Modified Azacitidine plus Cytarabine versus Traditional Cytarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia: A Retrospective and Propensity Score Matched Analysis

Modified Azacitidine plus Cytarabine versus Traditional Cytarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia: A Retrospective and 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 Research Article Modified Azacitidine plus Cytarabine versus Traditional Cytarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia: A Retrospective and Propensity Score Matched Analysis Zixuan Li, Jingdi Liu, Jiaxin Hong, Dairong Xie, Yuting Jiang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9409121/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background Azacitidine (AZA) is a hypomethylating agent with well-known antileukemic activity. The addition of AZA to intermediate-dose Cytarabine (IDAra-c) plus idarubicin (Ida) or etoposide (Eto) in consolidation may improve outcomes in acute myeloid leukemia (AML) patients and reduce side effect. Methods We retrospectively evaluated whether adding AZA to IDAra-c plus Ida or Eto during consolidation could improve outcomes and reduce toxicity in newly diagnosed AML patients who achieved complete remission (CR) or partial remission (PR) after induction therapy. Propensity score matching was performed between patients in AZA+ IDAra-c + Ida/Eto and patients received IDAra-c as consolidation in the corresponding period at a 1:1 ratio according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, European Leukemia Net 2022 risk stratification and induction therapy classification. Results Fifty patients treated with AZA+IDAra-c + Ida/Eto were matched with 50 patients receiving IDAra-c alone. AZA+ IDAra-c + Ida/Eto was associated with longer overall survival (OS, 90.0% vs. 53.4%, p = 0.0006) and event free survival (EFS, 81.7% vs. 45.9%, p = 0.0021) at 40 months. Subgroups analysis implied patients who ≦ 40 years, achieved MRD negative after induction therapy, diagnosed as adverse risk or patients carried methylation associated mutations may have potential beneficial survival choosing AZA+ IDAra-c + Ida/Eto as consolidation treatment. Myelosuppression was present in both groups, but the cells affected were different. Conclusion In conclusion, AZA+IDAra-c + Ida/Eto consolidation was associated with improved long-term survival and comparable toxicity versus IDAra-c alone in newly diagnosed AML. Acute myeloid leukemia Azacitidine Cytarabine Consolidation therapy Figures Figure 1 Figure 2 Introduction The achievement of complete remission (CR) is an important milestone for patients with acute myeloid leukemia (AML) and generally can be seen in 50%-70% AML patients with conventional high-intensity induction regimens. 1 – 3 However, 30%-40% of patients will relapse and end up with poor outcomes. 4 , 5 Meanwhile, measurable residual disease (MRD) is sensitive clinical predictor and detectable MRD while in CR is associated with higher relapse risk and shorter survival. 6 Thus, optimization of consolidation and maintenance therapies to maintain CR and MRD response to prevent relapse is a major challenge in AML. 7 Cytarabine (Ara-c) administered as six to twelve intravenous doses over three to six days, used to be the most traditional and widely established chemotherapeutic regimen for consolidation therapy. 8 , 9 While this regimen achieves CR in 78%-90% of AML patients, merely 39%-48% maintain CR after five years, highlighting the need for more effective long-term strategies. 10 , 11 Epigenetic dysregulation, particularly hypermethylation of tumor suppressor genes and the resulting epigenetic silencing, plays a key role in the pathogenesis of myeloid malignancies. 12 Thus, hypomethylating agents, such as azacitidine (AZA), have thus emerged as a promising therapeutic approach. AZA is able to incorporate into RNA, interfering with the synthesis of nucleic acids and proteins, and to a lesser extent, incorporate into DNA. 13 , 14 This process reactivates silenced tumor suppressor genes, promotes cell differentiation, induces apoptosis and conduct cytotoxic effect in myeloid leukemia cells. 15 When used as single agents, AZA has a CR rate up to 47% in treatment-naive AML patients. 13 Compared with conventional care regimens (including standard induction chemotherapy, low-dose Ara-c, or supportive care only), AZA increased elderly patients with newly diagnosed AML median overall survival (OS) from 6.5–16.0 to 10.4–24.5 months, one-year survival from 34.2% to 46.5% and two-year survival from 16% to 50%. Notably, the incidence of serious adverse events was comparable across AZA, low-dose Ara-c, and intensive chemotherapy groups. 16 , 17 Therefore, AZA is recommended as front-line treatment for older patients with AML who are not candidates for intensive treatment regimens. 15 , 18 Since the effectiveness and safety of AZA in AML patients was widely approved, 15,19,20 the addition of AZA to intermediate-dose Ara-c (IDAra-c) in consolidation treatment as a modified regimen may improve long-term outcomes in age-independent newly diagnosed AML patients. Meanwhile, the combination of cytarabine with idarubicin (Ida) or etoposide (Eto) has demonstrated good efficacy and tolerance.[21] Above all, we conducted a retrospective propensity score–matched study to compare the therapeutic responses and survival outcomes of patients with newly diagnosed AML who underwent consolidation therapy with AZA+ IDAra-c + Ida/Eto to those who received Intermediate-dose (ID) Ara-c. Materials and Methods Patients and treatment We conducted a retrospective study to compare outcomes with AZA+ IDAra-c + Ida/Eto or IDAra-c as consolidation treatment in patients with newly diagnosed AML who had achieved CR or partial remission (PR) after induction treatment. All patients enrolled in this study were evaluated by physicians and met the indications for intensive chemotherapy. Patients in the AZA+ IDAra-c + Ida/Eto received a consolidation regimen of AZA (75 mg/m 2 for day 1–7), Ara-c (2 g/m 2 q12h for day 1–3). Sequential regimen was alternative idarubicin (10mg for day 4–5) or etoposide (100mg for day 4–5). The comparison cohort was selected from patients treated with traditional intensive chemotherapy containing high dose of Ara-c (3g/m 2 /12h for day 1–3). Other agents administered in combination included idarubicin or etoposide. All patients received up to 6 consolidation courses and no maintenance course was applied in patients. FLT3-ITD/TKD mutated patients received FLT3 inhibitor as directed by their physician, while no patients with IDH1/IDH2 mutated or other mutations received corresponding inhibitors. Eligible patients in either group could proceed to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) after achievement of a response with the final decision made based on the patients’ informed consent and the attending physicians’ clinical recommendations. Response evaluation and endpoints Bone marrow evaluation was performed after blood count recovery at each consolidation cycle. Minimal residual disease (MRD) was evaluated in bone marrow specimens by flow cytometry with a cutoff value of 0.01%. Next-generation sequencing (NGS)-based MRD testing, using a customized hematological malignancy-targeted gene panel (covering 80 genes including FLT3, NPM1, DNMT3A, IDH1/2, and IKZF1), achieves a detection sensitivity of 10⁻⁵ for residual clonal malignant cells and the results were collected if available. Overall survival (OS) was determined from diagnosis until death, or censored at last follow-up. Event-free survival (EFS) was determined from start of consolidation therapy until date of refractory disease, relapse, death, or censored at last follow-up. The cumulative incidence of relapse (CIR) and duration of response (DOR) was calculated from the time of CR until relapse. The duration of neutrophil recovery was calculated from the first day the neutrophil count dropped to 0.5×10⁹/L until the count was sustainedly recovered to at or above 0.5×10⁹/L. The same applies to platelets, with a threshold of 50×10⁹/L. Other safety analysis was evaluated using the Common Terminology Criteria for Adverse Events version 5.0. Propensity score matching and statistical analysis Propensity score matching was performed between patients in AZA+ IDAra-c + Ida/Eto and IDAra-c cohort in the corresponding period at a 1:1 ratio with a caliper value of 0.05 according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status (ECOG), European Leukemia Net (ELN) 2022 risk stratification and induction therapy classification to minimize bias. 21 , 22 The effectiveness of PSM in minimizing group differences was evaluated using the standardized mean difference (SMD), considering a variable unbalanced if SMD exceeded 0.1. 23 Wilcoxon signed-rank tests were used to analyze continuous variable, Fisher exact tests were used for categorical variables. The Kaplan‒Meier method was used to compare time‐to‐event variables. Univariable Cox model was used to examine the associations among patient characteristics and outcomes. Prism version 8.0 (GraphPad Software) and SPSS 25 (IBM Corp) were used for statistical analyses. Results Patients A total of 50 newly diagnosed patients treated with AZA+ IDAra-c + Ida/Eto were matched with 50 newly diagnosed patients treated with IDAra-c therapies (Table 1 ). The patients in the AZA+ IDAra-c + Ida/Eto cohort were diagnosed between September 2020 and August 2024.The patients in the IDAra-C cohort were diagnosed between March 2020 and February 2023. The median age was 43 years (range, 16–66 years) in the AZA+ IDAra-c + Ida/Eto cohort and 44 years (range, 15–66 years) in the IDAra-C cohort. Age group, gender, proportions of patients with an ELN 2022 adverse risk, ECOG performance status and induction therapy classification were matched between two cohort. Table 1 Baseline characteristics of propensity score–matched patients with newly diagnosed acute myeloid leukemia treated with AZA+ IDAra-c + Ida/Eto versus IDAra-c. Parameters AZA+ IDAra-c + Ida/Eto cohort (n = 50) IDAra-C cohort (n = 50) P SMD Age, years (%) Median (range) ≦ 40 40–60 ≥ 60 43 (16–66) 23 (46) 26 (52) 1 (2) 44 (15–66) 23 (46) 26 (52) 1 (2) 1.00 < 0.001 Gender Male: female 27:23 27:23 1.00 < 0.001 Cytogenetic risk group at diagnosis, No. (%) Favorable Intermediate Adverse 18 (36) 18 (36) 14 (28) 18 (36) 18 (36) 14 (28) 1.00 < 0.001 Induction regimen, No. (%) Traditional regimen (IA/DA/HA) New regimen including HMA/Venetoclax 34 (68) 16 (32) 34 (68) 16 (32) 1.00 < 0.001 ECOG performance status (%) 0–2 3 50 (100) 0 50 (100) 0 NA NA Mutations at diagnosis, No. (%) FLT3-ITD/TKD RUNX1 ASXL1 TP53 EZH2 BCOR/BCORL1 NRAS/KRAS IDH1/2 DNMT3A NPM1 CEBPA Fusion gene at diagnosis, No. (%) AML1-ETO CEBFB-MYH11 Karyotype at diagnosis, No. (%) 11q23 complex 12 (24) 4 (8) 3 (6) 2 (4) 1 (2) 3 (6) 8 (16) 6 (12) 7 (14) 7 (14) 12 (24) 6 (12) 2 (4) 2 (4) 1 (2) 5 (10) 3 (6) 1 (2) 0 5 (10) 2 (4) 3 (6) 2 (4) 2 (4) 8 (16) 12 (24) 13 (26) 4 (8) 5 (10) 2 (4) 0.06 1.00 0.62 0.50 0.21 1.00 0.20 0.27 0.16 1.00 1.00 0.07 0.67 0.44 1.00 Induction response, No. (%) CR PR MRD negative by flow cytometry NGS-MRD negative 41 (82) 9 (18) 34 (68) 23 (52.27) 45 (90) 5 (10) 32(64) 17 (60.71) 0.67 0.39 0.70 0.60 Allo-HSCT, No. (%) in CR1 in CR2 14 (31.82) 1 (33.33) 9 (32.14) 4 (66.67) 0.47 1.00 IA, idarubicin and cytarabine; DA, daunorubicin and cytarabine, HA, homoharringtonine and cytarabine; HMA, hypomethylating agents; Ven, venetoclax; CR, complete remission; PR, partial remission; MRD, minimal residual disease; NGS, next generation sequencing; allo-HSCT, allogeneic hematopoietic stem-cell transplantation. 49 patients in AZA+ IDAra-c + Ida/Eto cohort and 48 in IDAra-C cohort had at least one cytogenetic abnormality. All patients in two cohort achieved CR or PR after induction therapy and were all available for MRD results, with 34 (68%) and 32 (64%) patients achieved MRD negative after induction regimen in two cohort ( p = 0.67). 44 and 28 patients who had available NGS-MRD results after induction therapy. Of them 23 (52.27%) and 17 (60.71%) achieved NGS-MRD negativity in AZA+ IDAra-c + Ida/Eto and IDAra-c cohort respectively ( p = 0.70). 14 (31.82%) and 9 (32.14%) patients in two cohorts chose to undergo allo-HSCT in CR1 ( p = 0.47). One (33.33%) and four (66.67%) patients in two cohort accepted allo-HSCT in CR2 ( p = 1.00). Response rates Median circles of 3 (range1-6) AZA+ IDAra-c + Ida/Eto and 4 (range 1–6) IDAra-c consolidation therapy were administered. The percent of patients achieving CR (92% vs. 92%), MRD (91.3% vs. 91.3%) and NGS MRD negativity (62.5% vs. 53.5%) in two group was comparable after the first two consolidation therapy (Table 2 ). Then the percent of above response rate declined in IDAra-c group (CR rate 56%, MRD rate 60% and NGS MRD rate 39.1%), while that in AZA+ IDAra-c + Ida/Eto group stayed stable up to the end of consolidation treatment for each patient (90%, 82% and 79.4%), which showed a significant disparity between two group. AZA+ IDAra-c + Ida/Eto was associated with significantly lower rate of relapse compared to IDAra-c (10% vs. 44%, p = 0.00). Five patients of AZA+ IDAra-c + Ida/Eto cohort had NGS MRD results when relapsed and three of them were detected with DNA Methylation associated mutations, including three DNMT3A mutations and one IDH1 mutation. Among the three patients, two had persistent positivity for DNMT3A mutations, and one had concurrent IDH1 mutation from diagnosis throughout the entire treatment process. One patient had a transient negative result for DNMT3A mutation after induction therapy, but the mutation reappeared at relapse. Four patients detected with mutated IDH1, DNMT3A or TET2 among 13 relapsed patients with available NGS-MRD results in ID/IDAra-c cohort. Among them, the genetic basis of the two patients with DNMT3A or TET2 mutation at relapse was consistent with that at the time of diagnosis. The mutation of IDH1 or DNMT3A in other two patients at relapse were newly emerged. Among all relapsed patients above, three and six patients re-achieved CR2 through salvage treatment. The overall mortality during consolidation therapy in two cohort was significantly different (10% vs. 36%, p = 0.00) including two and three patients in each cohort died of septic shock (4% vs. 6%, p = 1.00, Table 2 ). Table 2 Comparison of outcomes according to two matched cohort Outcomes AZA+ IDAra-c + Ida/Eto cohort (n = 50) IDAra-C cohort (n = 50) P Median circles of consolidation regimen (Range) 3 (1–6) 4 (1–6) 0.70 CR response after, No. (%) Cycle 2 The end of consolidation 46 (92) 45 (90) 44 (92) 28 (56) 0.51 0.00 MRD response after, No. (%) Cycle 2 The end of consolidation 42 (91.3) 42 (82) 42 (91.3) 27 (54) 1.00 0.01 NGS MRD response after, No. (%) Cycle 2 The end of consolidation 15 (62.5) 27 (79.4) 8 (53.3) 9 (39.1) 0.57 0.00 Relapse, No. (%) 6 (12) 22 (44) 0.00 Overall deaths, No. (%) Non-relapse deaths, No. (%) 5 (10) 2 (4) 18 (36) 3 (6) 0.00 1.00 CR, complete remission; MRD, minimal residual disease; NGS, next generation sequencing; Survival outcomes The median follow-up period was 27.5 months (range, 4–59 months) in the AZA+ IDAra-c + Ida/Eto cohort and 27months (range, 6–66 months) in the ID/IDAra-c cohort. OS and EFS in AZA+ IDAra-c + Ida/Eto cohort was significantly longer compared to IDAra-c cohort. The estimated OS rates at 40 months were 90.0% (95% CI, 85.8%-94.2%) in the AZA+ IDAra-c + Ida/Eto cohort and 53.4% (95% CI, 46.1%-60.7%, p = 0.0006) in the ID/IDAra-c cohort (Fig. 1 A). EFS at 40 months were 81.7% (95% CI, 76.2%–87.2%) in the AZA+ IDAra-c + Ida/Eto cohort and 45.9% (95% CI, 38.5%-53.3%, p = 0.0021) in the ID/IDAra-c cohort (Fig. 1 B). The median DOR was not reached in two cohort, but CIR was extraordinarily higher in the IDAra-c cohort. One-year CIR was 31.3% vs. 10.5% and two-year CIR was 42.5% vs.12.8% (Fig. 1 C/D). The survival condition was comparable in the AZA+ IDAra-c + Ida/Eto cohort but better in ID/IDAra-c cohort when considering allo-HSCT as an independent factor. Among patients received allo-HSCT, OS at 40 months was 100% vs. 68.40% (95% CI, 55.3%-81.5%) and EFS at 40 months was 92.9% (95% CI, 86.0%-99.8%) vs. 57.5% (95% CI, 42.9%-72.1%) in two cohort. In contrast, OS and EFS at 40 months in ID/IDAra-c cohort deteriorated when censoring allo-HSCT, with 47.9% (95% CI, 39.3%-56.6%) and 42.3% (95% CI, 33.8%-50.8%) compared with 85.7% (95% CI, 69.8%-93.9%) and 77.0% (95% CI, 69.9%–84.1%) in AZA+ IDAra-c + Ida/Eto cohort (Fig. 1 E&F). Subgroups analysis Exploratory subgroup analysis in matched cohorts favored AZA+ IDAra-c + Ida/Eto in most subgroups (Fig. 2 ). It revealed that AZA+ IDAra-c + Ida/Eto consolidation rather than IDAra-c was a protective factor in patients who ≦ 40 years, achieved MRD negative after induction therapy or diagnosed as adverse risk ( p = 0.02, 0.01& 0.05). Although no significant difference was found in patients > 40, or in favorable or intermediate risk group, the 40-month OS was relatively longer in AZA+ IDAra-c + Ida/Eto cohort, with 84.6% vs.52.3% in patients aged 40–60, 88.9% vs. 59.5% in cytogenetic favorable group and 88.9% vs. 55.9% in intermediate group. Certain molecular disorders at diagnosis conferred sensitivity to AZA+ IDAra-c + Ida/Eto therapy as well. Patients with mutations associated with DNA Methylation (DNMT3A, IDH1/2, TET2, WT1 or NPM1) were more likely to benefit in survival using AZA+ IDAra-c + Ida/Eto treatment, which prolonged the survival more than twice as long as that in ID/IDAra-c. 24 Toxicity assessment All patients enrolled in this trial were included in the toxicity analysis. The most frequent hematological toxicities were myelosuppression. Patients in AZA+ IDAra-c + Ida/Eto cohort had relatively higher lowest hemoglobin concentration in each consolidation cycle compared with those in IDAra-c, and obvious difference can be seen in the cycle 2 (77.27 g/L vs, 67.71 g/L), 4 (84.83 g/L vs.65.75 g/L) and 5 (80.53 g/L vs. 60.78 g/L). During the treatment of AZA+ IDAra-c + Ida/Eto, there were 20 transfusion episodes, and 83 units (U) of red blood cell (RBC) given. Twenty-nine transfusion episodes were required in IDAra-c cohort, with a total amount of 118.5 units. The average number of transfused units in each cycle was shown in Table 3 . The average days to neutrophil recovery (neutrophils ≥ 0.5 × 10 9 /L) were longer in AZA+ IDAra-c + Ida/Eto cohort especially in cycle 2 (10.00d vs. 7.25d), 3 (9.29d vs. 7.29d) and 4 (12.00d vs. 7.79d). The average days to recovery of platelets ≥ 50 × 10 9 /L and numbers of patients developing febrile neutropenia or pneumonia were similar in two cohort (Table 3 ). Table 3 Myelosuppression in two cohort. Cycle 1, pts Lowest, hemoglobin concentration g/L (range) Neutrophils to recover to 0.5 x 10 9 /L, days (range) Platelets to recover to 50 x 10 9 /L, days (range) Febrile neutropenia, pts Pneumonia, pts Average RBC transfusion, U (range) AZA+ IDAra-c + Ida/Eto IDAra-C p 50 71.72 (43–117) 8.07 (1–27) 11.48 (4–49) 6 2 1.07 (0–14) 50 66.00(30–95) 6.42 (1–17) 11.01 (5–19) 12 3 0.78 (0–13) 0.42 0.17 0.33 0.19 1.00 0.59 Cycle 2, pts Lowest hemoglobin concentration, g/L (range) Neutrophils to recover to 0.5 x 10 9 /L, days (range) Platelets to recover to 50 x 10 9 /L, days (range) Febrile neutropenia, pts Pneumonia, pts Average RBC transfusion, U (range) 45 77.27 (42–109) 10.00 (6–22) 12.24(7–27) 11 2 0.31 (0–5) 45 67.71 (30–101) 7.25 (1–24) 12.50 (6–32) 9 5 0.69 (0-13.5) 0.01 0.00 0.84 0.61 0.43 0.53 Cycle 3, pts Lowest hemoglobin concentration, g/L (range) Neutrophils to recover to 0.5 x 10 9 /L, days (range) Platelets to recover to 50 x 10 9 /L, days (range) Febrile neutropenia, pts Pneumonia, pts Average RBC transfusion, U (range) 33 76.83 (51–106) 9.29(3–24) 12.25 (7–32) 6 6 0.35 (0–6) 38 70.72(30–112) 7.29 (1–32) 12.54 (6–44) 5 3 0.40 (0-3.5) 0.24 0.03 0.76 0.74 0.35 0.43 Cycle 4, pts Lowest hemoglobin concentration, g/L (range) Neutrophils to recover to 0.5 x 10 9 /L, days (range) Platelets to recover to 50 x 10 9 /L, days (range) Febrile neutropenia, pts Pneumonia, pts Average RBC transfusion, U (range) 18 84.83(52–111) 12.00 (6–22) 13.66(6–22) 4 2 0.11 (0–2) 25 65.75 (34–116) 7.79 (1–28) 13.17 (7–30) 3 1 1.16 (0–9) 0.01 0.00 0.76 0.42 0.56 0.09 Cycle 5, pts Lowest hemoglobin concentration, g/L (range) Neutrophils to recover to 0.5 x 10 9 /L, days (range) Platelets to recover to 50 x 10 9 /L, days (range) Febrile neutropenia, pts Pneumonia, pts Average RBC transfusion, U (range) 17 80.53 (40–110) 9.73 (4–16) 11.80 (7–18) 5 2 0.4 (0–6) 9 60.78 (34–95) 7.89 (5–16) 13.78 (7–21) 3 1 1.00 (0–7) 0.01 0.11 0.24 1.00 1.00 0.52 Cycle 6, pts Lowest hemoglobin concentration, g/L (range) Neutrophils to recover to 0.5 x 10 9 /L, days (range) Platelets to recover to 50 x 10 9 /L, days (range) Febrile neutropenia, pts Pneumonia, pts Average RBC transfusion, U (range) 8 84.25 (65–103) 11.43 (5–15) 13 (5–17) 2 1 0 2 110 (99–121) 4 (4) 14 (14) 1 0 0 0.08 0.12 0.82 1.00 1.00 NA Discussion Since DNA methylation has been approved as a mechanism of resistance to chemotherapy 25 , 26 , hypomethylating agents (HMA) has been considered as an effective but less toxic regimen for elderly or unfit AML patients. In this study, we present a novel combination of AZA+ IDAra-c + Ida/Eto and sequential alternative Ida or Eto as consolidation therapy for newly diagnosed age-independently AML patients. The approach of propensity score matching helped to find a closely matched comparator group treated with IDAra-C to minimize the effect of confounders and bias inherent in retrospective comparisons. 21 , 22 Previous studies have highlighted that AZA and Ara-C hold clinical potential in AML treatment. 27 , 28 It was demonstrated that the combination of 5-Aza-2′-deoxycytidine (DAC) and Ara-C showed additive or synergistic effects on cell death in human leukemia cell lines in vitro, but there are limitations in terms of antagonism in epigenetic effects and common intracellular metabolic pathways. 29 , 30 In contrast, AZA bypasses this issue by utilizing uridine-cytidine kinase (UCK) for initial phosphorylation, avoiding competition with DAC and Ara-C for the deoxycytidine kinase (dCK) enzyme. Therefore, epigenetic priming with HMA prior to cytotoxic chemotherapy would sensitize malignant cells to chemotherapy and enhance the response to treatment. Clinical studies have explored the use of HMA and chemotherapy as induction regimen in AML. For instance, a phase 1 study analyzed the safety and biologic activity when assessing decitabine followed by standard cytarabine/daunorubicin induction in patients with intermediate/high-risk of AML. The study ended with a CR rate of 57% (up to 83% after second induction) and reported no excess toxicity. 31 Another phase 1 trial showed that induction chemotherapy using AZA in sequential combination with IDAra-c and mitoxantrone resulted in an overall response rate of 61% and a CR rate of 41% with 30-day mortality below 2% in high-risk AML patients. 32 Ara-C combined with Ida and Eto was relatively classic in AML treatment, and low-dose addition of Ida and Eto results in reduced cytotoxicity. 33 Our clinical findings aligned with prior preclinical evidence, demonstrating that consolidation chemotherapy with AZA+ IDAra-c + Ida/Eto regimen yielded superior outcomes in newly diagnosed AML patients compared to the IDAra-C cohort. This was reflected in durable MRD response rates, reduced relapse and mortality, and improved survival, regardless of allo-HSCT status. Previous studies showed the continued AZA therapy after the first response may benefit and lead to a further improvement. 34 – 36 For example, AZA-001 phase 3 study evaluated 179 patients with high risk of myelodysplastic syndromes (MDS) who received AZA treatment, found that 91% of responding patients achieved their first response (CR, PR, or hematological improvement) within 6 cycles and median time was 2 cycles, but continued AZA improved response category in 48% of patients. 34 In our study, the two cohorts showed comparable efficacy in the first two cycles. However, the disparity began to emerge as treatment progressed. AZA+ IDAra-c + Ida/Eto had advantages on MRD and NGS MRD response till to the end of consolidation therapies which is the key point to avoid relapse and keep long-term survival, while IDAra-C alone failed to do it. Therefore, we recommended a complete 6 cycles of AZA consolidation regimens followed by maintenance regimens as long as the patient continues to benefit. 13 We aimed to identify if patients with distinct clinical characteristics benefit from either consolidation therapy. Our results implied that patients with patients who ≦ 40 years, achieved MRD negative after induction therapy, or diagnosed as adverse risk or patients carried methylation associated mutations to choose AZA+ IDAra-c + Ida/Eto as consolidation treatment may be more likely to benefit in survival. The better treatment outcomes in younger patients may be related to their better tolerance to the treatment; meanwhile, the epigenetic regulatory effects of AZA may have a potential impact on certain gene mutations in high-risk patients, leading to a better prognosis. 37,38 Previous studies have demonstrated that DNMT3A and TET2 mutations are associated with increased sensitivity to HMA. 39 , 40 However, in our cohort, three out of six patients treated with the AZA+ IDAra-c + Ida/Eto regimen relapsed, and these relapses were linked to methylation‑related mutations. It has been reported that conventional DNA hypomethylating agents, such as AZA and DAC, can be incorporated into RNA or DNA, trap DNA methyltransferases (DNMTs), and form suicide complexes. This process is prone to errors and may contribute to cytotoxicity, genomic instability, and ultimately HMA resistance. 41 In addition, individual differences may also affect the activity of HMA metabolism and lead to drug resistance, such as low level of UCK or over expression of cytidine deaminase. 42 Meanwhile, among the relapsed patients with the methylated gene mutations, two also had concurrent NPM1 and SRSF2 mutations. Collectively, these findings indicate that HMA resistance mechanisms are highly complex, and demethylation alone is insufficient to substantially improve patient prognosis. Thus, it cannot be definitively concluded that the combination of AZA+ IDAra-c + Ida/Eto has a necessary advantage for patients with methylated gene mutations. It was preliminarily concluded that the combination of AZA and Ara-c can produce a synergistic effect in patients, thereby achieving a better prognosis. For patients with persistent genetic failure or suspected re-emergence of demethylation associated mutations, novel demethylating drug therapy or strong intervention measures are necessary. 41 , 43 Given the small sizes in above comparison group, our hypothesis-generating conclusion required a large and prospective study. Myelosuppression and related adverse effects have been a deterrent during treatment in patients with AML. 44 In our trial, AZA+ IDAra-c + Ida/Eto was linked to higher level of hemoglobin levels, but longer recovery time from neutropenia. Higher hemoglobin level reduced the dependency on blood transfusion of patients in AZA+ IDAra-c + Ida/Eto group. Neutropenia is a known side effect of hypomethylating therapy. 16 Although patients suffered from more days of neutropenia, the number of patients developing febrile neutropenia, pneumonia or non-relapse mortality was roughly equal. According to previous studies as well as our experience, the use of granulocyte colony stimulating factor (G-CSF) coupled with stringent antimicrobial prophylaxis and close monitoring may release the progression to severe infection during neutropenia. 45 Our retrospective study has several limitations. First, our results were limited by the small cohort size of the retrospective cohort. Second, compared with the conventional cytarabine regimen, our research protocol incorporates two additional drugs, AZA and Ida/Eto, resulting in distinct anti-tumor mechanisms. Therefore, the efficacy of the regimen cannot be attributed solely to the addition of any single drug. Despite the trend observed in our study in favor of AZA+ IDAra-c + Ida/Eto compared with our historical cohort treated with IDAra-c alone, the lack of a randomized comparator limits accuracy of conclusions. A randomized study will be required to meaningfully evaluate the contribution of AZA to this combination. In conclusion, our retrospective propensity score matching study demonstrated that in the absence of a substantial increase in severe or fatal adverse events, AZA+ IDAra-c + Ida/Eto consolidation may offer a more favorable prognosis in terms of long-term response and survival benefits compared to IDAra-c. Declarations Ethics Statement The protocol was approved by the ethics committee of the Clinical Trial Institution of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology in accordance with the Declaration of Helsinki and the guidelines of the ethics committee. The need for informed consent was waived due to its retrospective design, data anonymity, and non-interventional nature. Consent for publication Not applicable. Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Fundings Supported, in part, by grants from the National Natural Sciences Foundation of China (81570193 and 81770219) to QW. Author Contribution Z. L. collected date and wrote original draft preparation. J. L. and J.H. offered resources and charged patients. D.X., Y.J., R.J. and T.G. did the research. M.H. and Q. W. designed the research and modified the paper. All authors read and approved the final manuscript. Data Availability The raw data of this clinical study are not publicly available due to patient privacy protection and ethical constraints. De-identified data may be available from the corresponding author upon reasonable request, subject to ethical approval. References Estey, E. H. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol 93, 1267–1291, doi: 10.1002/ajh.25214 (2018). Iqbal, A. et al. Improved Treatment Outcomes With Modified Induction Therapy in Acute Myeloid Leukemia (AML): A Retrospective Observational Study From a Regional Cancer Center. Cureus 16, e53303, doi: 10.7759/cureus.53303 (2024). Thol, F., Schlenk, R. F., Heuser, M. & Ganser, A. How I treat refractory and early relapsed acute myeloid leukemia. Blood 126, 319–327, doi: 10.1182/blood-2014-10-551911 (2015). Burnett, A. K. et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 125, 3878–3885, doi: 10.1182/blood-2015-01-623447 (2015). Bose, P., Vachhani, P. & Cortes, J. E. Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Curr Treat Options Oncol 18, 17, doi: 10.1007/s11864-017-0456-2 (2017). Aitken, M. J. L., Ravandi, F., Patel, K. P. & Short, N. J. Prognostic and therapeutic implications of measurable residual disease in acute myeloid leukemia. J Hematol Oncol 14, 137, doi: 10.1186/s13045-021-01148-5 (2021). Medeiros, B. C., Chan, S. M., Daver, N. G., Jonas, B. A. & Pollyea, D. A. Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. Am J Hematol 94, 803–811, doi: 10.1002/ajh.25484 (2019). Weigert, N., Rowe, J. M., Lazarus, H. M. & Salman, M. Y. Consolidation in AML: Abundant opinion and much unknown. Blood Rev 51, 100873, doi: 10.1016/j.blre.2021.100873 (2022). Burnett, A. K. New induction and postinduction strategies in acute myeloid leukemia. Curr Opin Hematol 19, 76–81, doi: 10.1097/MOH.0b013e3283500a92 (2012). Schwarer, A. P. et al. A Comparison of High-Dose Cytarabine During Induction Versus Consolidation Therapy in Newly Diagnosed AML. Hemasphere 2, e158, doi: 10.1097/hs9.0000000000000158 (2018). Bassan, R. et al. Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML. Blood Adv 3, 1103–1117, doi: 10.1182/bloodadvances.2018026625 (2019). Leone, G., Voso, M. T., Teofili, L. & Lübbert, M. Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol 109, 89–102, doi: 10.1016/s1521-6616(03)00207-9 (2003). Cruijsen, M., Lübbert, M., Wijermans, P. & Huls, G. Clinical Results of Hypomethylating Agents in AML Treatment. J Clin Med 4, 1–17, doi: 10.3390/jcm4010001 (2014). Keating, G. M. Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Drugs 72, 1111–1136, doi: 10.2165/11209430-000000000-00000 (2012). Schuh, A. C. et al. Azacitidine in adult patients with acute myeloid leukemia. Crit Rev Oncol Hematol 116, 159–177, doi: 10.1016/j.critrevonc.2017.05.010 (2017). Dombret, H. et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood 126, 291–299, doi: 10.1182/blood-2015-01-621664 (2015). Fenaux, P. et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28, 562–569, doi: 10.1200/jco.2009.23.8329 (2010). Döhner, H. et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140, 1345–1377, doi: 10.1182/blood.2022016867 (2022). Scott, L. J. Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Drugs 76, 889–900, doi: 10.1007/s40265-016-0585-0 (2016). Kantarjian, H. M. et al. Acute myeloid leukemia management and research in 2025. CA Cancer J Clin 75, 46–67, doi: 10.3322/caac.21873 (2025). Huang, R. et al. Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis. Cancer 130, 2472–2481, doi: 10.1002/cncr.35278 (2024). Maiti, A. et al. Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: A propensity score matched analysis stratified by risk of treatment-related mortality. Am J Hematol 96, 282–291, doi: 10.1002/ajh.26061 (2021). Han, Y. Y., Tian, Y., Zhao, B. C. & Liu, K. X. Ramelteon exposure and survival of critically Ill sepsis patients: a retrospective study from MIMIC-IV. BMC Anesthesiol 24, 454, doi: 10.1186/s12871-024-02851-9 (2024). Coombs, C. C. et al. Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia. Haematologica 101, e457-e460, doi: 10.3324/haematol.2016.148999 (2016). Shih, A. H., Abdel-Wahab, O., Patel, J. P. & Levine, R. L. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 12, 599–612, doi: 10.1038/nrc3343 (2012). Klutstein, M., Nejman, D., Greenfield, R. & Cedar, H. DNA Methylation in Cancer and Aging. Cancer Res 76, 3446–3450, doi: 10.1158/0008-5472.CAN-15-3278 (2016). Borthakur, G. et al. Report of a phase 1/2 study of a combination of azacitidine and cytarabine in acute myelogenous leukemia and high-risk myelodysplastic syndromes. Leuk Lymphoma 51, 73–78, doi: 10.3109/10428190903318329 (2010). Vives, S. et al. A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia. Cancer 127, 2003–2014, doi: 10.1002/cncr.33403 (2021). Qin, T. et al. Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res 13, 4225–4232, doi: 10.1158/1078-0432.Ccr-06-2762 (2007). Qin, T., Jelinek, J., Si, J., Shu, J. & Issa, J. P. Mechanisms of resistance to 5-aza-2'-deoxycytidine in human cancer cell lines. Blood 113, 659–667, doi: 10.1182/blood-2008-02-140038 (2009). Scandura, J. M. et al. Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. Blood 118, 1472–1480, doi: 10.1182/blood-2010-11-320093 (2011). Cahill, K. E. et al. A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia. Blood Adv 4, 599–606, doi: 10.1182/bloodadvances.2019000795 (2020). Damon, L. E. et al. Treatment of acute leukemia with idarubicin, etoposide and cytarabine (IDEA). A randomized study of etoposide schedule. Cancer Chemother Pharmacol 53, 468–474, doi: 10.1007/s00280-003-0758-x (2004). Silverman, L. R. et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 117, 2697–2702, doi: 10.1002/cncr.25774 (2011). Silverman, L. R. et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 24, 3895–3903, doi: 10.1200/jco.2005.05.4346 (2006). Garcia-Manero, G. Improving survival in myelodysplastic syndromes. Lancet Oncol 10, 200–201, doi: 10.1016/s1470-2045(09)70048-8 (2009). Riabov, V. et al. ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms. Haematologica 109, 1426–1438, doi: 10.3324/haematol.2023.282921 (2024). Yu, H., Hong, J., Shin, D. Y. & Lee, C. H. The role of ASXL1, SRSF2, and EZH2 mutations in chromatin dysregulation of myelodysplastic neoplasia and acute myeloid leukemia. Leukemia 39, 2329–2339, doi: 10.1038/s41375-025-02657-9 (2025). Metzeler, K. H. et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia 26, 1106–1107, doi: 10.1038/leu.2011.342 (2012). Traina, F. et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 28, 78–87, doi: 10.1038/leu.2013.269 (2014). Cheng, X. & Blumenthal, R. M. Mediating and maintaining methylation while minimizing mutation: Recent advances on mammalian DNA methyltransferases. Curr Opin Struct Biol 75, 102433, doi: 10.1016/j.sbi.2022.102433 (2022). Saliba, A. N., John, A. J. & Kaufmann, S. H. Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia. Cancer Drug Resist 4, 125–142, doi: 10.20517/cdr.2020.95 (2021). Stomper, J., Rotondo, J. C., Greve, G. & Lübbert, M. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies. Leukemia 35, 1873–1889, doi: 10.1038/s41375-021-01218-0 (2021). Crawford, J., Herndon, D., Gmitter, K. & Weiss, J. The impact of myelosuppression on quality of life of patients treated with chemotherapy. Future Oncol 20, 1515–1530, doi: 10.2217/fon-2023-0513 (2024). Wei, A. H. et al. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med 383, 2526–2537, doi: 10.1056/NEJMoa2004444 (2020). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 17 May, 2026 Reviews received at journal 15 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviews received at journal 30 Apr, 2026 Reviewers agreed at journal 21 Apr, 2026 Reviewers invited by journal 21 Apr, 2026 Editor assigned by journal 20 Apr, 2026 Submission checks completed at journal 20 Apr, 2026 First submitted to journal 13 Apr, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9409121","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":631149369,"identity":"055e4076-d2e8-46f9-adb2-e867949720fb","order_by":0,"name":"Zixuan Li","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zixuan","middleName":"","lastName":"Li","suffix":""},{"id":631149370,"identity":"7088d83e-a12f-4633-a723-8cb221afc555","order_by":1,"name":"Jingdi Liu","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jingdi","middleName":"","lastName":"Liu","suffix":""},{"id":631149372,"identity":"f89be294-51fe-4105-9fcf-4855ee034f37","order_by":2,"name":"Jiaxin Hong","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiaxin","middleName":"","lastName":"Hong","suffix":""},{"id":631149374,"identity":"86ed35c6-7e17-471d-9fac-51a39c28ee75","order_by":3,"name":"Dairong Xie","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dairong","middleName":"","lastName":"Xie","suffix":""},{"id":631149376,"identity":"48ae094d-6f7a-4976-93a8-83f1bfa92185","order_by":4,"name":"Yuting Jiang","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuting","middleName":"","lastName":"Jiang","suffix":""},{"id":631149377,"identity":"2fc63e10-195f-407d-b186-12ca2ae51ca7","order_by":5,"name":"Tianran Gao","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tianran","middleName":"","lastName":"Gao","suffix":""},{"id":631149381,"identity":"d697eda0-0084-4b91-9406-d75e1c9733b8","order_by":6,"name":"Ruofeng Jin","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ruofeng","middleName":"","lastName":"Jin","suffix":""},{"id":631149382,"identity":"4d894082-95f2-4197-8d7f-863e90c39ebe","order_by":7,"name":"Mei Hong","email":"","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mei","middleName":"","lastName":"Hong","suffix":""},{"id":631149384,"identity":"c4c21a3b-652b-4178-af63-d912146e5343","order_by":8,"name":"Qiuling Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIiWNgGAWjYBACNvbmgw8YGyTq5eUPH4OKJeDXwsdzLNmAscEmwXAGWxqQb0BYi5xEjpkEY0NaAsMNHjPitLABtUjz7jicxzi759tjnj9/GPjZcwwYfu7Ao4XnWbHlzDOHi9llzm435m0zYJDseWPA2HsGjxb25I03PrYdZmxsyN0mzdtgwGBwI8eAmbENjxaGBAOJRKCWhgM5z6R5/hgw2BPUwpFiJPGxLS2x4UYOmzQPG9AWCUJagIFsOLPNxtiw55iZ5Nw2Yx6JM88KDvbi0SLf3nzwMW+bhJw8e/MziTd/5OT425M3PviJRwsG4AERB0jQMApGwSgYBaMACwAAJ7ZQsdHnvIEAAAAASUVORK5CYII=","orcid":"","institution":"Huazhong University of Science and Technology Tongji Medical College Union Hospital","correspondingAuthor":true,"prefix":"","firstName":"Qiuling","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2026-04-14 01:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9409121/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9409121/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108385299,"identity":"0f602fb7-6e0c-4830-9c74-74bd5659c5a4","added_by":"auto","created_at":"2026-05-04 06:02:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95719,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival of patients with newly diagnosed AML treated with AZA+ IDAra-c+ Ida/Eto or IDAra-c. (A) OS, (B) EFS, (C) DOR and (D) CIR of matched patients with newly diagnosed AML treated with AZA+ IDAra-c+ Ida/Eto or IDAra-c. (E) OS and (F) EFS of matched patients with newly diagnosed AML treated with AZA+ IDAra-c+ Ida/Eto or IDAra-c and considered the influence of allo-HSCT or not.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9409121/v1/2d882ce92955f442e107053c.png"},{"id":108385300,"identity":"54a889b3-dab0-44c2-8fcb-16abd8f1d499","added_by":"auto","created_at":"2026-05-04 06:02:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":132710,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of survival and forest plot of hazard ratio (95% CI) in matched patients with newly diagnosed AML.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9409121/v1/dbc50ab808a8e1346358d71e.png"},{"id":108804211,"identity":"2840d8f1-eb59-4347-9858-2ef806b4f596","added_by":"auto","created_at":"2026-05-08 15:17:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":678290,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9409121/v1/f9b08f3c-8ae3-4087-bc0c-d8476bbf07b5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Modified Azacitidine plus Cytarabine versus Traditional Cytarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia: A Retrospective and Propensity Score Matched Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe achievement of complete remission (CR) is an important milestone for patients with acute myeloid leukemia (AML) and generally can be seen in 50%-70% AML patients with conventional high-intensity induction regimens.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, 30%-40% of patients will relapse and end up with poor outcomes.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Meanwhile, measurable residual disease (MRD) is sensitive clinical predictor and detectable MRD while in CR is associated with higher relapse risk and shorter survival.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Thus, optimization of consolidation and maintenance therapies to maintain CR and MRD response to prevent relapse is a major challenge in AML.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCytarabine (Ara-c) administered as six to twelve intravenous doses over three to six days, used to be the most traditional and widely established chemotherapeutic regimen for consolidation therapy.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e While this regimen achieves CR in 78%-90% of AML patients, merely 39%-48% maintain CR after five years, highlighting the need for more effective long-term strategies.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Epigenetic dysregulation, particularly hypermethylation of tumor suppressor genes and the resulting epigenetic silencing, plays a key role in the pathogenesis of myeloid malignancies.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Thus, hypomethylating agents, such as azacitidine (AZA), have thus emerged as a promising therapeutic approach. AZA is able to incorporate into RNA, interfering with the synthesis of nucleic acids and proteins, and to a lesser extent, incorporate into DNA.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e This process reactivates silenced tumor suppressor genes, promotes cell differentiation, induces apoptosis and conduct cytotoxic effect in myeloid leukemia cells.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e When used as single agents, AZA has a CR rate up to 47% in treatment-naive AML patients.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Compared with conventional care regimens (including standard induction chemotherapy, low-dose Ara-c, or supportive care only), AZA increased elderly patients with newly diagnosed AML median overall survival (OS) from 6.5\u0026ndash;16.0 to 10.4\u0026ndash;24.5 months, one-year survival from 34.2% to 46.5% and two-year survival from 16% to 50%. Notably, the incidence of serious adverse events was comparable across AZA, low-dose Ara-c, and intensive chemotherapy groups.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Therefore, AZA is recommended as front-line treatment for older patients with AML who are not candidates for intensive treatment regimens.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSince the effectiveness and safety of AZA in AML patients was widely approved,\u003csup\u003e15,19,20\u003c/sup\u003e the addition of AZA to intermediate-dose Ara-c (IDAra-c) in consolidation treatment as a modified regimen may improve long-term outcomes in age-independent newly diagnosed AML patients. Meanwhile, the combination of cytarabine with idarubicin (Ida) or etoposide (Eto) has demonstrated good efficacy and tolerance.[21] Above all, we conducted a retrospective propensity score\u0026ndash;matched study to compare the therapeutic responses and survival outcomes of patients with newly diagnosed AML who underwent consolidation therapy with AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto to those who received Intermediate-dose (ID) Ara-c.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and treatment\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective study to compare outcomes with AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto or IDAra-c as consolidation treatment in patients with newly diagnosed AML who had achieved CR or partial remission (PR) after induction treatment. All patients enrolled in this study were evaluated by physicians and met the indications for intensive chemotherapy.\u003c/p\u003e \u003cp\u003ePatients in the AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto received a consolidation regimen of AZA (75 mg/m\u003csup\u003e2\u003c/sup\u003e for day 1\u0026ndash;7), Ara-c (2 g/m\u003csup\u003e2\u003c/sup\u003e q12h for day 1\u0026ndash;3). Sequential regimen was alternative idarubicin (10mg for day 4\u0026ndash;5) or etoposide (100mg for day 4\u0026ndash;5). The comparison cohort was selected from patients treated with traditional intensive chemotherapy containing high dose of Ara-c (3g/m\u003csup\u003e2\u003c/sup\u003e/12h for day 1\u0026ndash;3). Other agents administered in combination included idarubicin or etoposide. All patients received up to 6 consolidation courses and no maintenance course was applied in patients. FLT3-ITD/TKD mutated patients received FLT3 inhibitor as directed by their physician, while no patients with IDH1/IDH2 mutated or other mutations received corresponding inhibitors. Eligible patients in either group could proceed to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) after achievement of a response with the final decision made based on the patients\u0026rsquo; informed consent and the attending physicians\u0026rsquo; clinical recommendations.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eResponse evaluation and endpoints\u003c/h3\u003e\n\u003cp\u003eBone marrow evaluation was performed after blood count recovery at each consolidation cycle. Minimal residual disease (MRD) was evaluated in bone marrow specimens by flow cytometry with a cutoff value of 0.01%. Next-generation sequencing (NGS)-based MRD testing, using a customized hematological malignancy-targeted gene panel (covering 80 genes including FLT3, NPM1, DNMT3A, IDH1/2, and IKZF1), achieves a detection sensitivity of 10⁻⁵ for residual clonal malignant cells and the results were collected if available. Overall survival (OS) was determined from diagnosis until death, or censored at last follow-up. Event-free survival (EFS) was determined from start of consolidation therapy until date of refractory disease, relapse, death, or censored at last follow-up. The cumulative incidence of relapse (CIR) and duration of response (DOR) was calculated from the time of CR until relapse. The duration of neutrophil recovery was calculated from the first day the neutrophil count dropped to 0.5\u0026times;10⁹/L until the count was sustainedly recovered to at or above 0.5\u0026times;10⁹/L. The same applies to platelets, with a threshold of 50\u0026times;10⁹/L. Other safety analysis was evaluated using the Common Terminology Criteria for Adverse Events version 5.0.\u003c/p\u003e\n\u003ch3\u003ePropensity score matching and statistical analysis\u003c/h3\u003e\n\u003cp\u003ePropensity score matching was performed between patients in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto and IDAra-c cohort in the corresponding period at a 1:1 ratio with a caliper value of 0.05 according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status (ECOG), European Leukemia Net (ELN) 2022 risk stratification and induction therapy classification to minimize bias.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e The effectiveness of PSM in minimizing group differences was evaluated using the standardized mean difference (SMD), considering a variable unbalanced if SMD exceeded 0.1. \u003csup\u003e23\u003c/sup\u003e Wilcoxon signed-rank tests were used to analyze continuous variable, Fisher exact tests were used for categorical variables. The Kaplan‒Meier method was used to compare time‐to‐event variables. Univariable Cox model was used to examine the associations among patient characteristics and outcomes. Prism version 8.0 (GraphPad Software) and SPSS 25 (IBM Corp) were used for statistical analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003ePatients\u003c/h2\u003e\n \u003cp\u003eA total of 50 newly diagnosed patients treated with AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto were matched with 50 newly diagnosed patients treated with IDAra-c therapies (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The patients in the AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort were diagnosed between September 2020 and August 2024.The patients in the IDAra-C cohort were diagnosed between March 2020 and February 2023. The median age was 43 years (range, 16\u0026ndash;66 years) in the AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort and 44 years (range, 15\u0026ndash;66 years) in the IDAra-C cohort. Age group, gender, proportions of patients with an ELN 2022 adverse risk, ECOG performance status and induction therapy classification were matched between two cohort.\u0026nbsp;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics of propensity score\u0026ndash;matched patients with newly diagnosed acute myeloid leukemia treated with AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto versus IDAra-c.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameters\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIDAra-C cohort (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years (%)\u003c/p\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003cp\u003e≦\u0026thinsp;40\u003c/p\u003e\n \u003cp\u003e40\u0026ndash;60\u003c/p\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e43 (16\u0026ndash;66)\u003c/p\u003e\n \u003cp\u003e23 (46)\u003c/p\u003e\n \u003cp\u003e26 (52)\u003c/p\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e44 (15\u0026ndash;66)\u003c/p\u003e\n \u003cp\u003e23 (46)\u003c/p\u003e\n \u003cp\u003e26 (52)\u003c/p\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003eMale: female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27:23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27:23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCytogenetic risk group at diagnosis, No. (%)\u003c/p\u003e\n \u003cp\u003eFavorable\u003c/p\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003cp\u003eAdverse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (36)\u003c/p\u003e\n \u003cp\u003e18 (36)\u003c/p\u003e\n \u003cp\u003e14 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (36)\u003c/p\u003e\n \u003cp\u003e18 (36)\u003c/p\u003e\n \u003cp\u003e14 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInduction regimen, No. (%)\u003c/p\u003e\n \u003cp\u003eTraditional regimen (IA/DA/HA)\u003c/p\u003e\n \u003cp\u003eNew regimen including HMA/Venetoclax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e34 (68)\u003c/p\u003e\n \u003cp\u003e16 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e34 (68)\u003c/p\u003e\n \u003cp\u003e16 (32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG performance status (%)\u003c/p\u003e\n \u003cp\u003e0\u0026ndash;2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e50 (100)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e50 (100)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMutations at diagnosis, No. (%)\u003c/p\u003e\n \u003cp\u003eFLT3-ITD/TKD\u003c/p\u003e\n \u003cp\u003eRUNX1\u003c/p\u003e\n \u003cp\u003eASXL1\u003c/p\u003e\n \u003cp\u003eTP53\u003c/p\u003e\n \u003cp\u003eEZH2\u003c/p\u003e\n \u003cp\u003eBCOR/BCORL1\u003c/p\u003e\n \u003cp\u003eNRAS/KRAS\u003c/p\u003e\n \u003cp\u003eIDH1/2\u003c/p\u003e\n \u003cp\u003eDNMT3A\u003c/p\u003e\n \u003cp\u003eNPM1\u003c/p\u003e\n \u003cp\u003eCEBPA\u003c/p\u003e\n \u003cp\u003eFusion gene at diagnosis, No. (%)\u003c/p\u003e\n \u003cp\u003eAML1-ETO\u003c/p\u003e\n \u003cp\u003eCEBFB-MYH11\u003c/p\u003e\n \u003cp\u003eKaryotype at diagnosis, No. (%)\u003c/p\u003e\n \u003cp\u003e11q23\u003c/p\u003e\n \u003cp\u003ecomplex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (24)\u003c/p\u003e\n \u003cp\u003e4 (8)\u003c/p\u003e\n \u003cp\u003e3 (6)\u003c/p\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003cp\u003e3 (6)\u003c/p\u003e\n \u003cp\u003e8 (16)\u003c/p\u003e\n \u003cp\u003e6 (12)\u003c/p\u003e\n \u003cp\u003e7 (14)\u003c/p\u003e\n \u003cp\u003e7 (14)\u003c/p\u003e\n \u003cp\u003e12 (24)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (12)\u003c/p\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (10)\u003c/p\u003e\n \u003cp\u003e3 (6)\u003c/p\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e5 (10)\u003c/p\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003cp\u003e3 (6)\u003c/p\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003cp\u003e8 (16)\u003c/p\u003e\n \u003cp\u003e12 (24)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (26)\u003c/p\u003e\n \u003cp\u003e4 (8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (10)\u003c/p\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInduction response, No. (%)\u003c/p\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003cp\u003eMRD negative by flow cytometry\u003c/p\u003e\n \u003cp\u003eNGS-MRD negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e41 (82)\u003c/p\u003e\n \u003cp\u003e9 (18)\u003c/p\u003e\n \u003cp\u003e34 (68)\u003c/p\u003e\n \u003cp\u003e23 (52.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45 (90)\u003c/p\u003e\n \u003cp\u003e5 (10)\u003c/p\u003e\n \u003cp\u003e32(64)\u003c/p\u003e\n \u003cp\u003e17 (60.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAllo-HSCT, No. (%)\u003c/p\u003e\n \u003cp\u003ein CR1\u003c/p\u003e\n \u003cp\u003ein CR2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (31.82)\u003c/p\u003e\n \u003cp\u003e1 (33.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (32.14)\u003c/p\u003e\n \u003cp\u003e4 (66.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eIA, idarubicin and cytarabine; DA, daunorubicin and cytarabine, HA, homoharringtonine and cytarabine; HMA, hypomethylating agents; Ven, venetoclax; CR, complete remission; PR, partial remission; MRD, minimal residual disease; NGS, next generation sequencing; allo-HSCT, allogeneic hematopoietic stem-cell transplantation.\u003c/p\u003e\n \u003cp\u003e49 patients in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort and 48 in IDAra-C cohort had at least one cytogenetic abnormality. All patients in two cohort achieved CR or PR after induction therapy and were all available for MRD results, with 34 (68%) and 32 (64%) patients achieved MRD negative after induction regimen in two cohort (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.67). 44 and 28 patients who had available NGS-MRD results after induction therapy. Of them 23 (52.27%) and 17 (60.71%) achieved NGS-MRD negativity in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto and IDAra-c cohort respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.70). 14 (31.82%) and 9 (32.14%) patients in two cohorts chose to undergo allo-HSCT in CR1 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.47). One (33.33%) and four (66.67%) patients in two cohort accepted allo-HSCT in CR2 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eResponse rates\u003c/h2\u003e\n \u003cp\u003eMedian circles of 3 (range1-6) AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto and 4 (range 1\u0026ndash;6) IDAra-c consolidation therapy were administered. The percent of patients achieving CR (92% vs. 92%), MRD (91.3% vs. 91.3%) and NGS MRD negativity (62.5% vs. 53.5%) in two group was comparable after the first two consolidation therapy (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Then the percent of above response rate declined in IDAra-c group (CR rate 56%, MRD rate 60% and NGS MRD rate 39.1%), while that in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto group stayed stable up to the end of consolidation treatment for each patient (90%, 82% and 79.4%), which showed a significant disparity between two group. AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto was associated with significantly lower rate of relapse compared to IDAra-c (10% vs. 44%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.00). Five patients of AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort had NGS MRD results when relapsed and three of them were detected with DNA Methylation associated mutations, including three DNMT3A mutations and one IDH1 mutation. Among the three patients, two had persistent positivity for DNMT3A mutations, and one had concurrent IDH1 mutation from diagnosis throughout the entire treatment process. One patient had a transient negative result for DNMT3A mutation after induction therapy, but the mutation reappeared at relapse. Four patients detected with mutated IDH1, DNMT3A or TET2 among 13 relapsed patients with available NGS-MRD results in ID/IDAra-c cohort. Among them, the genetic basis of the two patients with DNMT3A or TET2 mutation at relapse was consistent with that at the time of diagnosis. The mutation of IDH1 or DNMT3A in other two patients at relapse were newly emerged. Among all relapsed patients above, three and six patients re-achieved CR2 through salvage treatment. The overall mortality during consolidation therapy in two cohort was significantly different (10% vs. 36%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.00) including two and three patients in each cohort died of septic shock (4% vs. 6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003eTable 2\u003c/div\u003e\n \u003ctable id=\"Tab2\" style=\"width: 608px;\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of outcomes according to two matched cohort\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth style=\"width: 265.611px;\" align=\"left\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"width: 147.389px;\" align=\"left\"\u003e\n \u003cp\u003eAZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto\u003c/p\u003e\n \u003cp\u003ecohort (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"width: 146px;\" align=\"left\"\u003e\n \u003cp\u003eIDAra-C cohort (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"width: 24px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 265.611px;\" align=\"left\"\u003e\n \u003cp\u003eMedian circles of consolidation regimen (Range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147.389px;\" align=\"left\"\u003e\n \u003cp\u003e3 (1\u0026ndash;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\" align=\"left\"\u003e\n \u003cp\u003e4 (1\u0026ndash;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\" align=\"char\" char=\".\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 265.611px;\" align=\"left\"\u003e\n \u003cp\u003eCR response after, No. (%)\u003c/p\u003e\n \u003cp\u003eCycle 2\u003c/p\u003e\n \u003cp\u003eThe end of consolidation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147.389px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e46 (92)\u003c/p\u003e\n \u003cp\u003e45 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e44 (92)\u003c/p\u003e\n \u003cp\u003e28 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 265.611px;\" align=\"left\"\u003e\n \u003cp\u003eMRD response after, No. (%)\u003c/p\u003e\n \u003cp\u003eCycle 2\u003c/p\u003e\n \u003cp\u003eThe end of consolidation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147.389px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e42 (91.3)\u003c/p\u003e\n \u003cp\u003e42 (82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e42 (91.3)\u003c/p\u003e\n \u003cp\u003e27 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 265.611px;\" align=\"left\"\u003e\n \u003cp\u003eNGS MRD response after, No. (%)\u003c/p\u003e\n \u003cp\u003eCycle 2\u003c/p\u003e\n \u003cp\u003eThe end of consolidation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147.389px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15 (62.5)\u003c/p\u003e\n \u003cp\u003e27 (79.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (53.3)\u003c/p\u003e\n \u003cp\u003e9 (39.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 265.611px;\" align=\"left\"\u003e\n \u003cp\u003eRelapse, No. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147.389px;\" align=\"left\"\u003e\n \u003cp\u003e6 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\" align=\"left\"\u003e\n \u003cp\u003e22 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\" align=\"char\" char=\".\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 265.611px;\" align=\"left\"\u003e\n \u003cp\u003eOverall deaths, No. (%)\u003c/p\u003e\n \u003cp\u003eNon-relapse deaths, No. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147.389px;\" align=\"left\"\u003e\n \u003cp\u003e5 (10)\u003c/p\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 146px;\" align=\"left\"\u003e\n \u003cp\u003e18 (36)\u003c/p\u003e\n \u003cp\u003e3 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\" align=\"char\" char=\".\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eCR, complete remission; MRD, minimal residual disease; NGS, next generation sequencing;\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSurvival outcomes\u003c/h3\u003e\n\u003cp\u003eThe median follow-up period was 27.5 months (range, 4\u0026ndash;59 months) in the AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort and 27months (range, 6\u0026ndash;66 months) in the ID/IDAra-c cohort. OS and EFS in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort was significantly longer compared to IDAra-c cohort. The estimated OS rates at 40 months were 90.0% (95% CI, 85.8%-94.2%) in the AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort and 53.4% (95% CI, 46.1%-60.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0006) in the ID/IDAra-c cohort (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA). EFS at 40 months were 81.7% (95% CI, 76.2%\u0026ndash;87.2%) in the AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort and 45.9% (95% CI, 38.5%-53.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0021) in the ID/IDAra-c cohort (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB). The median DOR was not reached in two cohort, but CIR was extraordinarily higher in the IDAra-c cohort. One-year CIR was 31.3% vs. 10.5% and two-year CIR was 42.5% vs.12.8% (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eC/D).\u003c/p\u003e\n\u003cp\u003eThe survival condition was comparable in the AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort but better in ID/IDAra-c cohort when considering allo-HSCT as an independent factor. Among patients received allo-HSCT, OS at 40 months was 100% vs. 68.40% (95% CI, 55.3%-81.5%) and EFS at 40 months was 92.9% (95% CI, 86.0%-99.8%) vs. 57.5% (95% CI, 42.9%-72.1%) in two cohort. In contrast, OS and EFS at 40 months in ID/IDAra-c cohort deteriorated when censoring allo-HSCT, with 47.9% (95% CI, 39.3%-56.6%) and 42.3% (95% CI, 33.8%-50.8%) compared with 85.7% (95% CI, 69.8%-93.9%) and 77.0% (95% CI, 69.9%\u0026ndash;84.1%) in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eE\u0026amp;F).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eSubgroups analysis\u003c/h3\u003e\n\u003cp\u003eExploratory subgroup analysis in matched cohorts favored AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto in most subgroups (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). It revealed that AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto consolidation rather than IDAra-c was a protective factor in patients who ≦\u0026thinsp;40 years, achieved MRD negative after induction therapy or diagnosed as adverse risk (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02, 0.01\u0026amp; 0.05). Although no significant difference was found in patients\u0026thinsp;\u0026gt;\u0026thinsp;40, or in favorable or intermediate risk group, the 40-month OS was relatively longer in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort, with 84.6% vs.52.3% in patients aged 40\u0026ndash;60, 88.9% vs. 59.5% in cytogenetic favorable group and 88.9% vs. 55.9% in intermediate group. Certain molecular disorders at diagnosis conferred sensitivity to AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto therapy as well. Patients with mutations associated with DNA Methylation (DNMT3A, IDH1/2, TET2, WT1 or NPM1) were more likely to benefit in survival using AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto treatment, which prolonged the survival more than twice as long as that in ID/IDAra-c.\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eToxicity assessment\u003c/h2\u003e\n \u003cp\u003eAll patients enrolled in this trial were included in the toxicity analysis. The most frequent hematological toxicities were myelosuppression. Patients in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort had relatively higher lowest hemoglobin concentration in each consolidation cycle compared with those in IDAra-c, and obvious difference can be seen in the cycle 2 (77.27 g/L vs, 67.71 g/L), 4 (84.83 g/L vs.65.75 g/L) and 5 (80.53 g/L vs. 60.78 g/L). During the treatment of AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto, there were 20 transfusion episodes, and 83 units (U) of red blood cell (RBC) given. Twenty-nine transfusion episodes were required in IDAra-c cohort, with a total amount of 118.5 units. The average number of transfused units in each cycle was shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. The average days to neutrophil recovery (neutrophils\u0026thinsp;\u0026ge;\u0026thinsp;0.5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) were longer in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto cohort especially in cycle 2 (10.00d vs. 7.25d), 3 (9.29d vs. 7.29d) and 4 (12.00d vs. 7.79d). The average days to recovery of platelets\u0026thinsp;\u0026ge;\u0026thinsp;50 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L and numbers of patients developing febrile neutropenia or pneumonia were similar in two cohort (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMyelosuppression in two cohort.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eCycle 1, pts\u003c/p\u003e\n \u003cp\u003eLowest, hemoglobin concentration g/L (range)\u003c/p\u003e\n \u003cp\u003eNeutrophils to recover to 0.5\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003ePlatelets to recover to 50\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003eFebrile neutropenia, pts\u003c/p\u003e\n \u003cp\u003ePneumonia, pts\u003c/p\u003e\n \u003cp\u003eAverage RBC transfusion, U (range)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eIDAra-C\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003cp\u003e71.72 (43\u0026ndash;117)\u003c/p\u003e\n \u003cp\u003e8.07 (1\u0026ndash;27)\u003c/p\u003e\n \u003cp\u003e11.48 (4\u0026ndash;49)\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1.07 (0\u0026ndash;14)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003cp\u003e66.00(30\u0026ndash;95)\u003c/p\u003e\n \u003cp\u003e6.42 (1\u0026ndash;17)\u003c/p\u003e\n \u003cp\u003e11.01 (5\u0026ndash;19)\u003c/p\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e0.78 (0\u0026ndash;13)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCycle 2, pts\u003c/p\u003e\n \u003cp\u003eLowest hemoglobin concentration, g/L (range)\u003c/p\u003e\n \u003cp\u003eNeutrophils to recover to 0.5\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003ePlatelets to recover to 50\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003eFebrile neutropenia, pts\u003c/p\u003e\n \u003cp\u003ePneumonia, pts\u003c/p\u003e\n \u003cp\u003eAverage RBC transfusion, U (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003cp\u003e77.27 (42\u0026ndash;109)\u003c/p\u003e\n \u003cp\u003e10.00 (6\u0026ndash;22)\u003c/p\u003e\n \u003cp\u003e12.24(7\u0026ndash;27)\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e0.31 (0\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003cp\u003e67.71 (30\u0026ndash;101)\u003c/p\u003e\n \u003cp\u003e7.25 (1\u0026ndash;24)\u003c/p\u003e\n \u003cp\u003e12.50 (6\u0026ndash;32)\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e0.69 (0-13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCycle 3, pts\u003c/p\u003e\n \u003cp\u003eLowest hemoglobin concentration, g/L (range)\u003c/p\u003e\n \u003cp\u003eNeutrophils to recover to 0.5\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003ePlatelets to recover to 50\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003eFebrile neutropenia, pts\u003c/p\u003e\n \u003cp\u003ePneumonia, pts\u003c/p\u003e\n \u003cp\u003eAverage RBC transfusion, U (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003cp\u003e76.83 (51\u0026ndash;106)\u003c/p\u003e\n \u003cp\u003e9.29(3\u0026ndash;24)\u003c/p\u003e\n \u003cp\u003e12.25 (7\u0026ndash;32)\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e0.35 (0\u0026ndash;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003cp\u003e70.72(30\u0026ndash;112)\u003c/p\u003e\n \u003cp\u003e7.29 (1\u0026ndash;32)\u003c/p\u003e\n \u003cp\u003e12.54 (6\u0026ndash;44)\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e0.40 (0-3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCycle 4, pts\u003c/p\u003e\n \u003cp\u003eLowest hemoglobin concentration, g/L (range)\u003c/p\u003e\n \u003cp\u003eNeutrophils to recover to 0.5\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003ePlatelets to recover to 50\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003eFebrile neutropenia, pts\u003c/p\u003e\n \u003cp\u003ePneumonia, pts\u003c/p\u003e\n \u003cp\u003eAverage RBC transfusion, U (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e84.83(52\u0026ndash;111)\u003c/p\u003e\n \u003cp\u003e12.00 (6\u0026ndash;22)\u003c/p\u003e\n \u003cp\u003e13.66(6\u0026ndash;22)\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e0.11 (0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003cp\u003e65.75 (34\u0026ndash;116)\u003c/p\u003e\n \u003cp\u003e7.79 (1\u0026ndash;28)\u003c/p\u003e\n \u003cp\u003e13.17 (7\u0026ndash;30)\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1.16 (0\u0026ndash;9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCycle 5, pts\u003c/p\u003e\n \u003cp\u003eLowest hemoglobin concentration, g/L (range)\u003c/p\u003e\n \u003cp\u003eNeutrophils to recover to 0.5\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003ePlatelets to recover to 50\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003eFebrile neutropenia, pts\u003c/p\u003e\n \u003cp\u003ePneumonia, pts\u003c/p\u003e\n \u003cp\u003eAverage RBC transfusion, U (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e80.53 (40\u0026ndash;110)\u003c/p\u003e\n \u003cp\u003e9.73 (4\u0026ndash;16)\u003c/p\u003e\n \u003cp\u003e11.80 (7\u0026ndash;18)\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e0.4 (0\u0026ndash;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e60.78 (34\u0026ndash;95)\u003c/p\u003e\n \u003cp\u003e7.89 (5\u0026ndash;16)\u003c/p\u003e\n \u003cp\u003e13.78 (7\u0026ndash;21)\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1.00 (0\u0026ndash;7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCycle 6, pts\u003c/p\u003e\n \u003cp\u003eLowest hemoglobin concentration, g/L (range)\u003c/p\u003e\n \u003cp\u003eNeutrophils to recover to 0.5\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003ePlatelets to recover to 50\u0026nbsp;x 10\u003csup\u003e9\u003c/sup\u003e/L, days (range)\u003c/p\u003e\n \u003cp\u003eFebrile neutropenia, pts\u003c/p\u003e\n \u003cp\u003ePneumonia, pts\u003c/p\u003e\n \u003cp\u003eAverage RBC transfusion, U (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e84.25 (65\u0026ndash;103)\u003c/p\u003e\n \u003cp\u003e11.43 (5\u0026ndash;15)\u003c/p\u003e\n \u003cp\u003e13 (5\u0026ndash;17)\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e110 (99\u0026ndash;121)\u003c/p\u003e\n \u003cp\u003e4 (4)\u003c/p\u003e\n \u003cp\u003e14 (14)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSince DNA methylation has been approved as a mechanism of resistance to chemotherapy\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, hypomethylating agents (HMA) has been considered as an effective but less toxic regimen for elderly or unfit AML patients. In this study, we present a novel combination of AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto and sequential alternative Ida or Eto as consolidation therapy for newly diagnosed age-independently AML patients. The approach of propensity score matching helped to find a closely matched comparator group treated with IDAra-C to minimize the effect of confounders and bias inherent in retrospective comparisons.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePrevious studies have highlighted that AZA and Ara-C hold clinical potential in AML treatment.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e It was demonstrated that the combination of 5-Aza-2\u0026prime;-deoxycytidine (DAC) and Ara-C showed additive or synergistic effects on cell death in human leukemia cell lines in vitro, but there are limitations in terms of antagonism in epigenetic effects and common intracellular metabolic pathways.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e In contrast, AZA bypasses this issue by utilizing uridine-cytidine kinase (UCK) for initial phosphorylation, avoiding competition with DAC and Ara-C for the deoxycytidine kinase (dCK) enzyme. Therefore, epigenetic priming with HMA prior to cytotoxic chemotherapy would sensitize malignant cells to chemotherapy and enhance the response to treatment. Clinical studies have explored the use of HMA and chemotherapy as induction regimen in AML. For instance, a phase 1 study analyzed the safety and biologic activity when assessing decitabine followed by standard cytarabine/daunorubicin induction in patients with intermediate/high-risk of AML. The study ended with a CR rate of 57% (up to 83% after second induction) and reported no excess toxicity.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Another phase 1 trial showed that induction chemotherapy using AZA in sequential combination with IDAra-c and mitoxantrone resulted in an overall response rate of 61% and a CR rate of 41% with 30-day mortality below 2% in high-risk AML patients.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Ara-C combined with Ida and Eto was relatively classic in AML treatment, and low-dose addition of Ida and Eto results in reduced cytotoxicity.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Our clinical findings aligned with prior preclinical evidence, demonstrating that consolidation chemotherapy with AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto regimen yielded superior outcomes in newly diagnosed AML patients compared to the IDAra-C cohort. This was reflected in durable MRD response rates, reduced relapse and mortality, and improved survival, regardless of allo-HSCT status.\u003c/p\u003e \u003cp\u003ePrevious studies showed the continued AZA therapy after the first response may benefit and lead to a further improvement.\u003csup\u003e\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e For example, AZA-001 phase 3 study evaluated 179 patients with high risk of myelodysplastic syndromes (MDS) who received AZA treatment, found that 91% of responding patients achieved their first response (CR, PR, or hematological improvement) within 6 cycles and median time was 2 cycles, but continued AZA improved response category in 48% of patients.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e In our study, the two cohorts showed comparable efficacy in the first two cycles. However, the disparity began to emerge as treatment progressed. AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto had advantages on MRD and NGS MRD response till to the end of consolidation therapies which is the key point to avoid relapse and keep long-term survival, while IDAra-C alone failed to do it. Therefore, we recommended a complete 6 cycles of AZA consolidation regimens followed by maintenance regimens as long as the patient continues to benefit.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe aimed to identify if patients with distinct clinical characteristics benefit from either consolidation therapy. Our results implied that patients with patients who ≦\u0026thinsp;40 years, achieved MRD negative after induction therapy, or diagnosed as adverse risk or patients carried methylation associated mutations to choose AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto as consolidation treatment may be more likely to benefit in survival. The better treatment outcomes in younger patients may be related to their better tolerance to the treatment; meanwhile, the epigenetic regulatory effects of AZA may have a potential impact on certain gene mutations in high-risk patients, leading to a better prognosis. \u003csup\u003e37,38\u003c/sup\u003e Previous studies have demonstrated that DNMT3A and TET2 mutations are associated with increased sensitivity to HMA.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e However, in our cohort, three out of six patients treated with the AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto regimen relapsed, and these relapses were linked to methylation‑related mutations. It has been reported that conventional DNA hypomethylating agents, such as AZA and DAC, can be incorporated into RNA or DNA, trap DNA methyltransferases (DNMTs), and form suicide complexes. This process is prone to errors and may contribute to cytotoxicity, genomic instability, and ultimately HMA resistance.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e In addition, individual differences may also affect the activity of HMA metabolism and lead to drug resistance, such as low level of UCK or over expression of cytidine deaminase. \u003csup\u003e42\u003c/sup\u003e Meanwhile, among the relapsed patients with the methylated gene mutations, two also had concurrent NPM1 and SRSF2 mutations. Collectively, these findings indicate that HMA resistance mechanisms are highly complex, and demethylation alone is insufficient to substantially improve patient prognosis. Thus, it cannot be definitively concluded that the combination of AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto has a necessary advantage for patients with methylated gene mutations. It was preliminarily concluded that the combination of AZA and Ara-c can produce a synergistic effect in patients, thereby achieving a better prognosis. For patients with persistent genetic failure or suspected re-emergence of demethylation associated mutations, novel demethylating drug therapy or strong intervention measures are necessary.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e Given the small sizes in above comparison group, our hypothesis-generating conclusion required a large and prospective study.\u003c/p\u003e \u003cp\u003eMyelosuppression and related adverse effects have been a deterrent during treatment in patients with AML.\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e In our trial, AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto was linked to higher level of hemoglobin levels, but longer recovery time from neutropenia. Higher hemoglobin level reduced the dependency on blood transfusion of patients in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto group. Neutropenia is a known side effect of hypomethylating therapy.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Although patients suffered from more days of neutropenia, the number of patients developing febrile neutropenia, pneumonia or non-relapse mortality was roughly equal. According to previous studies as well as our experience, the use of granulocyte colony stimulating factor (G-CSF) coupled with stringent antimicrobial prophylaxis and close monitoring may release the progression to severe infection during neutropenia.\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur retrospective study has several limitations. First, our results were limited by the small cohort size of the retrospective cohort. Second, compared with the conventional cytarabine regimen, our research protocol incorporates two additional drugs, AZA and Ida/Eto, resulting in distinct anti-tumor mechanisms. Therefore, the efficacy of the regimen cannot be attributed solely to the addition of any single drug. Despite the trend observed in our study in favor of AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto compared with our historical cohort treated with IDAra-c alone, the lack of a randomized comparator limits accuracy of conclusions. A randomized study will be required to meaningfully evaluate the contribution of AZA to this combination.\u003c/p\u003e \u003cp\u003eIn conclusion, our retrospective propensity score matching study demonstrated that in the absence of a substantial increase in severe or fatal adverse events, AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto consolidation may offer a more favorable prognosis in terms of long-term response and survival benefits compared to IDAra-c.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthics Statement\u003c/h2\u003e \u003cp\u003eThe protocol was approved by the ethics committee of the Clinical Trial Institution of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology in accordance with the Declaration of Helsinki and the guidelines of the ethics committee. The need for informed consent was waived due to its retrospective design, data anonymity, and non-interventional nature.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConsent for publication\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting Interests\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFundings\u003c/h2\u003e \u003cp\u003eSupported, in part, by grants from the National Natural Sciences Foundation of China (81570193 and 81770219) to QW.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eZ. L. collected date and wrote original draft preparation. J. L. and J.H. offered resources and charged patients. D.X., Y.J., R.J. and T.G. did the research. M.H. and Q. W. designed the research and modified the paper. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe raw data of this clinical study are not publicly available due to patient privacy protection and ethical constraints. De-identified data may be available from the corresponding author upon reasonable request, subject to ethical approval.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEstey, E. H. Acute myeloid leukemia: 2019 update on risk-stratification and management. \u003cem\u003eAm J Hematol\u003c/em\u003e 93, 1267\u0026ndash;1291, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ajh.25214\u003c/span\u003e\u003cspan address=\"10.1002/ajh.25214\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIqbal, A. \u003cem\u003eet al.\u003c/em\u003e Improved Treatment Outcomes With Modified Induction Therapy in Acute Myeloid Leukemia (AML): A Retrospective Observational Study From a Regional Cancer Center. \u003cem\u003eCureus\u003c/em\u003e 16, e53303, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.53303\u003c/span\u003e\u003cspan address=\"10.7759/cureus.53303\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThol, F., Schlenk, R. F., Heuser, M. \u0026amp; Ganser, A. How I treat refractory and early relapsed acute myeloid leukemia. \u003cem\u003eBlood\u003c/em\u003e 126, 319\u0026ndash;327, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood-2014-10-551911\u003c/span\u003e\u003cspan address=\"10.1182/blood-2014-10-551911\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurnett, A. K. \u003cem\u003eet al.\u003c/em\u003e A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. \u003cem\u003eBlood\u003c/em\u003e 125, 3878\u0026ndash;3885, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood-2015-01-623447\u003c/span\u003e\u003cspan address=\"10.1182/blood-2015-01-623447\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBose, P., Vachhani, P. \u0026amp; Cortes, J. E. Treatment of Relapsed/Refractory Acute Myeloid Leukemia. \u003cem\u003eCurr Treat Options Oncol\u003c/em\u003e 18, 17, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11864-017-0456-2\u003c/span\u003e\u003cspan address=\"10.1007/s11864-017-0456-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAitken, M. J. L., Ravandi, F., Patel, K. P. \u0026amp; Short, N. J. Prognostic and therapeutic implications of measurable residual disease in acute myeloid leukemia. \u003cem\u003eJ Hematol Oncol\u003c/em\u003e 14, 137, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13045-021-01148-5\u003c/span\u003e\u003cspan address=\"10.1186/s13045-021-01148-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMedeiros, B. C., Chan, S. M., Daver, N. G., Jonas, B. A. \u0026amp; Pollyea, D. A. Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. \u003cem\u003eAm J Hematol\u003c/em\u003e 94, 803\u0026ndash;811, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ajh.25484\u003c/span\u003e\u003cspan address=\"10.1002/ajh.25484\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeigert, N., Rowe, J. M., Lazarus, H. M. \u0026amp; Salman, M. Y. Consolidation in AML: Abundant opinion and much unknown. \u003cem\u003eBlood Rev\u003c/em\u003e 51, 100873, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.blre.2021.100873\u003c/span\u003e\u003cspan address=\"10.1016/j.blre.2021.100873\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurnett, A. K. New induction and postinduction strategies in acute myeloid leukemia. \u003cem\u003eCurr Opin Hematol\u003c/em\u003e 19, 76\u0026ndash;81, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MOH.0b013e3283500a92\u003c/span\u003e\u003cspan address=\"10.1097/MOH.0b013e3283500a92\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwarer, A. P. \u003cem\u003eet al.\u003c/em\u003e A Comparison of High-Dose Cytarabine During Induction Versus Consolidation Therapy in Newly Diagnosed AML. \u003cem\u003eHemasphere\u003c/em\u003e 2, e158, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/hs9.0000000000000158\u003c/span\u003e\u003cspan address=\"10.1097/hs9.0000000000000158\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBassan, R. \u003cem\u003eet al.\u003c/em\u003e Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML. \u003cem\u003eBlood Adv\u003c/em\u003e 3, 1103\u0026ndash;1117, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/bloodadvances.2018026625\u003c/span\u003e\u003cspan address=\"10.1182/bloodadvances.2018026625\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeone, G., Voso, M. T., Teofili, L. \u0026amp; L\u0026uuml;bbert, M. Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. \u003cem\u003eClin Immunol\u003c/em\u003e 109, 89\u0026ndash;102, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1521-6616(03)00207-9\u003c/span\u003e\u003cspan address=\"10.1016/s1521-6616(03)00207-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCruijsen, M., L\u0026uuml;bbert, M., Wijermans, P. \u0026amp; Huls, G. Clinical Results of Hypomethylating Agents in AML Treatment. \u003cem\u003eJ Clin Med\u003c/em\u003e 4, 1\u0026ndash;17, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jcm4010001\u003c/span\u003e\u003cspan address=\"10.3390/jcm4010001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeating, G. M. Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. \u003cem\u003eDrugs\u003c/em\u003e 72, 1111\u0026ndash;1136, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2165/11209430-000000000-00000\u003c/span\u003e\u003cspan address=\"10.2165/11209430-000000000-00000\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchuh, A. C. \u003cem\u003eet al.\u003c/em\u003e Azacitidine in adult patients with acute myeloid leukemia. \u003cem\u003eCrit Rev Oncol Hematol\u003c/em\u003e 116, 159\u0026ndash;177, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.critrevonc.2017.05.010\u003c/span\u003e\u003cspan address=\"10.1016/j.critrevonc.2017.05.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDombret, H. \u003cem\u003eet al.\u003c/em\u003e International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with \u0026gt;\u0026thinsp;30% blasts. \u003cem\u003eBlood\u003c/em\u003e 126, 291\u0026ndash;299, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood-2015-01-621664\u003c/span\u003e\u003cspan address=\"10.1182/blood-2015-01-621664\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFenaux, P. \u003cem\u003eet al.\u003c/em\u003e Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. \u003cem\u003eJ Clin Oncol\u003c/em\u003e 28, 562\u0026ndash;569, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/jco.2009.23.8329\u003c/span\u003e\u003cspan address=\"10.1200/jco.2009.23.8329\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026ouml;hner, H. \u003cem\u003eet al.\u003c/em\u003e Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. \u003cem\u003eBlood\u003c/em\u003e 140, 1345\u0026ndash;1377, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood.2022016867\u003c/span\u003e\u003cspan address=\"10.1182/blood.2022016867\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScott, L. J. Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. \u003cem\u003eDrugs\u003c/em\u003e 76, 889\u0026ndash;900, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40265-016-0585-0\u003c/span\u003e\u003cspan address=\"10.1007/s40265-016-0585-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKantarjian, H. M. \u003cem\u003eet al.\u003c/em\u003e Acute myeloid leukemia management and research in 2025. \u003cem\u003eCA Cancer J Clin\u003c/em\u003e 75, 46\u0026ndash;67, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3322/caac.21873\u003c/span\u003e\u003cspan address=\"10.3322/caac.21873\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang, R. \u003cem\u003eet al.\u003c/em\u003e Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis. \u003cem\u003eCancer\u003c/em\u003e 130, 2472\u0026ndash;2481, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cncr.35278\u003c/span\u003e\u003cspan address=\"10.1002/cncr.35278\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaiti, A. \u003cem\u003eet al.\u003c/em\u003e Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: A propensity score matched analysis stratified by risk of treatment-related mortality. \u003cem\u003eAm J Hematol\u003c/em\u003e 96, 282\u0026ndash;291, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ajh.26061\u003c/span\u003e\u003cspan address=\"10.1002/ajh.26061\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan, Y. Y., Tian, Y., Zhao, B. C. \u0026amp; Liu, K. X. Ramelteon exposure and survival of critically Ill sepsis patients: a retrospective study from MIMIC-IV. \u003cem\u003eBMC Anesthesiol\u003c/em\u003e 24, 454, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12871-024-02851-9\u003c/span\u003e\u003cspan address=\"10.1186/s12871-024-02851-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoombs, C. C. \u003cem\u003eet al.\u003c/em\u003e Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia. \u003cem\u003eHaematologica\u003c/em\u003e 101, e457-e460, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3324/haematol.2016.148999\u003c/span\u003e\u003cspan address=\"10.3324/haematol.2016.148999\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShih, A. H., Abdel-Wahab, O., Patel, J. P. \u0026amp; Levine, R. L. The role of mutations in epigenetic regulators in myeloid malignancies. \u003cem\u003eNat Rev Cancer\u003c/em\u003e 12, 599\u0026ndash;612, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nrc3343\u003c/span\u003e\u003cspan address=\"10.1038/nrc3343\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlutstein, M., Nejman, D., Greenfield, R. \u0026amp; Cedar, H. DNA Methylation in Cancer and Aging. \u003cem\u003eCancer Res\u003c/em\u003e 76, 3446\u0026ndash;3450, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/0008-5472.CAN-15-3278\u003c/span\u003e\u003cspan address=\"10.1158/0008-5472.CAN-15-3278\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorthakur, G. \u003cem\u003eet al.\u003c/em\u003e Report of a phase 1/2 study of a combination of azacitidine and cytarabine in acute myelogenous leukemia and high-risk myelodysplastic syndromes. \u003cem\u003eLeuk Lymphoma\u003c/em\u003e 51, 73\u0026ndash;78, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3109/10428190903318329\u003c/span\u003e\u003cspan address=\"10.3109/10428190903318329\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVives, S. \u003cem\u003eet al.\u003c/em\u003e A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia. \u003cem\u003eCancer\u003c/em\u003e 127, 2003\u0026ndash;2014, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cncr.33403\u003c/span\u003e\u003cspan address=\"10.1002/cncr.33403\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQin, T. \u003cem\u003eet al.\u003c/em\u003e Effect of cytarabine and decitabine in combination in human leukemic cell lines. \u003cem\u003eClin Cancer Res\u003c/em\u003e 13, 4225\u0026ndash;4232, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/1078-0432.Ccr-06-2762\u003c/span\u003e\u003cspan address=\"10.1158/1078-0432.Ccr-06-2762\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQin, T., Jelinek, J., Si, J., Shu, J. \u0026amp; Issa, J. P. Mechanisms of resistance to 5-aza-2'-deoxycytidine in human cancer cell lines. \u003cem\u003eBlood\u003c/em\u003e 113, 659\u0026ndash;667, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood-2008-02-140038\u003c/span\u003e\u003cspan address=\"10.1182/blood-2008-02-140038\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScandura, J. M. \u003cem\u003eet al.\u003c/em\u003e Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. \u003cem\u003eBlood\u003c/em\u003e 118, 1472\u0026ndash;1480, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood-2010-11-320093\u003c/span\u003e\u003cspan address=\"10.1182/blood-2010-11-320093\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCahill, K. E. \u003cem\u003eet al.\u003c/em\u003e A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia. \u003cem\u003eBlood Adv\u003c/em\u003e 4, 599\u0026ndash;606, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/bloodadvances.2019000795\u003c/span\u003e\u003cspan address=\"10.1182/bloodadvances.2019000795\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDamon, L. E. \u003cem\u003eet al.\u003c/em\u003e Treatment of acute leukemia with idarubicin, etoposide and cytarabine (IDEA). A randomized study of etoposide schedule. \u003cem\u003eCancer Chemother Pharmacol\u003c/em\u003e 53, 468\u0026ndash;474, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00280-003-0758-x\u003c/span\u003e\u003cspan address=\"10.1007/s00280-003-0758-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilverman, L. R. \u003cem\u003eet al.\u003c/em\u003e Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. \u003cem\u003eCancer\u003c/em\u003e 117, 2697\u0026ndash;2702, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cncr.25774\u003c/span\u003e\u003cspan address=\"10.1002/cncr.25774\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilverman, L. R. \u003cem\u003eet al.\u003c/em\u003e Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. \u003cem\u003eJ Clin Oncol\u003c/em\u003e 24, 3895\u0026ndash;3903, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/jco.2005.05.4346\u003c/span\u003e\u003cspan address=\"10.1200/jco.2005.05.4346\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia-Manero, G. Improving survival in myelodysplastic syndromes. \u003cem\u003eLancet Oncol\u003c/em\u003e 10, 200\u0026ndash;201, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1470-2045(09)70048-8\u003c/span\u003e\u003cspan address=\"10.1016/s1470-2045(09)70048-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiabov, V. \u003cem\u003eet al.\u003c/em\u003e ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms. \u003cem\u003eHaematologica\u003c/em\u003e 109, 1426\u0026ndash;1438, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3324/haematol.2023.282921\u003c/span\u003e\u003cspan address=\"10.3324/haematol.2023.282921\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu, H., Hong, J., Shin, D. Y. \u0026amp; Lee, C. H. The role of ASXL1, SRSF2, and EZH2 mutations in chromatin dysregulation of myelodysplastic neoplasia and acute myeloid leukemia. \u003cem\u003eLeukemia\u003c/em\u003e 39, 2329\u0026ndash;2339, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41375-025-02657-9\u003c/span\u003e\u003cspan address=\"10.1038/s41375-025-02657-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMetzeler, K. H. \u003cem\u003eet al.\u003c/em\u003e DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. \u003cem\u003eLeukemia\u003c/em\u003e 26, 1106\u0026ndash;1107, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/leu.2011.342\u003c/span\u003e\u003cspan address=\"10.1038/leu.2011.342\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTraina, F. \u003cem\u003eet al.\u003c/em\u003e Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. \u003cem\u003eLeukemia\u003c/em\u003e 28, 78\u0026ndash;87, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/leu.2013.269\u003c/span\u003e\u003cspan address=\"10.1038/leu.2013.269\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng, X. \u0026amp; Blumenthal, R. M. Mediating and maintaining methylation while minimizing mutation: Recent advances on mammalian DNA methyltransferases. \u003cem\u003eCurr Opin Struct Biol\u003c/em\u003e 75, 102433, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.sbi.2022.102433\u003c/span\u003e\u003cspan address=\"10.1016/j.sbi.2022.102433\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaliba, A. N., John, A. J. \u0026amp; Kaufmann, S. H. Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia. \u003cem\u003eCancer Drug Resist\u003c/em\u003e 4, 125\u0026ndash;142, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.20517/cdr.2020.95\u003c/span\u003e\u003cspan address=\"10.20517/cdr.2020.95\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStomper, J., Rotondo, J. C., Greve, G. \u0026amp; L\u0026uuml;bbert, M. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies. \u003cem\u003eLeukemia\u003c/em\u003e 35, 1873\u0026ndash;1889, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41375-021-01218-0\u003c/span\u003e\u003cspan address=\"10.1038/s41375-021-01218-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrawford, J., Herndon, D., Gmitter, K. \u0026amp; Weiss, J. The impact of myelosuppression on quality of life of patients treated with chemotherapy. \u003cem\u003eFuture Oncol\u003c/em\u003e 20, 1515\u0026ndash;1530, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2217/fon-2023-0513\u003c/span\u003e\u003cspan address=\"10.2217/fon-2023-0513\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei, A. H. \u003cem\u003eet al.\u003c/em\u003e Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. \u003cem\u003eN Engl J Med\u003c/em\u003e 383, 2526\u0026ndash;2537, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2004444\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2004444\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Acute myeloid leukemia, Azacitidine, Cytarabine, Consolidation therapy","lastPublishedDoi":"10.21203/rs.3.rs-9409121/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9409121/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAzacitidine (AZA) is a hypomethylating agent with well-known antileukemic activity. The addition of AZA to intermediate-dose Cytarabine (IDAra-c) plus idarubicin (Ida) or etoposide (Eto) in consolidation may improve outcomes in acute myeloid leukemia (AML) patients and reduce side effect.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe retrospectively evaluated whether adding AZA to IDAra-c plus Ida or Eto during consolidation could improve outcomes and reduce toxicity in newly diagnosed AML patients who achieved complete remission (CR) or partial remission (PR) after induction therapy. Propensity score matching was performed between patients in AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto and patients received IDAra-c as consolidation in the corresponding period at a 1:1 ratio according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, European Leukemia Net 2022 risk stratification and induction therapy classification.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFifty patients treated with AZA+IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto were matched with 50 patients receiving IDAra-c alone. AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto was associated with longer overall survival (OS, 90.0% vs. 53.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0006) and event free survival (EFS, 81.7% vs. 45.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0021) at 40 months. Subgroups analysis implied patients who ≦\u0026thinsp;40 years, achieved MRD negative after induction therapy, diagnosed as adverse risk or patients carried methylation associated mutations may have potential beneficial survival choosing AZA+ IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto as consolidation treatment. Myelosuppression was present in both groups, but the cells affected were different.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn conclusion, AZA+IDAra-c\u0026thinsp;+\u0026thinsp;Ida/Eto consolidation was associated with improved long-term survival and comparable toxicity versus IDAra-c alone in newly diagnosed AML.\u003c/p\u003e","manuscriptTitle":"Modified Azacitidine plus Cytarabine versus Traditional Cytarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia: A Retrospective and Propensity Score Matched Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-04 06:02:54","doi":"10.21203/rs.3.rs-9409121/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-17T14:43:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-15T11:51:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"226179856255301871023965269609422059137","date":"2026-05-06T12:02:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T08:12:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134340099989572805071397637178623315418","date":"2026-04-21T09:59:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-21T09:19:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-20T18:42:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-20T18:41:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Medical Research","date":"2026-04-14T01:17:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e598f69e-dc0a-4bf4-ba42-ec2ffbb98181","owner":[],"postedDate":"May 4th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-17T14:43:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-15T11:51:13+00:00","index":119,"fulltext":""},{"type":"reviewerAgreed","content":"226179856255301871023965269609422059137","date":"2026-05-06T12:02:53+00:00","index":117,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T08:12:06+00:00","index":81,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-17T14:54:22+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-04 06:02:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9409121","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9409121","identity":"rs-9409121","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}