The impact of venetoclax treatment duration on efficacy and hematologic toxicity in acute myeloid leukemia: a systematic review and meta-analysis

Abstract

Venetoclax (VEN) combined with hypomethylating agents (HMA) is a standard treatment for unfit acute myeloid leukemia (AML) patients, but the conventional 28-day cycle often leads to prolonged cytopenias and infection risks. Recent studies suggest shorter VEN regimens may improve safety without compromising efficacy, but this remains controversial. To this end, we performed a systematic review and meta-analysis to compare the impact of VEN duration in patients receiving VEN-HMA. A comprehensive literature search was conducted in PubMed and Embase up to May 28, 2025. The Cochran Q test and I-squared statistics were used to identify the heterogeneity among the included studies. The network meta-analysis was performed by employing The mtc.model and mtc.run functions of the gemtc R package. We performed all statistical analyses using R 4.0.3. Six studies with 728 patients were included. Meta-analysis showed no significant difference in remission rates between shorter (≤ 14 days) and longer (> 14 days) treatments (RR = 1.07, 95% CI: 0.95–1.20). Network meta-analysis of 14-day (VEN14), 21-day (VEN21), and 28-day (VEN28) regimens found no statistically significant differences in remission rates or overall survival (OS), with VEN14 ranking first for both remission efficacy and survival benefit. Although grade 3/4 granulocytopenia was similar across groups, VEN21 correlated with significantly lower febrile neutropenia versus VEN28 (RR = 0.56, 95% CI: 0.29–0.98). Shorter VEN courses (14–21 days) appear to maintain comparable efficacy to the standard 28-day course, with VEN21 potentially offering a better safety profile regarding febrile neutropenia, supporting the individualization of treatment duration to improve tolerability in unfit AML patients.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00277-026-06844-1.

Introduction

Venetoclax (VEN) in combination with hypomethylating agents (HMAs) has become the standard first-line treatment for older or unfit patients with acute myeloid leukemia (AML) who are unable to tolerate intensive chemotherapy [1]. This regimen has markedly improved response rates and overall survival compared to HMA monotherapy, representing a major advancement in the therapeutic landscape of AML. However, the conventional 28-day continuous VEN administration schedule is frequently associated with profound and prolonged hematologic toxicities, including severe neutropenia and thrombocytopenia, which often lead to life-threatening infections, bleeding complications, and significant treatment interruptions [1]. These adverse events not only diminish patients’ quality of life but also compromise treatment tolerance and delivery, highlighting an urgent need for more manageable dosing strategies.

In recent years, efforts to reduce treatment-related toxicity while maintaining efficacy have prompted investigation into abbreviated VEN schedules. Several single-arm and retrospective studies have explored shorter durations of VEN administration, such as 7, 14, or 21 days per cycle, with emerging evidence suggesting that these regimens may achieve comparable response rates to the standard 28-day course, alongside improved hematologic recovery and reduced infection rates [2–4]. Despite these promising findings, there is considerable heterogeneity in clinical practice regarding VEN scheduling, with wide variation across institutions and a lack of consensus on the optimal duration. Furthermore, no randomized controlled trials or direct comparative studies have been conducted to evaluate the trade-offs between efficacy and toxicity across these different schedules.

This absence of robust comparative evidence has resulted in a fragmented understanding of how treatment duration influences clinical outcomes, leaving practitioners without clear guidance for personalizing therapy.This lack of standardized evaluation has hindered the identification of an optimal duration, leaving clinicians without clear guidance. To address this critical knowledge gap, we conducted a systematic review and network meta-analysis aimed at comprehensively evaluating the impact of VEN treatment duration on both hematologic toxicity and treatment response in AML patients receiving VEN-HMA combinations. Our study seeks to synthesize available evidence to inform future clinical decision-making and trial design.

Method

Literature collection

Literature collection two independent individuals (Linhui Hu and Ying Pan) employed Embase, and PubMed to identify relevant studies (last updated on May 28, 2025). The detailed search strategy is provided in supplementary files.

Eligibility criteria

Inclusion criteria:

1. Adult patients with a diagnosis of AML

2. Articles that compare different courses of Venetoclax in AML patients

3. Studies that report the remission rate and/or hematological toxicities in order to compare the efficacy or safety of patients with different courses of Venetoclax.

Exclusion criteria: duplicate articles, reviews, non-human studies, and those without usable data.

Data extraction and study quality assessment

Data extraction and study quality assessment were independently conducted by two authors (Linhui Hu and Ying Pan). The following information was collected form the studies: first author, year of publication, study region, sample size, age, treatment, remission rate, hematologic toxicities. Since all eligible studies were of cohort design, the quality of each study was assessed by the Newcastle–Ottawa Quality Assessment Scale (NOS) [5].

Statistical analysis

The Cochran Q test and I-squared statistics were used to identify the heterogeneity among the included studies. If heterogeneity was significant (Cochran Q test: P value < 0.10 or I-squared > 50%), the random-effects model was used, otherwise, the fixed-effects model was used. Publication bias was evaluated using Begg’s funnel plot and Egger’s test. The network meta-analysis was performed by employing the mtc.model and mtc.run functions of the gemtc R package. We performed all statistical analyses using R 4.0.3, and P < 0.05 was considered statistically significant.

Results

Eligible studies

A total of 4652 publications were initially identified through searches of PubMed and Embase. According to inclusion and exclusion criteria, 6 studies[2–4, 6–8] involving 728 patients were included (Fig. 1). The detail information of included studies was list in Table 1. All studies adopted a retrospective design. The VEN treatment duration ranged from 7 to 28 days. The mean age of patients across cohorts ranged from 64 to 79 years. Composite complete remission (CRc) was defined as the composite of complete remission (CR) and CR with incomplete hematologic recovery (CRi). The studies included were published between 2021 and 2025: 1 in 2021 [2], 1 in 2023[6], 2 in 2024 [3, 7], and 2 in 2025 [4, 8]. Geographically, the studies were conducted in different regions: 2 in Japan [3, 6], 2 in America [2, 7], 1 in France [4] and 1 in Switzerland [8]. Sample sizes ranged from 13 to 270, with a median of 86. Among them, 656 patients were newly diagnosed, and the rest were unknown.

Fig. 1.

Flow chart of the study selection

Table 1.

Studies on Venetoclax dosing schedule in AML

First author	Year	Country	Newly diagnosed	Group	Sample size	CRc rate (%)	Median OS	Median EFS/PFS	Grade ≥ 3 neutropenia (%)	FN (%)	Infection (%)
Kanaya [3]	2024	Japan	Yes	VEN 14	31	67.7	Not reached	-	67.7 (grade = 4)	54.8	25.8
				VEN 21	51	51.0	430 days	-	78.4 (grade = 4)	47.1	11.7
				VEN 28	18	38.9	328 days	-	50.0 (grade = 4)	38.9	16.7
Karrar [7]	2024	USA	Yes	VEN 14	40	68	18.6 months	-	45.5	-	20 (grade ≥ 3)
				VEN 21	41	66	21.3 months	-	39	-	18 (grade ≥ 3)
				VEN 28	189	62	13.2 months	-	42	-	28 (grade ≥ 3)
Schüpbach [8]	2025	Switzerland	Unknown	VEN ≤ 14	18	56	10 months	5 months	-	-	-
				VEN > 14	54	54	11 months	6.5 months	-	-	-
Blanding [2]	2021	USA	Yes	VEN ≤ 14	9	78	18 months	16 months	-	-	-
				VEN ≥ 21	16	75	Not reached	11 months	-	-	-
Willekens [4]	2025	France	Yes	VEN 7	82	72	11.2 months	6.5 months	-	48	-
				VEN ≥ 14	166	72	10.3 months	7.4 months	-	55	-
Aiba [6]	2023	Japan	Yes	VEN 14	8	75	Not reached	Not reached	-	37.5	-
				VEN 28	5	80	254 days	178 days	-	80	-

The meta-analysis of VEN administration schedules

Given the variability in VEN administration schedules across centers, we first stratified the studies into two groups based on a 14-day cutoff for meta-analysis. This results was shown in Fig. 2. Pooled estimates under both common effect (relative risk [RR] = 1.07, 95% confidence interval [CI] [0.95, 1.20]) and random effects models (RR = 1.06, 95% CI [0.94, 1.19]) revealed no significant association between VEN duration (≤ 14 days vs. > 14 days) and remission rate. Heterogeneity was absent across studies (I² = 0%, P = 0.63), indicating consistent effects. Due to limited reporting of adverse events in these subgroups, further toxicity analyses were not performed for this stratification. We used Begg’s funnel plot and Egger’s test and found no published bias for above results.

Fig. 2.

Forest plots of risk ratio (RR) for efficacity by meta-analysis. The forest plot for the association between duration of VEN admisistration (≤ 14 days vs. > 14 days) and remission rate of AML patients

The network meta-analysis of VEN administration schedules in AML

To further clarify differences among specific durations, a network meta-analysis was conducted focusing on 14-day (VEN14), 21-day (VEN21), and 28-day (VEN28) schedules. In terms of efficacy, no statistically significant differences in remission rates were observed among the three groups (Fig. 3A). Scura ranking analysis indicated that VEN14 ranked first in terms of remission efficacy (Fig. S1A). Overall survival (OS) was comparable among the three groups, with no statistically significant differences observed (Fig. 3B). Scura ranking analysis indicated a preference for the 14-day regimen (VEN14), as shown in Fig. S1B.

Fig. 3.

Forest plots for efficacity and toxicity by the network meta-analysis. A The difference in remission rate between different VEN days, and the 14-day VEN administration is the best. B The difference of OS. C Incidence of grade 3/4 granulocytopenia events. D Incidence of febrile neutropenia

Regarding hematologic toxicity, consistent with the absence of efficacy differences, there were no significant variations in the incidences of grade 3/4 granulocytopenia across the three groups (Fig. 3C). Interestingly, a notable distinction emerged in the context of febrile neutropenia: compared with VEN28, the incidence of febrile neutropenia was significantly lower in the VEN21 group (RR = 0.56, 95% CI [0.29, 0.98]), whereas no statistically significant difference was observed between VEN14 and VEN28 (Fig. 3D). Scura ranking analysis indicated that VEN21 ranked first in terms of incidence of infection and febrile neutropenia (Fig. S1C and S1D).

Discussion

AML is a genomically heterogeneous malignancy that mainly affects the elderly, with a median age at diagnosis of 68 years [9]. The introduction of standard-dose VEN in combination with HMAs has revolutionized the treatment landscape for patients unfit for intensive chemotherapy, demonstrating notably high CR rates and significantly improved overall survival [1, 5, 6]. Despite these advances, approximately one-third of patients exhibit primary resistance and fail to achieve an initial response, over half will eventually experience disease relapse after respond [10]. Additionally, the clinical application of these regimens is constrained by considerable toxicity, particularly myelosuppression and infectious complications, as observed in real-world settings [5, 6, 11]. Consequently, the optimal duration of VEN-based therapy remains a subject of ongoing debate and requires further investigation [12, 13]. Our current analysis highlights critical trade-offs between efficacy and toxicity related to myelosuppression across different VEN durations, with implications for clinical decision-making. This study has two major advantages. First, this meta-analysis included more than 700 patients, a substantial sample size for this clinical question, allowing us to better optimal the schedule of VEN. Besides, we mitigated selection bias and comprehensive collection of literature by waiving restrictions on language and publication status.

In terms of efficacy outcomes, our primary meta-analysis compared shorter (≤ 14 days) versus longer (> 14 days) VEN-based treatment durations. The pooled results indicated no statistically significant difference in remission rates between the two groups. Using a common effect model, the risk ratio (RR) was 1.07 (95% CI [0.95, 1.20]), while the random effects model yielded a similar estimate (RR = 1.06, 95% CI [0.94, 1.19]). Notably, we observed negligible heterogeneity among the included studies (I² = 0%, P = 0.63), reinforcing the robustness and consistency of the findings. This result suggests that reducing VEN exposure to 14 days or less does not adversely affect the likelihood of achieving remission, corroborating earlier observations from single-center cohort studies [2, 3]. To further elucidate the dose-duration efficacy relationship, we performed a network meta-analysis, which allowed for simultaneous comparison across multiple VEN dosing schedules. Interestingly, the 14-day regimen (VEN14) emerged with the highest point estimate for remission rates (RR = 1.1, 95% CI [0.93, 1.4]) among all evaluated protocols, suggesting a potential advantage of this condensed schedule, though the wide confidence interval indicates the need for further validation. Importantly, this comparable efficacy was also reflected in survival outcomes. Although no statistically significant difference in OS was detected across the three regimens. However, Scura ranking analysis favored VEN14 as the preferred regimen for survival benefit, lending additional support to the potential value of this shorter course. These findings contribute to an evolving paradigm in which shorter-duration VEN therapy may offer comparable efficacy.

Regarding safety outcomes, our analysis shed light on critical toxicity profiles. Although the incidence of grade 3/4 granulocytopenia was comparable across the 14-, 21-, and 28-day treatment cycles, a statistically significant reduction in febrile neutropenia (FN) was observed with shorter therapy durations. Specifically, the VEN21 regimen was associated with a 44% reduction in the risk of FN when compared to the VEN28 schedule (RR = 0.56, 95% CI [0.29, 0.98]). A similarly favorable, though not statistically significant, trend was noted for the VEN14 regimen. This is clinically meaningful, as febrile neutropenia frequently leads to hospitalization and antibiotic administration, adding to patient burden and healthcare costs. These safety findings are further reinforced by economic analyses. A prior investigation included in our review indicated that treatment costs associated with VEN28 were approximately twice those of VEN14, with total cost ranges of $2,811–$15,829 and $1,360–$7,544, respectively [6]. The convergence of reduced febrile neutropenia risk and lower financial burden underscores the value of abbreviated venetoclax regimens in achieving an optimized risk–benefit profile and enhancing overall cost-effectiveness. This supports a shifting paradigm toward shorter-duration therapy in appropriate patient subsets, without compromising antileukemic efficacy—an especially pertinent consideration in resource-conscious clinical environments.

Despite these insights, our study has limitations. First and foremost, all included evidence originates from observational studies, as no prospective randomized controlled trials are currently available. Consequently, the findings may be influenced by inherent biases such as selection bias and unmeasured confounding. Additionally, the small number of adverse event reports limited our ability to conduct detailed toxicity analyses for the ≤ 14 days vs. > 14 days stratification. Other outcomes, such as quality of life, were not systematically evaluated here, impairing a comprehensive assessment of treatment tolerability. Furthermore, clinical heterogeneity across studies (e.g. patient characteristics and supportive care) could affect the stability of the pooled results. Future randomized trials are warranted to validate these findings.

In conclusion, this meta-analysis of observational studies suggests that abbreviated VEN regimens (14–21 days) may maintain efficacy while potentially reducing the risk of febrile neutropenia compared to the standard 28-day schedule. Among these, VEN14 might be associated with the highest remission rates, and VEN21 with the most favorable safety profile for febrile neutropenia. These results offer practical insights to inform the personalization of VEN duration in clinical practice, aiming to improve tolerance without apparent efficacy compromise. Given the retrospective nature of the included data, prospective multicenter trials are urgently needed to confirm these findings, evaluate long-term outcomes, quality-of-life outcomes, and define optimal schedules for distinct patient subsets (e.g., by age, comorbidities, or genetic risk).

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

AML

Acute myeloid leukemia

CR

With incomplete hematologic recovery

CRc

Composite complete remission

FN

Febrile neutropenia

HMAs

Hypomethylating agents

RR

Relative risk

VEN

Venetoclax

Author contribution

LHH and YP performed data collection; LHH analyzed the data, YP, YYS, SHM, CYY, ZMZ, QST wrote the manuscript; YD and LHH revised the manuscript. All authors reviewed the manuscript.

Funding

This work was supported by Health Research Program of Anhui (AHWJ2024BAc20066) and the Natural Science Research Project of Anhui Provincial Department of Education (KJ2021A0324).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

This article does not contain any studies with human participants performed by any of the authors.

Conflict of interest

The authors declare no competing interests.