Azacitidine plus venetoclax as post-transplant maintenance therapy in high-risk myeloid malignancies: a propensity score-matched analysis

Azacitidine plus venetoclax as post-transplant maintenance therapy in high-risk myeloid malignancies: a propensity score-matched analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Azacitidine plus venetoclax as post-transplant maintenance therapy in high-risk myeloid malignancies: a propensity score-matched analysis Liping Wan, Changmeng Zhang, Jinchun Wu, Yu Cai, yang jun, Huiying Qiu, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8886738/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 7 You are reading this latest preprint version Abstract Relapse is a major cause of treatment failure after allogeneic hematopoietic stem-cell transplantation(allo-HSCT) for high-risk myeloid malignancies. This single center, retrospective study enrolled patients with high-risk acute myeloid leukemia or myelodysplastic syndromes who received allo-HSCT from January 1, 2022 to December 31, 2024. Post-transplant maintenance therapy consisted of azacitidine (32 mg/m²/day, day 1-5) plus venetoclax (400 mg/day, day 1-7), starting from the 60th day posttransplant and repeated every 28 days until up to 1-year posttransplant. Outcomes were compared with a contemporaneous control group constructed via propensity score matching (azacitidine-venetoclax, n = 35; control, n = 59). After a median follow-up of 22.5 months, the 1-year disease-free survival was 88.6% (95% CI, 78.6%-99.8%), the 1-year cumulative incidence of relapse was 5.7% (95% CI, 0%-13.5%). The azacitidine-venetoclax group demonstrated significantly superior 1-year overall survival compared to control (P = 0.037). Win ratio analysis further confirmed a significant overall clinical benefit (P < 0.001). Subgroup analysis revealed a pronounced overall survival benefit for MRD-positive patients (HR, 0.288; P = 0.037). The safety profile was manageable, no significant increase in the incidences of EBV and CMV infection or graft-versus-host disease. Immune reconstitution analysis showed delayed B-cell recovery but preserved T-cell and NK-cell recovery. Biological sciences/Cancer/Haematological cancer/Leukaemia/Acute myeloid leukaemia Biological sciences/Cancer/Haematological cancer/Myelodysplastic syndrome Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Relapse remains the leading cause of treatment failure and mortality in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) following allogeneic hematological stem cell transplantation (allo-HSCT) 1 . Adverse-risk disease features and presence of measurable residual disease (MRD) before transplant are strongly associated with post-transplant relapse and inferior survival 2-6 . These outcomes highlight a critical unmet need for effective relapse prevention strategies after allo-HSCT. Post-transplant maintenance therapies had showed promising efficacy in myeloid malignancies 7 . Previous studies showed post-transplant maintenance therapy with FLT3 inhibitors sorafenib significantly reduced disease relapse and improved overall survival in patients with FLT3-ITD mutation 8-11 . However, preventing relapse in patients without targetable mutations remains a major therapeutic challenge. Azacitidine, a hypomethylating agent, exerts dual beneficial effects in the post‑transplant setting. It directly targets myeloid leukemia cells by reversing aberrant DNA hypermethylation, thereby restoring expression of tumor‑suppressor genes and promoting differentiation or apoptosis of residual malignant cells 12, 13 . Concurrently, azacitidine modulates the immune system, particularly T‑cell responses. It can enhance the activity and proliferation of tumor‑reactive T cells while promoting regulatory T‑cell function, thereby potentially rebalancing immune reconstitution 14, 15 . Thus, when used after transplantation, azacitidine may synergistically reduce relapse risk by simultaneously eliminating minimal residual disease and fostering a more leukemia‑specific immune response, without a proportional increase in graft‑versus‑host disease. By inhibiting BCL-2, venetoclax synergizes with hypomethylating agents to trigger mitochondrial apoptosis and target leukemia stem cells 16, 17 . This combination also exhibits a favorable safety profile 1, 18-24 . Based on the established clinical activity of azacitidine-venetoclax (AZA-VEN), we hypothesized that this combination as maintenance therapy would effectively reduce disease relapse in patients with high-risk myeloid malignancies following allo-HSCT. We therefore conducted a retrospective study to evaluate the efficacy and safety of AZA-VEN maintenance. A contemporaneous cohort of patients who did not receive this regimen served as a non-randomized control. To strengthen the comparative analysis, we applied propensity score matching (PSM) and the win ratio method. Exploratory analyses were also performed to identify patient subgroups most likely to benefit from this maintenance strategy. METHODS Patients This retrospective study enrolled patients with high-risk AML or MDS aged 18 to 70 years who received allogeneic HSCT in Shanghai General Hospital from January 1, 2022 to December 31, 2024. We compared patients who received azacitidine plus venetoclax as maintenance therapy with patients who did not by propensity score matched analysis. The maintenance therapy consisted of administering 32 mg/m² subcutaneous azacytidine daily for 5 days and 400 mg oral venetoclax or equivalent (with concomitant azole antifungals) daily for 7 days, started from the 60th day posttransplant, repeated every 28 days until up to 1-year posttransplant. Patients with AML should fulfill one of the following criteria: (1) 2022 ELN adverse-risk genetics, (2) ≥ 2 induction cycles to achieve CR, (3) extramedullary myeloid malignancy, (4) ≥ CR2 status, or (5) detectable MRD before transplant. Patients with MDS should fulfill one of the following criteria: (1) IPSS-R high/very-high risk (2) TP53 mutation, or (3) detectable MRD before transplant. All patients were required to have adequate hematologic function (ANC ≥ 1.0×10⁹/L, Hb ≥ 80 g/L, PLT ≥ 50×10⁹/L) and score 0-2 of Eastern Co-operative Oncology Group performance status. Patients were excluded if met any of the following criteria: (1) concurrent use of target drugs, such as FLT3 inhibitors, (2) grade II-IV active acute GVHD, (3) moderate or severe chronic GVHD, (4) disease relapse (abnormal myeloid cells detected by flow cytometry > 0.01%, presence of WT1 or other genes, extramedullary malignancy) or donor chimerism < 90%. The primary endpoint was 1-year disease-free survival (DFS). The secondary endpoints included 1-year overall survival (OS) and 1-year cumulative incidence of relapse (CIR). The trial was conducted according to principles of the Declaration of Helsinki, Good Clinical Practice. The Protocol was approved by institutional review boards and ethics committee of Shanghai General Hospital. Definition and safety assessments Disease relapse was defined as morphologic evidence of relapse, meeting any of the following criteria: the appearance of blasts in the peripheral blood, ≥ 5% blasts in a bone marrow aspirate smear, or pathologically confirmed extramedullary disease. The non-complete remission (non-CR) category included persistent morphological disease (bone marrow blast percentage ≥ 5%) or partial remission with incomplete hematologic recovery. Measurable residual disease (MRD) was considered positive when either bone marrow blasts were ≥ 0.01% by flow cytometry or disease-associated genetic markers were detectable by quantitative PCR. EBV DNAemia and CMV DNAemia were defined as plasma EBV-DNA or CMV-DNA load ≥ 1000 copies/mL by quantitative PCR respectively. DFS was measured from the date of transplant to the date of disease relapse or death from any cause. OS was measured from the date of transplant until death or censorship at last follow-up. CIR was defined as the probability of experiencing disease relapse over time, treating death without prior relapse as a competing event. Adverse events (AEs) were determined per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 25 . Propensity score matching We employed PSM to minimize potential confounding 26 . The propensity score was estimated using a logistic regression model that incorporated the following variables: age, ECOG performance status, ELN 2022 genetic risk for AML (favorable, intermediate, adverse) or IPSS-R risk category for MDS, pre-transplant MRD status (negative vs. positive), and donor type (haploidentical donor vs. matched related/unrelated donor). To minimize confounding by disease type, we performed a 1:2 nearest-neighbor matching algorithm with a 0.2 caliper width separately for AML and MDS cohorts. A standardized mean difference < 0.1 was considered suggestive of adequate covariate balance. We pooled the matched cohorts, and evaluate the treatment effect on survival using a Cox proportional hazards model stratified by disease type. To assess the consistency of the treatment effect across disease subtypes, we tested the treatment-by-disease interaction. No significant interaction was found for either OS (P = 0.997) or DFS (P = 0.997), supporting a consistent treatment effect of azacitidine plus venetoclax in both AML and MDS. This justified the use of a stratified Cox model for the combined analysis. Win ratio approach We selected the win ratio approach as it enables the analysis of multiple, hierarchically ordered endpoints, prioritizing more severe events (e.g., death over relapse), thereby providing a clinically interpretable composite outcome that complementing traditional time-to-event analyses 27, 28 . The win ratio analysis followed these steps: (1) forming all possible patient-patient pairs; (2) comparing outcomes within each pair in a prespecified order of importance (death > relapse) until a decisive better outcome was identified; (3) designating pairs as a “tie” if outcomes were equal at all compared levels. Confidence intervals and p-values were subsequently calculated using the Finkelstein-Schoenfeld test 27, 29 . Statistical Analysis The Mann-Whitney U test was used to compare the continuous variables. The Chi-square test and Fisher’s exact test were used to compare the categorical variables. OS and DFS were estimated by Kaplan-Meier method. CIR was estimated in the competing risks framework treating each other as a competing event. Cumulative incidence of chronic GVHD was also estimated in the competing risks framework, treating death without developing GVHD as a competing event. To identify prognostic factors, univariate and multivariate Cox regression analysis were performed. Statistical significance was set at p < 0.05. All statistical analyses were performed using R version 4.4.2. RESULTS Patient characteristics A total of 52 consecutive patients with high-risk AML or MDS received azacitidine plus venetoclax as maintenance therapy posttransplant. After excluding 12 ineligible patients (age 70 years, n = 4; FLT3-ITD mutation or BCR-ABL fusion, n = 8), 40 eligible patients were 1:2 propensity score matched to a contemporaneous control cohort (n = 155). This yielded a final balanced cohort of 94 patients (AZA-VEN, n = 35; control, n = 59). The baseline characteristics were shown in Table 1. At the data cutoff (October 31, 2025), the median follow-up after transplant was 22.5 (range, 2.4-46.5) months. In the matched cohort, eighty-two patients were diagnosed with AML; the other 12 patients were diagnosed with MDS. Pre-transplant MRD positivity was common overall (57.4%, 54/94) and did not show a marked difference between the AZA-VEN (60.0%) and control (55.9%) groups. A history of pre-transplant venetoclax exposure was frequent and well-balanced between the two groups (AZA-VEN, 54.29% vs. control, 50.85%). The most frequent genetic abnormalities at diagnosis were WT1 mutations (24.4%) and RUNX1 mutations (16.0%). TP53 mutations were observed in 7.4% (7/94) of the entire cohort and were distributed with comparable frequency between the AZA-VEN (5.7%, 2/35) and control (8.4%, 5/59) groups. EBV and CMV reactivation The incidence of EBV DNAemia within 6 months post-transplant was comparable between AZA-VEN and the control group (42.8% vs 45.8%). Similarly, no significant difference was observed in the incidence of CMV DNAemia within 6 months post-transplant between AZA-VEN and the control group (11.4% vs. 10.2%) Acute and chronic GVHD The cumulative incidence of II-IV acute GVHD did not differ significantly between groups (17.1% vs. 13.6%; P = 0.64). Acute GVHD occurred in 5 patients (grade II) and 1 patient (grade III) in the AZA-VEN group compared with 6 (grade II) and 2 (grade IV) in the control group. The 2-year cumulative incidence of moderate/severe chronic GVHD was 15.3% (95% CI, 7.5%-23.2%) for the entire cohort. No significant differences were observed between AZA-VEN and the control group (15.9% [95% CI, 2.5%-9.3%] vs.14.9% [95% CI, 5.1%-24.6%], respectively; P = 0.965). Immune reconstitution Lymphocyte subsets of peripheral blood post-transplant revealed that AZA-VEN maintenance had a limited effect on the recovery of T cells (CD4 + and CD8 + ) and NK cells. The absolute counts of CD4 + and CD8 + T cells and NK cells on 12 months were comparable to those in the control group (P > 0.05). However, patients receiving AZA-VEN had significantly delayed reconstitution of CD19 + B cells compared with the control group, significant lower counts of CD19+B cells both on 9-month (59.5 cells/μL vs. 215 cells/μL; P = 0.001) and 12-month (60.5 cells/μL vs. 271.5 cells/μL; P = 0.001) (Figure 1). Survival Patients of the AZA-VEN group received a median of 5 cycles (range, 1-10), 62.9% (22/35) completing ≥ 4 cycles. After a median follow-up of 22.5 (range, 2.4-46.5) months, there were 15 relapses in this propensity score matched cohorts. Four patients (11.4%) were from AZA-VEN group and 11 patients (18.6%) were from control group. A total of 20 patients died: 4 from the AZA-VEN group and 16 from the control group. In the AZA-VEN group, three patients died from disease relapse, one patient died from septic shock secondary to enterogenous bacteremia, with cultures positive for both Klebsiella pneumoniae and Enterococcus faecalis. Notably, this patient had successfully completed four cycles of maintenance therapy without any observed hematological toxicity, but subsequently developed a severe infection attributed to the consumption of contaminated food. In the control group, ten patients died from disease relapse and 6 from infections. Notably, 30 of 35 patients (85.7%) who received AZA-VEN remained alive and MRD negative. In the matched cohort, the 1-year DFS was 88.6% (95% CI, 78.6%-99.8%) for the AZA-VEN group compared with 76.3% (95% CI, 66.2%-87.9%) for the control group. The 1-year OS was 91.4% (95% CI, 82.6%-100%) for the AZA-VEN group versus 76.2% (95% CI, 66.1%-87.9%) for the control group (P = 0.037)(Figure 2 A, 2B). The 1-year CIR was 5.7% (95% CI, 0%-13.5%) in the AZA-VEN group versus 15.3% (95% CI, 6%-24.5%) in the control group (Figure 2C). Maintenance therapy with AZA-VEN resulted in a significant reduction in relapse risk, corresponding to a 42.1% relative and a 7.2% absolute decrease. The number needed to treat was 14, indicating that one relapse could be prevented for every 14 patients treated with this maintenance regimen. The median time to relapse was longer in the AZA-VEN group (7.55 months; range, 3.8-20.3) than in control group (5 months; range, 1.4-14.3). Among the 7 patients with TP53 mutation, 5 died: 1 from the AZA-VEN group (relapse), and 4 from control group (3 relapse, 1 infection). To further integrate the competing endpoints of death and relapse, a win ratio analysis was performed. This yielded a ratio of 1.18 (95% CI, 1.09-1.29; P < 0.001), demonstrating a significant clinical benefit favoring the AZA-VEN group (Figure 2D). Subgroup and multivariable analyses In order to determine who benefit most from the maintenance therapy, we carried out a multivariable analysis. By using multivariable Cox regression model adjusted for time from diagnosis to transplant, we identified low disease risk stratification, pre-transplant MRD negativity, and AZA-VEN maintenance as independent favorable prognostic factors. These were associated with improved DFS (HR, 0.4; p=0.075) and OS (HR, 0.3; p=0.036) (Figure 3A, 3B). Subsequent exploratory subgroup analyses of DFS and OS confirmed a consistent benefit from AZA-VEN maintenance (all subgroup HRs < 1). Moreover, a benefit of borderline statistical significance was observed in the pre-transplant MRD positivity subgroup (HR=0.29, 95% CI 0.08-1.00, P=0.050). In the pre-transplant MRD-positive subgroup (AZA-VEN, n=21; control, n=33), the 1-year DFS was 85.7% in the AZA-VEN group compared with 63.6% in control (P = 0.051). Correspondingly, the 1-year OS was 90.5% versus 63.6% (HR, 0.288; P = 0.037). (Figure 4A, 4B) Safety and toxicity The most common adverse events were cytopenias. Neutropenia developed in 21 patients (52.5%), including grade 3 in 9 and grade 4 in 3 patients. Thrombocytopenia was observed in 14 patients (35.0%), with three grade 3 and one grade 4 events. Anemia was observed in 18 patients (45.0%). Predominant non-hematologic toxicities were nausea (45%), vomiting (22.5%) and elevated liver transaminases (alanine aminotransferase 40.0%; aspartate aminotransferase 37.5%). Grade 3-4 events were uncommon, with each occurring in ≤ 2.5% of patients (Table 2). DISCUSSION Our study demonstrated that post-transplant maintenance with azacitidine plus venetoclax is an effective and safe strategy for high-risk AML and MDS. After a median follow-up of 22.5 months, we observed promising outcomes, with 1-year DFS of 88.6%, 1-year OS of 91.4%, and 1-year CIR of only 5.7%. The win ratio analysis affirmed the regimen’s overall clinical benefit. A meta-analysis of posttransplant azacitidine monotherapy including 13 studies showed a pooled 2-year CIR of 25% and OS of 65%, underscoring the limitation of single-agent hypomethylating therapy 30 . Antin et al. reported AZA-VEN as maintenance therapy (azacitidine 36 mg/m²/day on day 1-5; venetoclax 400 mg/day on day 1-14) for 27elderly patients (median age 67 years; range, 47-78 years) after reduced-intensity conditioning allo-HSCT , which produced a 2-year OS of 67% , PFS of 59% , and CIR of 41% 1 . The median time from transplant to maintenance was 57 days (range, 42-103 days). The relatively high incidence of relapse may be attributable, in part, to the older patient population and the reduced-intensity conditioning employed. Combination of hypomethylating agents and other supportive or novel agents also showed improved survival in small cohort studies. For instance, decitabine combined with granulocyte colony-stimulating factor (5 mg/m 2 of decitabine and 100 µg/m 2 of G-CSF on day 1-5) showed improved 2-year OS of 89.0% in older patients(median age 65 years; range, 26-76 years) and 2-year CIR of 15.0% in younger cohorts 31, 32 . Recently, a French team reported that oral decitabine-cedazuridine (a combination where cedazuridine, a cytidine deaminase inhibitor, enhances oral bioavailability of decitabine, 35 mg decitabine and 100 mg cedazuridine on days 1-3) administered from day 40 post-HSCT, achieving a 1-year DFS of 70.4% in 28 very high-risk patients 33 . In patients with TP53-mutant myeloid malignancies, combination of azacitidine (36 mg/m²/day for days 1-5) and eprenetapopt (3.7 g/day for days 1-4) achieved a 1-year OS of 78.8% (95% CI, 60.6%-89.3%) 34 . Collectively, these data provided evidence for the efficacy of hypomethylating agents-based regimen as posttransplant maintenance therapy. In the present study, a short-course combination of azacitidine and venetoclax yielded a 1-year DFS of 88.6% and a correspondingly low 1-year CIR of 5.7%. The median time to relapse was significantly prolonged with therapy (7.55 months vs. 5 months in controls). At last follow-up, 85.7% (30/35) of treated patients remained alive and free of leukemia, including those with adverse-risk genetics such as TP53 or RUNX1 mutations. These outcomes compare favorably with those of recent innovative regimens, implicating a potential efficacy advantage of adding a BCL-2 inhibitor 35, 36 . Our study demonstrated that post-transplant AZA-VEN maintenance significantly improved OS in patients with detectable MRD before transplant (HR, 0.288; P = 0.037). Previous study has confirmed that achieving multiparametric flow cytometry MRD clearance after AZA-VEN therapy is linked to a better EFS and OS 37 . Another study demonstrated a strong correlation between MRD negativity by flow cytometry and improved overall survival in patients receiving venetoclax plus decitabine 38 , the comparative prognostic value of flow cytometry and molecular MRD monitoring in the post-transplant setting has not been fully elucidated 39 . Further prospective studies are needed to define the optimal MRD monitoring modality (flow cytometry vs molecular techniques), the ideal timing for assessment, and clinically actionable thresholds. This will enhance its utility in guiding post-transplant interventions and predicting relapse-free and overall survival. In addition, the incidence of acute and chronic GVHD did not differ significantly between the matched cohorts. This finding further corroborates the favorable safety profile of the regimen. Notably, the regimen had limited inhibitory effects on T-cell reconstitution, preserving both CD4 + and CD8 + populations. Although B-cell recovery was delayed, this did not lead to an increased incidence of clinically significant infection, supporting the overall immunologic safety of this approach. Longer follow-up and functional immunologic assays, such as evaluation of CMV and EBV-specific T-cell responses and antibody titers, is needed to fully characterize the late safety profile of this maintenance strategy. This study demonstrated a manageable safety profile for post-transplant AZA-VEN maintenance. Adverse events were primarily hematologic, consisting of neutropenia and thrombocytopenia. Grade 3-4 neutropenia and thrombocytopenia occurred in 30.0% (12/40) and 10.0% (4/40) of patients respectively.Anemia of any grade was observed in 45.0% (18/40). Grade 1-2 non-hematologic toxicities, such as nausea, vomiting and elevated liver transaminases were frequent, while grade 3-4 events were uncommon 40 . However, gastrointestinal events and cytopenias affected treatment tolerance. Future studies might explore strategies modification, which include delaying the initiation of maintenance therapy until 3-4 months post‑transplant and investigating dose reduction to mitigate toxicity without compromising efficacy. Several limitations must be acknowledged. As a retrospective analysis, the findings are subject to unmeasured confounding and bias, limiting causal conclusions. Additionally, the infrequency of non-relapse death events limited the evaluation of the regimen's impact on this endpoint. In conclusion, this study demonstrated the efficacy of AZA-VEN as post-transplant maintenance for high-risk AML and MDS patients, particularly in patients with pre-transplant MRD. These promising survival and relapse outcomes merit further investigation in a randomized placebo-controlled trial, especially among MRD-positive and non-CR populations. Further research should also refine predictive biomarkers, particularly in TP53-mutated patients, to optimize patient selection and guide personalized therapy. Declarations DATA AVAILABILITY The data that support the findings of this study are available from the corresponding author upon reasonable request. ACKNOWLEDGMENTS The authors thank the patients and their families, as well as the clinical study teams. We also acknowledge Huizhong Shi, Xiao Zhou, Fangfang Yu for their assistance with manuscript. AUTHOR CONTRIBUTIONS LW and XS designed and supervised the study, revised the manuscript. CZ and JW collected and analyzed data interpreted results, and wrote the manuscript. YC, JY, HQ, KZ, JN, CH, YZ, YW, BD, JS, JC, LG, MY, and YT, contributed to the treatment of patients and interpretation of results. All authors reviewed and approved the final version of the manuscript. 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Oral decitabine and cedazuridine maintenance after haematopoietic stem-cell transplantation in very high-risk acute myeloid leukaemia or myelodysplastic syndrome (GFM-DACORAL-DLI): a multicentre, single-arm, phase 2 trial. Lancet Haematol 2025; 12 (9) : e705-e716. Mishra A, Tamari R, DeZern AE, Byrne MT, Gooptu M, Chen YB et al. Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol 2022; 40 (34) : 3985-3993. Chyla B, Daver N, Doyle K, McKeegan E, Huang X, Ruvolo V et al. Genetic Biomarkers Of Sensitivity and Resistance to Venetoclax Monotherapy in Patients With Relapsed Acute Myeloid Leukemia. Am J Hematol 2018; 93 (8) : E202-205. Guillaume T, Malard F, Magro L, Labopin M, Tabrizi R, Borel C et al. Prospective phase II study of prophylactic low-dose azacitidine and donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation for high-risk acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant 2019; 54 (11) : 1815-1826. Pratz KW, Jonas BA, Pullarkat V, Recher C, Schuh AC, Thirman MJ et al. Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine. J Clin Oncol 2022; 40 (8) : 855-865. Maiti A, DiNardo CD, Wang SA, Jorgensen J, Kadia TM, Daver NG et al. Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia. Blood Adv 2021; 5 (7) : 1876-1883. Gong B, Yang M, Qiu S, Liu B, Wang Y, Mi Y et al. Measurable residual disease recurrence as early warning of relapse in acute myeloid leukemia. Haematologica 2025; 110 (12) : 2954-2964. Chen EC, Liu Y, Harris CE, Winer ES, Wadleigh M, Lane AA et al. Outcomes of antifungal prophylaxis for newly diagnosed AML patients treated with a hypomethylating agent and venetoclax. Leuk Lymphoma 2022; 63 (8) : 1934-1941. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations The authors have declared there is NO conflict of interest to disclose. Supplementary Files table1.pdf Table 1. table2.docx Table 2. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: revise 26 Mar, 2026 Review # 1 received at journal 10 Mar, 2026 Reviewer # 1 agreed at journal 17 Feb, 2026 Reviewers invited by journal 17 Feb, 2026 Submission checks completed at journal 17 Feb, 2026 Editor assigned by journal 15 Feb, 2026 First submitted to journal 15 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1.","description":"","filename":"table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8886738/v1/5679300fcc55b06ffb2598b4.pdf"},{"id":103176849,"identity":"493c04ee-e77e-4b2f-b18b-8bcc66a83f10","added_by":"auto","created_at":"2026-02-22 16:39:13","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18231,"visible":true,"origin":"","legend":"Table 2.","description":"","filename":"table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8886738/v1/175fd6597f60adae77a6b996.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Azacitidine plus venetoclax as post-transplant maintenance therapy in high-risk myeloid malignancies: a propensity score-matched analysis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eRelapse remains the leading cause of treatment failure and mortality in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) following allogeneic hematological stem cell transplantation (allo-HSCT)\u003csup\u003e1\u003c/sup\u003e. Adverse-risk disease features and presence of measurable residual disease (MRD) before transplant are strongly associated with post-transplant relapse and inferior survival\u003csup\u003e2-6\u003c/sup\u003e. These outcomes highlight a critical unmet need for effective relapse prevention strategies after allo-HSCT.\u003c/p\u003e\n\u003cp\u003ePost-transplant maintenance therapies had showed promising efficacy in myeloid malignancies\u003csup\u003e7\u003c/sup\u003e. Previous studies showed post-transplant maintenance therapy with FLT3 inhibitors sorafenib significantly reduced disease relapse and improved overall survival in patients with FLT3-ITD mutation\u003csup\u003e8-11\u003c/sup\u003e. However, preventing relapse in patients without targetable mutations remains a major therapeutic challenge.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAzacitidine, a hypomethylating agent, exerts dual beneficial effects in the post‑transplant setting. It directly targets myeloid leukemia cells by reversing aberrant DNA hypermethylation, thereby restoring expression of tumor‑suppressor genes and promoting differentiation or apoptosis of residual malignant cells\u003csup\u003e12, 13\u003c/sup\u003e. Concurrently, azacitidine modulates the immune system, particularly T‑cell responses. It can enhance the activity and proliferation of tumor‑reactive T cells while promoting regulatory T‑cell function, thereby potentially rebalancing immune reconstitution\u003csup\u003e14, 15\u003c/sup\u003e. Thus, when used after transplantation, azacitidine may synergistically reduce relapse risk by simultaneously eliminating minimal residual disease and fostering a more leukemia‑specific immune response, without a proportional increase in graft‑versus‑host disease. By inhibiting BCL-2, venetoclax synergizes with hypomethylating agents to trigger mitochondrial apoptosis and target leukemia stem cells\u003csup\u003e16, 17\u003c/sup\u003e. This combination also exhibits a favorable safety profile\u003csup\u003e1, 18-24\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBased on the established clinical activity of azacitidine-venetoclax (AZA-VEN), we hypothesized that this combination as maintenance therapy would effectively reduce disease relapse in patients with high-risk myeloid malignancies following allo-HSCT. We therefore conducted a retrospective study to evaluate the efficacy and safety of AZA-VEN maintenance. A contemporaneous cohort of patients who did not receive this regimen served as a non-randomized control. To strengthen the comparative analysis, we applied propensity score matching (PSM) and the win ratio method. Exploratory analyses were also performed to identify patient subgroups most likely to benefit from this maintenance strategy.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003ePatients\u003c/p\u003e\n\u003cp\u003eThis retrospective study enrolled patients with high-risk AML or MDS aged 18 to 70 years who received allogeneic HSCT in Shanghai General Hospital from January 1, 2022 to December 31, 2024.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe compared patients who received azacitidine plus venetoclax as maintenance therapy with patients who did not by propensity score matched analysis. The maintenance therapy consisted of administering 32 mg/m\u0026sup2; subcutaneous azacytidine daily for 5 days and 400 mg oral venetoclax or equivalent (with concomitant azole antifungals) daily for 7 days, started from the 60th day posttransplant, repeated every 28 days until up to 1-year posttransplant.\u003c/p\u003e\n\u003cp\u003ePatients with AML should fulfill one of the following criteria: (1) 2022 ELN adverse-risk genetics, (2) \u0026ge; 2 induction cycles to achieve CR, (3) extramedullary myeloid malignancy, (4) \u0026ge; CR2 status, or (5) detectable MRD before transplant. Patients with MDS should fulfill one of the following criteria: (1) IPSS-R high/very-high risk (2) TP53 mutation, or (3) detectable MRD before transplant. All patients were required to have adequate hematologic function (ANC \u0026ge; 1.0\u0026times;10⁹/L, Hb \u0026ge; 80 g/L, PLT \u0026ge; 50\u0026times;10⁹/L) and score 0-2 of Eastern Co-operative Oncology Group performance status.\u003c/p\u003e\n\u003cp\u003ePatients were excluded if met any of the following criteria: (1) concurrent use of target drugs, such as FLT3 inhibitors, (2) grade II-IV active acute GVHD, (3) moderate or severe chronic GVHD, (4) disease relapse (abnormal myeloid cells detected by flow cytometry \u0026gt; 0.01%, presence of WT1 or other genes, extramedullary malignancy) or donor chimerism \u0026lt; 90%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was 1-year disease-free survival (DFS). The secondary endpoints included 1-year overall survival (OS) and 1-year cumulative incidence of relapse (CIR).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial was conducted according to principles of the Declaration of Helsinki, Good Clinical Practice. The Protocol was approved by institutional review boards and ethics committee of Shanghai General Hospital.\u003c/p\u003e\n\u003cp\u003eDefinition and safety assessments\u003c/p\u003e\n\u003cp\u003eDisease relapse was defined as morphologic evidence of relapse, meeting any of the following criteria: the appearance of blasts in the peripheral blood, \u0026ge; 5% blasts in a bone marrow aspirate smear, or pathologically confirmed extramedullary disease. The non-complete remission (non-CR) category included persistent morphological disease (bone marrow blast percentage \u0026ge; 5%) or partial remission with incomplete hematologic recovery. Measurable residual disease (MRD) was considered positive when either bone marrow blasts were \u0026ge; 0.01% by flow cytometry or disease-associated genetic markers were detectable by quantitative PCR. EBV DNAemia and CMV DNAemia were defined as plasma EBV-DNA or CMV-DNA load \u0026ge; 1000 copies/mL by quantitative PCR respectively.\u003c/p\u003e\n\u003cp\u003eDFS was measured from the date of transplant to the date of disease relapse or death from any cause. OS was measured from the date of transplant until death or censorship at last follow-up. CIR was defined as the probability of experiencing disease relapse over time, treating death without prior relapse as a competing event.\u003c/p\u003e\n\u003cp\u003eAdverse events (AEs) were determined per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0\u003csup\u003e25\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePropensity score matching\u003c/p\u003e\n\u003cp\u003eWe employed PSM to minimize potential confounding\u003csup\u003e26\u003c/sup\u003e. The propensity score was estimated using a logistic regression model that incorporated the following variables: age, ECOG performance status, ELN 2022 genetic risk for AML (favorable, intermediate, adverse) or IPSS-R risk category for MDS, pre-transplant MRD status (negative vs. positive), and donor type (haploidentical donor vs. matched related/unrelated donor). To minimize confounding by disease type, we performed a 1:2 nearest-neighbor matching algorithm with a 0.2 caliper width separately for AML and MDS cohorts. A standardized mean difference \u0026lt; 0.1 was considered suggestive of adequate covariate balance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe pooled the matched cohorts, and evaluate the treatment effect on survival using a Cox proportional hazards model stratified by disease type. To assess the consistency of the treatment effect across disease subtypes, we tested the treatment-by-disease interaction. No significant interaction was found for either OS (P = 0.997) or DFS (P = 0.997), supporting a consistent treatment effect of azacitidine plus venetoclax in both AML and MDS. This justified the use of a stratified Cox model for the combined analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWin ratio approach\u003c/p\u003e\n\u003cp\u003eWe selected the win ratio approach as it enables the analysis of multiple, hierarchically ordered endpoints, prioritizing more severe events (e.g., death over relapse), thereby providing a clinically interpretable composite outcome that complementing traditional time-to-event analyses\u003csup\u003e27, 28\u003c/sup\u003e. The win ratio analysis followed these steps: (1) forming all possible patient-patient pairs; (2) comparing outcomes within each pair in a prespecified order of importance (death \u0026gt; relapse) until a decisive better outcome was identified; (3) designating pairs as a \u0026ldquo;tie\u0026rdquo; if outcomes were equal at all compared levels. Confidence intervals and p-values were subsequently calculated using the Finkelstein-Schoenfeld test\u003csup\u003e27, 29\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eStatistical Analysis\u003c/p\u003e\n\u003cp\u003eThe Mann-Whitney U test was used to compare the continuous variables. The Chi-square test and Fisher\u0026rsquo;s exact test were used to compare the categorical variables. OS and DFS were estimated by Kaplan-Meier method. CIR was estimated in the competing risks framework treating each other as a competing event. Cumulative incidence of chronic GVHD was also estimated in the competing risks framework, treating death without developing GVHD as a competing event. To identify prognostic factors, univariate and multivariate Cox regression analysis were performed. Statistical significance was set at p \u0026lt; 0.05. All statistical analyses were performed using R version 4.4.2.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e\n\u003cp\u003eA total of 52 consecutive patients with high-risk AML or MDS received azacitidine plus venetoclax as maintenance therapy posttransplant. After excluding 12 ineligible patients (age \u0026lt; 18 or \u0026gt; 70 years, n = 4; FLT3-ITD mutation or BCR-ABL fusion, n = 8), 40 eligible patients were 1:2 propensity score matched to a contemporaneous control cohort (n = 155). This yielded a final balanced cohort of 94 patients (AZA-VEN, n = 35; control, n = 59). The baseline characteristics were shown in Table 1.\u003c/p\u003e\n\u003cp\u003eAt the data cutoff (October 31, 2025), the median follow-up after transplant was 22.5 (range, 2.4-46.5) months. In the matched cohort, eighty-two patients were diagnosed with AML; the other 12 patients were diagnosed with MDS. Pre-transplant MRD positivity was common overall (57.4%, 54/94) and did not show a marked difference between the AZA-VEN (60.0%) and control (55.9%) groups. A history of pre-transplant venetoclax exposure was frequent and well-balanced between the two groups (AZA-VEN, 54.29% vs. control, 50.85%). The most frequent genetic abnormalities at diagnosis were WT1 mutations (24.4%) and RUNX1 mutations (16.0%). TP53 mutations were observed in 7.4% (7/94) of the entire cohort and were distributed with comparable frequency between the AZA-VEN (5.7%, 2/35) and control (8.4%, 5/59) groups.\u003c/p\u003e\n\u003cp\u003eEBV and CMV reactivation\u003c/p\u003e\n\u003cp\u003eThe incidence of EBV DNAemia within 6 months post-transplant was comparable between AZA-VEN and the control group (42.8% vs 45.8%). Similarly, no significant difference was observed in the incidence of CMV DNAemia within 6 months post-transplant between AZA-VEN and the control group (11.4% vs. 10.2%)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcute and chronic GVHD\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of II-IV acute GVHD did not differ significantly between groups (17.1% vs. 13.6%; P = 0.64). Acute GVHD occurred in 5 patients (grade II) and 1 patient (grade III) in the AZA-VEN group compared with 6 (grade II) and 2 (grade IV) in the control group. The 2-year cumulative incidence of moderate/severe chronic GVHD was 15.3% (95% CI, 7.5%-23.2%) for the entire cohort. No significant differences were observed between AZA-VEN and the control group (15.9% [95% CI, 2.5%-9.3%] vs.14.9% [95% CI, 5.1%-24.6%], respectively; P = 0.965).\u003c/p\u003e\n\u003cp\u003eImmune reconstitution\u003c/p\u003e\n\u003cp\u003eLymphocyte subsets of peripheral blood post-transplant revealed that AZA-VEN maintenance had a limited effect on the recovery of T cells (CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e) and NK cells. The absolute counts of CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells and NK cells on 12 months were comparable to those in the control group (P \u0026gt; 0.05). However, patients receiving AZA-VEN had significantly delayed reconstitution of CD19\u003csup\u003e+\u003c/sup\u003e B cells compared with the control group, significant lower counts of CD19+B cells both on 9-month (59.5 cells/μL vs. 215 cells/μL; P = 0.001) and 12-month (60.5 cells/μL vs. 271.5 cells/μL; P = 0.001) (Figure 1).\u003c/p\u003e\n\u003cp\u003eSurvival\u003c/p\u003e\n\u003cp\u003ePatients of the AZA-VEN group received a median of 5 cycles (range, 1-10), 62.9% (22/35) completing ≥ 4 cycles. After a median follow-up of 22.5 (range, 2.4-46.5) months, there were 15 relapses in this propensity score matched cohorts. Four patients (11.4%) were from AZA-VEN group and 11 patients (18.6%) were from control group. A total of 20 patients died: 4 from the AZA-VEN group and 16 from the control group. In the AZA-VEN group, three patients died from disease relapse, one patient died from septic shock secondary to enterogenous bacteremia, with cultures positive for both Klebsiella pneumoniae and Enterococcus faecalis. Notably, this patient had successfully completed four cycles of maintenance therapy without any observed hematological toxicity, but subsequently developed a severe infection attributed to the consumption of contaminated food. In the control group, ten patients died from disease relapse and 6 from infections. Notably, 30 of 35 patients (85.7%) who received AZA-VEN remained alive and MRD negative.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the matched cohort, the 1-year DFS was 88.6% (95% CI, 78.6%-99.8%) for the AZA-VEN group compared with 76.3% (95% CI, 66.2%-87.9%) for the control group. The 1-year OS was 91.4% (95% CI, 82.6%-100%) for the AZA-VEN group versus 76.2% (95% CI, 66.1%-87.9%) for the control group (P = 0.037)(Figure 2 A, 2B).\u003c/p\u003e\n\u003cp\u003eThe 1-year CIR was 5.7% (95% CI, 0%-13.5%) in the AZA-VEN group versus 15.3% (95% CI, 6%-24.5%) in the control group (Figure 2C). Maintenance therapy with AZA-VEN resulted in a significant reduction in relapse risk, corresponding to a 42.1% relative and a 7.2% absolute decrease. The number needed to treat was 14, indicating that one relapse could be prevented for every 14 patients treated with this maintenance regimen. The median time to relapse was longer in the AZA-VEN group (7.55 months; range, 3.8-20.3) than in control group (5 months; range, 1.4-14.3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the 7 patients with TP53 mutation, 5 died: 1 from the AZA-VEN group (relapse), and 4 from control group (3 relapse, 1 infection).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo further integrate the competing endpoints of death and relapse, a win ratio analysis was performed. This yielded a ratio of 1.18 (95% CI, 1.09-1.29; P \u0026lt; 0.001), demonstrating a significant clinical benefit favoring the AZA-VEN group (Figure 2D).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubgroup and multivariable analyses\u003c/p\u003e\n\u003cp\u003eIn order to determine who benefit most from the maintenance therapy, we carried out a multivariable analysis. By using multivariable Cox regression model adjusted for time from diagnosis to transplant, we identified low disease risk stratification, pre-transplant MRD negativity, and AZA-VEN maintenance as independent favorable prognostic factors. These were associated with improved DFS (HR, 0.4; p=0.075) and OS (HR, 0.3; p=0.036) (Figure 3A, 3B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubsequent exploratory subgroup analyses of DFS and OS confirmed a consistent benefit from AZA-VEN maintenance (all subgroup HRs \u0026lt; 1). Moreover, a benefit of borderline statistical significance was observed in the pre-transplant MRD positivity subgroup (HR=0.29, 95% CI 0.08-1.00, P=0.050).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the pre-transplant MRD-positive subgroup (AZA-VEN, n=21; control, n=33), the 1-year DFS was 85.7% in the AZA-VEN group compared with 63.6% in control (P = 0.051). Correspondingly, the 1-year OS was 90.5% versus 63.6% (HR, 0.288; P = 0.037). (Figure 4A, 4B)\u003c/p\u003e\n\u003cp\u003eSafety and toxicity\u003c/p\u003e\n\u003cp\u003eThe most common adverse events were cytopenias. Neutropenia developed in 21 patients (52.5%), including grade 3 in 9 and grade 4 in 3 patients. Thrombocytopenia was observed in 14 patients (35.0%), with three grade 3 and one grade 4 events. Anemia was observed in 18 patients (45.0%). Predominant non-hematologic toxicities were nausea (45%), vomiting (22.5%) and elevated liver transaminases (alanine aminotransferase 40.0%; aspartate aminotransferase 37.5%). Grade 3-4 events were uncommon, with each occurring in ≤ 2.5% of patients (Table 2).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur study demonstrated that post-transplant maintenance with azacitidine plus venetoclax is an effective and safe strategy for high-risk AML and MDS. After a median follow-up of 22.5 months, we observed promising outcomes, with 1-year DFS of 88.6%, 1-year OS of 91.4%, and 1-year CIR of only 5.7%. The win ratio analysis affirmed the regimen’s overall clinical benefit.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA meta-analysis of posttransplant azacitidine monotherapy including 13 studies showed a pooled 2-year CIR of 25% and OS of 65%, underscoring the limitation of single-agent hypomethylating therapy\u003csup\u003e30\u003c/sup\u003e. Antin et al. reported AZA-VEN as maintenance therapy (azacitidine 36 mg/m²/day on day 1-5; venetoclax 400 mg/day on day 1-14) for 27elderly patients (median age 67 years; range, 47-78 years) after reduced-intensity conditioning allo-HSCT , which produced a 2-year OS of 67% , PFS of 59% , and CIR of 41%\u003csup\u003e1\u003c/sup\u003e. The median time from transplant to maintenance was 57 days (range, 42-103 days). The relatively high incidence of relapse may be attributable, in part, to the older patient population and the reduced-intensity conditioning employed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCombination of hypomethylating agents and other supportive or novel agents also showed improved survival in small cohort studies. For instance, decitabine combined with granulocyte colony-stimulating factor (5 mg/m\u003csup\u003e2\u003c/sup\u003e of decitabine and 100 µg/m\u003csup\u003e2\u003c/sup\u003e of G-CSF on day 1-5) showed improved 2-year OS of 89.0% in older patients(median age 65 years; range, 26-76 years) and 2-year CIR of 15.0% in younger cohorts\u003csup\u003e31, 32\u003c/sup\u003e. Recently, a French team reported that oral decitabine-cedazuridine (a combination where cedazuridine, a cytidine deaminase inhibitor, enhances oral bioavailability of decitabine, 35 mg decitabine and 100 mg cedazuridine on days 1-3) administered from day 40 post-HSCT, achieving a 1-year DFS of 70.4% in 28 very high-risk patients\u003csup\u003e33\u003c/sup\u003e. In patients with TP53-mutant myeloid malignancies, combination of azacitidine (36 mg/m²/day for days 1-5) and eprenetapopt (3.7 g/day for days 1-4) achieved a 1-year OS of 78.8% (95% CI, 60.6%-89.3%)\u003csup\u003e34\u003c/sup\u003e. Collectively, these data provided evidence for the efficacy of hypomethylating agents-based regimen as posttransplant maintenance therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the present study, a short-course combination of azacitidine and venetoclax yielded a 1-year DFS of 88.6% and a correspondingly low 1-year CIR of 5.7%. The median time to relapse was significantly prolonged with therapy (7.55 months vs. 5 months in controls). At last follow-up, 85.7% (30/35) of treated patients remained alive and free of leukemia, including those with adverse-risk genetics such as TP53 or RUNX1 mutations. These outcomes compare favorably with those of recent innovative regimens, implicating a potential efficacy advantage of adding a BCL-2 inhibitor\u003csup\u003e35, 36\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study demonstrated that post-transplant AZA-VEN maintenance significantly improved OS in patients with detectable MRD before transplant (HR, 0.288; P = 0.037). Previous study has confirmed that achieving multiparametric flow cytometry MRD clearance after AZA-VEN therapy is linked to a better EFS and OS\u003csup\u003e37\u003c/sup\u003e. Another study demonstrated a strong correlation between MRD negativity by flow cytometry and improved overall survival in patients receiving venetoclax plus decitabine\u003csup\u003e38\u003c/sup\u003e, the comparative prognostic value of flow cytometry and molecular MRD monitoring in the post-transplant setting has not been fully elucidated\u003csup\u003e39\u003c/sup\u003e. Further prospective studies are needed to define the optimal MRD monitoring modality (flow cytometry vs molecular techniques), the ideal timing for assessment, and clinically actionable thresholds. This will enhance its utility in guiding post-transplant interventions and predicting relapse-free and overall survival.\u003c/p\u003e\n\u003cp\u003eIn addition, the incidence of acute and chronic GVHD did not differ significantly between the matched cohorts. This finding further corroborates the favorable safety profile of the regimen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNotably, the regimen had limited inhibitory effects on T-cell reconstitution, preserving both CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e populations. Although B-cell recovery was delayed, this did not lead to an increased incidence of clinically significant infection, supporting the overall immunologic safety of this approach. Longer follow-up and functional immunologic assays, such as evaluation of CMV and EBV-specific T-cell responses and antibody titers, is needed to fully characterize the late safety profile of this maintenance strategy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study demonstrated a manageable safety profile for post-transplant AZA-VEN maintenance. Adverse events were primarily hematologic, consisting of neutropenia and thrombocytopenia. Grade 3-4 neutropenia and thrombocytopenia occurred in 30.0% (12/40) and 10.0% (4/40) of patients respectively.Anemia of any grade was observed in 45.0% (18/40). Grade 1-2 non-hematologic toxicities, such as nausea, vomiting and elevated liver transaminases were frequent, while grade 3-4 events were uncommon\u003csup\u003e40\u003c/sup\u003e. However, gastrointestinal events and cytopenias affected treatment tolerance. Future studies might explore strategies modification, which include delaying the initiation of maintenance therapy until 3-4 months post‑transplant and investigating dose reduction to mitigate toxicity without compromising efficacy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeveral limitations must be acknowledged. As a retrospective analysis, the findings are subject to unmeasured confounding and bias, limiting causal conclusions. Additionally, the infrequency of non-relapse death events limited the evaluation of the regimen's impact on this endpoint.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this study demonstrated the efficacy of AZA-VEN as post-transplant maintenance for high-risk AML and MDS patients, particularly in patients with pre-transplant MRD. These promising survival and relapse outcomes merit further investigation in a randomized placebo-controlled trial, especially among MRD-positive and non-CR populations. Further research should also refine predictive biomarkers, particularly in TP53-mutated patients, to optimize patient selection and guide personalized therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eDATA AVAILABILITY\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\u003cp\u003eACKNOWLEDGMENTS\u003c/p\u003e\n\u003cp\u003eThe authors thank the patients and their families, as well as the clinical study teams. We also acknowledge Huizhong Shi, Xiao Zhou, Fangfang Yu for their assistance with manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAUTHOR CONTRIBUTIONS\u003c/p\u003e\n\u003cp\u003eLW and XS designed and supervised the study, revised the manuscript. CZ and JW collected and analyzed data interpreted results, and wrote the manuscript. YC, JY, HQ, KZ, JN, CH, YZ, YW, BD, JS, JC, LG, MY, and YT, contributed to the treatment of patients and interpretation of results. All authors reviewed and approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFUNDING\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Clinical Research Innovation Plan of Shanghai General Hospital (Grant Number: CCTR-2022B01).\u003c/p\u003e\n\u003cp\u003eCOMPETING INTERESTS\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGarcia JS, Kim HT, Murdock HM, Ansuinelli M, Brock J, Cutler CS\u003cem\u003e et al.\u003c/em\u003e Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML. \u003cem\u003eBlood Adv \u003c/em\u003e2024; \u003cstrong\u003e8\u003c/strong\u003e(4)\u003cstrong\u003e: \u003c/strong\u003e978-990.\u003c/li\u003e\n\u003cli\u003eGarcia-Manero G. 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\u003cstrong\u003e63\u003c/strong\u003e(8)\u003cstrong\u003e: \u003c/strong\u003e1934-1941.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8886738/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8886738/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Relapse is a major cause of treatment failure after allogeneic hematopoietic stem-cell transplantation(allo-HSCT) for high-risk myeloid malignancies. This single center, retrospective study enrolled patients with high-risk acute myeloid leukemia or myelodysplastic syndromes who received allo-HSCT from January 1, 2022 to December 31, 2024. Post-transplant maintenance therapy consisted of azacitidine (32 mg/m²/day, day 1-5) plus venetoclax (400 mg/day, day 1-7), starting from the 60th day posttransplant and repeated every 28 days until up to 1-year posttransplant. Outcomes were compared with a contemporaneous control group constructed via propensity score matching (azacitidine-venetoclax, n = 35; control, n = 59). After a median follow-up of 22.5 months, the 1-year disease-free survival was 88.6% (95% CI, 78.6%-99.8%), the 1-year cumulative incidence of relapse was 5.7% (95% CI, 0%-13.5%). The azacitidine-venetoclax group demonstrated significantly superior 1-year overall survival compared to control (P = 0.037). Win ratio analysis further confirmed a significant overall clinical benefit (P \u003c 0.001). Subgroup analysis revealed a pronounced overall survival benefit for MRD-positive patients (HR, 0.288; P = 0.037). The safety profile was manageable, no significant increase in the incidences of EBV and CMV infection or graft-versus-host disease. Immune reconstitution analysis showed delayed B-cell recovery but preserved T-cell and NK-cell recovery.","manuscriptTitle":"Azacitidine plus venetoclax as post-transplant maintenance therapy in high-risk myeloid malignancies: a propensity score-matched analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 16:38:20","doi":"10.21203/rs.3.rs-8886738/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-03-26T17:43:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-10T23:00:20+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-17T22:25:59+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-02-17T19:32:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-17T19:14:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-15T14:40:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2026-02-15T14:40:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ee47796f-eb76-4364-8712-0334e87f1998","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":63092679,"name":"Biological sciences/Cancer/Haematological cancer/Leukaemia/Acute myeloid leukaemia"},{"id":63092680,"name":"Biological sciences/Cancer/Haematological cancer/Myelodysplastic syndrome"}],"tags":[],"updatedAt":"2026-03-26T17:45:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 16:38:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8886738","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8886738","identity":"rs-8886738","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}