng He. (III) Provision of study materials or patients: Lina Xing and Shukai Qiao. (IV) Collection and assembly of data: Feng He and Tian Tian. (V) Data analysis and interpretation: Feng He. (VI) Manuscript writing: All authors. (VII) Final approval of manuscript: All authors.

Funding

This study was supported by Hebei Province Medical Science Research Key Project (No.20221077).

Availability of data and materials

All data generated or analyzed during this study are included in this article and supplementary information files.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval and consent to participate

This article is a meta-analysis. The data comes from published articles and does not require ethical approval and written informed consent.