Data sources and literature search strategy
This meta-analysis has been conducted in the International Prospective System of Register of systematic reviews (PROSPERO) (Registration No. CRD42023398349). The present work was conducted by six researchers. PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to February 2023, and the language was limited to English. The subject terms of this study were "acute, myeloid, leukemia", "myelodysplastic syndrome", "venetoclax", "hematopoietic stem cell transplantation", "azacitidine", "decitabine", and "recurrence". The complete search strategy is shown in Table S1.
Literature inclusion and exclusion criteria
Inclusion criteria: (1) Study population: Adult AML/MDS patients who relapsed after transplantation; (2) Intervention: Ven + HMAs regimens; (3) Comparison: IC ± DLI group, DLI group, supportive care group or no control group; (4) Outcome: The primary outcome indicators were the CR/CRi rate, the ORR and survival rate; the secondary indicators were grade 3–4 hematological AEs and incidence of infection; (5) Study design: randomized controlled trial (RCT), retrospective study, prospective study; (6) The number of participants in each study was more than 10 patients.
Exclusion criteria: (1) Case reports, reviews, meta-analysis, commentaries, and non-human studies; (2) Treatment regimens including agents other than Ven in combination with HMAs. (3) Study results without primary outcome indicators; (4) Duplicate publication of literature.
Three investigators (YFD, CHL, and ZJZ) independently read the title, abstract, and full text to decide whether to include a study. Any discrepancy in the included literature was resolved by consensus or by consulting another senior investigator.
Definition of treatment response
We selected included complete response (CR)/complete response with incomplete blood count recovery (CRi) rate, overall response rate (ORR), and survival rate as primary outcome indicators. ORR included the rate of CR/CRi, morphologic leukemia-free status (MLFS), partial remission (PR), and stable disease (SD). Survival rate was defined as the percentage of treated patients who survived after a period of follow-up. The response criteria referred to the 2003 International Working Group, 2017 European Leukemia Network, and the International Response Unified Criteria revised by the MDS International Working Group in 2006 [18–20].
Grade 3–4 hemocytopenia and incidence of infection were secondary outcome indicators in this research. The different degrees of AEs were rated according to the National Cancer Institute Common Terminology Standard for Adverse Events VERSION 4.03 [21].
Article quality evaluation
This study assessed the risk of bias using the Methodological Index of Non-Randomized Studies (MINORS) guidelines [22]. Among a total of 12 items in MINORS, the first 8 items are related to non-comparative studies, and the rest 12 items are related to comparative studies. These items were scored as 0 (not reported), 1 (reported but inadequate), or 2 (reported but adequate). Three investigators (YFD, CHL, and ZJZ) independently evaluated the risk bias of the included studies, and any discrepancy was resolved by consensus.
Data extraction and statistical analysis
Data were independently collected by three investigators (YFD, CHL, and ZJZ) according to a pre-designed Excel sheet. The discrepancy was resolved by consensus or consultation with senior collaborators. R 4.2.2 software was utilized in the meta-analysis. Analysis of dichotomous variables was performed for dichotomous information CR/CRi, ORR, and AEs using generalized inverse variance without a control group. A 95% confidence interval (CI) was reported for each measure. Q-test and I2 test (I2 ≤ 25%: no heterogeneity; 26–50%: low heterogeneity; 51–75%: moderate heterogeneity, and > 75%: high heterogeneity) were used for heterogeneity analysis. p < 0.1 or I2 > 50% indicated a statistical heterogeneity among references, and a random-effects model was used. When p > 0.1 or I² < 50%, a fixed-effects model was employed for analysis [23]. Subgroup analysis or sensitivity analysis was carried out for results with high heterogeneity to determine the cause of heterogeneity. The sensitivity analysis was performed to evaluate the effect of each study on the statistical results by excluding individual studies one by one.