<scp>DIA</scp> Regimen Versus <scp>IA</scp> Regimen for Induction Therapy in Younger Adults With Acute Myeloid Leukemia: A Multicenter Open‐Label Randomized Controlled Trial

Anthracyclines and cytarabine remain the cornerstone of intensive chemotherapy for patients with newly diagnosed acute myeloid leukemia (ND AML), typically delivered as a “7 + 3” regimen, which involves cytarabine (Ara-C) for 7 days and anthracycline (idarubicin (IDA) or daunorubicin (DNR)) for 3 days [1]. Various studies have evaluated optimal anthracycline and Ara-C dosing and explored adding a third drug to improve long-term outcomes and enhance response rates. Azanucleoside DNA hypomethylating agents (HMAs) are cytidine analogs that epigenetically reactivate genes via DNA methyltransferase-1 inhibition through aberrant gene silencing reversal [2, 3]. Due to its favorable toxicity profile and anti-leukemic activity, decitabine (DAC) has become the standard treatment foundation for patients with AML who are older or unfit for intensive chemotherapy [4]. However, no prospective clinical studies have compared the efficacy of adding decitabine to the IA (DIA) regimen versus the IA regimen alone. Therefore, we conducted a multicenter, prospective, randomized, controlled trial to evaluate the effects of these two treatment approaches. We conducted a multicenter, open-label, randomized controlled clinical trial across four hospitals in China from September 2020 to March 2024, where eligible patients were randomly assigned (1:1) to receive either the DIA or IA regimen. A total of 130 participants were enrolled in the study for interim analysis 65 participants were assigned to receive the DIA induction regimen, while the remaining 65 were assigned to the IA induction regimen (Figure S1). Baseline data are shown in Table S1. In the DIA group, 56 patients (86.2%) achieved CR/CRi and eight patients (12.3%) achieved partial remission (PR), resulting in an overall response rate (ORR) of 98.5%. In the IA group, 51 patients (78.5%) achieved CR/CRi and five patients (7.7%) achieved PR, resulting in an ORR of 86.2%. Among those achieving CR, 39 patients (69.6%) in the DIA group achieved deep remission (CRMRD-), compared to 19 patients (37.3%) in the IA group (p < 0.006) (Table 1). Analysis of molecular abnormalities indicated that patients with methylation mutations (p = 0.030) or CEBPA mutations (p = 0.002) treated with the DIA regimen had significantly higher CRMRD- rates than those in the IA group. ELN genetic typing revealed that intermediate-risk (p = 0.038) and adverse-risk patients (p = 0.045) showed a significantly higher CRMRD- rate in the DIA group compared to the IA group (Table 2). The median follow-up time for the entire cohort was 1027 days (95% confidence interval [CI], 903–1151 days). At the end of follow-up, 35 patients (53.8%) in the DIA group and 43 (66.2%) patients in the IA group underwent allo-HSCT and 51 patients (78.5%) survived in each group. Among patients who achieved CR, relapse occurred in 12 cases in the DIA group (21.4%) and 11 cases in the IA group (21.6%) (Table 1). The estimated 3-year OS was 74.2% in the DIA group and 76.5% in the IA group (p = 0.912), while the estimated 3-year EFS were 65.8% in the DIA group and 58.6% in the IA group (p = 0.206) (Figure 1A,B). We stratified all patients into transplantation or non-transplantation subgroups for survival analysis. Among patients who underwent transplantation, those receiving the DIA induction regimen showed a trend toward superior EFS compared to those receiving the IA regimen, with the difference approaching statistical significance (p = 0.053) (Figure 1D). Among high-risk patients with AML who underwent transplantation, those receiving the DIA induction regimen showed a superior EFS (p = 0.027) (Figure 1H). Both groups experienced grade III-IV hematologic toxicities, including leukopenia, neutropenia, and thrombocytopenia (Table S2). Although CR rates were similar between the DIA and IA groups, the DIA group had a significantly higher proportion of MRD-negative patients (69.6% vs. 37.3%). Patients who achieved CR but remained MRD-positive retained residual leukemia cells with high proliferative potential, often leading to relapse and poorer prognosis compared to MRD-negative patients [5]. Typically, achieving MRD-negative remission correlates with improved survival outcomes and is increasingly recognized as a crucial endpoint for intensive induction therapy, given its association with reduced relapse risk before and after transplantation [5, 6]. The DIA regimen can improve MRD negativity rates, reduce relapse, and create favorable conditions for follow-up allo-HSCT. Our findings suggest that patients with methylation mutations and those with CEBPA mutations achieved higher CRMRD- rates and may benefit more from the DIA regimen. Methylation-related gene mutations (e.g., DNMT3A, TET2, IDH1, IDH2) significantly impact DNA methylation patterns. Mutations in TET2 and IDH1/2 induce genome-wide hypermethylation and promoter-specific hypermethylation of tumor suppressor genes [7]. Acquisition of secondary genetic lesions (e.g., FLT3-ITD, NPM1, or IDH1 mutations) in these epigenetically primed cells drives malignant transformation [8]. Collectively, these methylation-related gene mutations exert distinct but synergistic effects on DNA methylation dynamics, ultimately driving disease progression through epigenetic dysregulation. This mechanistic insight may explain why patients with methylation mutations achieve CRMRD- on the DIA regimen. Methylation patterns change significantly in patients with AML mutations in epigenetic regulators and those with CEBPA mutations [9]. The methylation-silencing gene CEBPA has been identified as a critical decitabine-sensitive gene in t (8;21) AML [10]. These factors may explain why patients with CEBPA mutations had higher MRD rates with the DIA regimen compared to the IA regimen. However, these interpretations must be considered strictly exploratory. The analysis is inherently limited by the interim sample size and baseline imbalances (the higher frequency of DNMT3A mutations in the IA group), which may confound the observed associations. Consequently, these findings should be interpreted with caution and await validation in a larger, prospectively designed cohort. Notably, our results revealed that the DIA regimen significantly improved the rate of CRMRD- compared to the IA regimen in intermediate- and adverse-risk patients with AML. Beyond its DNA methyltransferase inhibitory effects, decitabine demonstrates significant chemosensitizing activity in AML cells, potentiating their responsiveness to conventional chemotherapeutic agents, including cytarabine and daunorubicin [11]. Adverse cytogenetics significantly influenced decitabine efficacy. Among patients with AML receiving decitabine-based induction, those with 17p deletions (17p-) and complex karyotypes achieved significantly higher response rates compared to patients without these abnormalities (71% vs. 36%, p = 0.010) [12]. These findings may explain why the DIA regimen led to higher rates of MRD-negative remission in intermediate- and adverse-risk patients with AML. The CR rate of the DIA regimen in our prospective study was similar to or higher than those reported in other DAC studies. A retrospective study comparing the effectiveness of DIA and IA regimens in the treatment of patients with ND AML with MDS features found a higher CR rate with DIA (85.2% vs. 68.5%, p = 0.040), showing particular benefits for intermediate- and high-risk patients [13]. An open-label phase I study combining decitabine and a DA regimen achieved a CR rate of 57% in patients with ND AML [11]. A prospective multicenter study evaluating the efficacy of combining DAC with a low-dose IA regimen for treating AML evolving from MDS reported a 63.6% CR rate [14]. In induction regimens to treat patients with ND AML, DAC is sometimes incorporated into the traditional “7 + 3” regimen, and other drugs are also used in combination. Among 47 patients with ND AML, cladribine combined with an IA (CLIA) regimen achieved an 81% CR rate, with 55% achieving MRD negative and an estimated 1-year OS rate of 75% [15]. In patients with ND AML who received a sorafenib combined with an IA regimen, 54 (87%) achieved CR [16]. Additionally, a phase II study reported a 77% CR rate and a 70% MRD negativity rate with the CLIA regimen among patients with ND AML [17]. The efficacy of our treatment regimen is equal to or even exceeds these regimens. Studies on human leukemia cell lines show that administering Ara-C after decitabine enhances cytotoxicity, with cytarabine preferentially killing hypomethylated cells. These findings suggest that decitabine-induced hypomethylation increases leukemia cell line sensitivity to cytarabine's cytotoxic effects [18]. A previous study also demonstrated synergistic anti-leukemic effects between DAC and IDA [19]. Decitabine shows a synergistic effect with idarubicin and cytarabine, enhancing its anti-leukemic effect, which may explain the higher MRD conversion rate observed with the DIA regimen compared to the IA regimen. The DIA regimen is safe, tolerable (mild, manageable drug-related AEs), with no significant difference in hematologic/non-hematologic AE incidence versus the IA regimen. Although the higher MRD negativity rate achieved with the DIA regimen in this study did not translate into improved OS or EFS, this may be due to the relatively short follow-up period in our study or the higher number of patients in the IA group who underwent allo-HSCT after achieving CR (53.8% in the DIA group vs. 66.2% in the IA group, p = 0.210). For intermediate- to high-risk patients with AML, undergoing allo-HSCT soon after achieving CR can lead to a better prognosis [20]. Our findings revealed that the use of DIA induction therapy was associated with significantly longer EFS in high-risk patients with AML who underwent allo-HSCT (p = 0.027). This study is an interim analysis of a clinical trial with a limited sample size and a short follow-up period. Additional participant recruitment, a larger sample size, and extended follow-up are necessary to confirm the efficacy of the decitabine combined with the IA regimen. In conclusion, younger patients with ND AML receiving the DIA regimen as an induction therapy achieved a higher CRMRD- with good tolerability. Patients with intermediate−/adverse-risk and those carrying methylation mutations or CEBPA mutations may particularly benefit from the DIA regimen, as these groups showed higher CRMRD- rates. In patients who underwent transplantation, the DIA induction regimen was associated with a trend toward improved EFS relative to the IA regimen. For high-risk patients with AML undergoing transplantation, EFS was significantly better in those treated with the DIA induction regimen than in those given IA. X.T. wrote the protocol, did the data curation, formal analysis, and wrote the original manuscript. B.X. wrote the protocol, did the data curation, and formal analysis. X.T. and B.X. contributed equally to this work. S.Z., M.L., and S.S. collected the data. Y.Z. collected the data. Z.H., Y.W., Y.X., L.H., D.L., W.H., J.W., M.H., Z.H., Y.T., and H.R. conducted the study. D.Z. designed the study, wrote the protocol, did the data curation, and was responsible for project administration. All the authors critically reviewed and approved the final manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors would like to thank the participants, the investigators, and the study staff for their contributions to this study. The authors have nothing to report. This study involved human participants and was approved by the Medical Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Informed consent was obtained from all participants before participation. This study was registered with the Chinese Clinical Trial Registry (ChiCTR2000037928). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflicts of interest. Clinical results from published parts of this trial can be made available upon request to the corresponding author and the decision of the principal investigator. Figure S1: Trial profile. Table S1: Clinical characteristics between the two groups. Table S2: Adverse events. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.