In recent years, Venetoclax (Ven) has gained a prominent position in the treatment of newly diagnosed acute myeloid leukemia (AML) patients. Combinations of Ven with hypomethylating agents (HMA), Azacitidine (AZA) or decitabine (DEC), have become the first-line treatment for newly diagnosed AML patients who are elderly or not suitable for intensive chemotherapy (IC), with CR rates around 60–70% [1,2,3]. Other studies have demonstrated that ten-day DEC combined with Ven can significantly improve the CR rate in newly diagnosed AML patients, albeit at the cost of a notably prolonged bone marrow suppression period [4]. The optimal method of combining Ven with HMA remains an area of ongoing investigation.

DEC is a cytosine analog that exerts epigenetic effects by reducing aberrant DNA methylation. Notably, high-dose DEC exhibits cytotoxicity in addition to its DNA demethylation properties. Previous studies have demonstrated that the cytotoxicity of high-dose DEC was more active than cytarabine, and 5-azacytidine [5,6,7,8]. A 3-day regimen of DEC showed good efficacy in previous research involving myelodysplastic syndromes (MDS) or AML [9,10,11]. Consequently, we designed Ven combined with 3-day, multi-frequency DEC (DEC3-VEN) as induction therapy for elderly or IC ineligible de novo AML patients. This study was conducted following the Declaration of Helsinki and institutional guidelines. The informed consent was signed by the patients or their guardians before the treatment.

The regimen consisted of Ven (100 mg Day 1; 200 mg Day 2; 400 mg Days 3–9 or 3–14), DEC (20 mg/m²/q8h, Days 4–6 and infusion time ≥ 2 h). Hydroxyurea or Ara-c were permitted for cytoreduction in patients with high white blood cells (WBC) at diagnosis until the WBC count was ≤25 × 109/L. For patients administered potent CYP3A inhibitors (voriconazole or posaconazole), the dosage of Ven was reduced to 100 mg/day. Granulocyte colony-stimulating factor (G-csf) was permitted for use during the neutropenia phase after induction therapy. Bone marrow examinations were conducted on days 28–35 post-induction therapy for efficacy evaluation. Young patients who achieved CR or CRi after the induction therapy, received consolidation and maintenance therapy refer to VEN combined with DA (2 + 6) [12]. Ven combined DEC (Ven 400 mg d1-7; DEC 20 mg/m2/q8h d2–3) was administered once every 4–6 weeks as consolidation therapy for elderly patients or those who were unwilling to undergo IC until disease relapse or occurrence of serious adverse events (severe myelosuppression, infection, etc.). Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) was recommended according to ELN guidelines. Patients who failed to achieve CR, CRi, or MLFS received the induction therapy again or other salvage therapy. Regular assessments of bone marrow morphology and MRD (assessed by flow cytometry with a sensitivity range of 0.01–0.1%) were performed.

Between January 2023 and October 2023, 47 patients with newly diagnosed AML adopted DEC3-VEN as induction treatment. All patients met the AML criteria of the WHO (2022) classification. The baseline characteristics of 47 patients are summarized in Table 1. The median age was 70 (20–82) years, and 24 (51.1%) patients were male. The median WBC was 24.12 (0.65–370.73) × 109/L. Twenty-seven (57.4%) patients belonged to the adverse risk group according to the ELN 2022 risk classification. Gene mutations are depicted in Supplementary Fig. 1. Ven was administered for a duration of 9 days in 33 patients (70.2%) and 14 days in 14 patients (29.8%).

After one cycle of induction treatment, one patient died, and one patient declined response evaluation (with blood routine tests remaining normal at the 4-month follow-up), 45 patients were assessed for efficacy. The overall response rate (CR + CRi + PR) was 93.3% (42/45, 95% confidence interval [CI], 85.8–100%.) with cCR(CR + CRi) rate 86.7% (39/45, 95% CI, 76.1–99.6%). Thirty-three patients underwent MRD evaluation via flow cytometry, and 25 (75.8%) achieved MRD negativity (Table 2). Three patients achieved PR, two patients received re-induction therapy with the same regimen, one patient died because of bacteremia, and another patient achieved CR. The third patient entered an alternative clinical trial and achieved CR. In three NR patients, one patient accepted the same regimen and achieved CR. Another patient was treated with salvage therapy involving Ven plus AZA + HA and achieved CR. The third patient, however, opted against further treatment. After salvage treatment, 95.6% (43/45) of patients achieved cCR (CR + CRi). Neutropenia, anemia, and thrombocytopenia were the most prevalent hematological adverse events during the induction treatment. For patients who achieved CR or CRi, the median duration of WBC ≥ 1 × 109/L and PLT ≥ 30 × 109/L post-induction therapy was 15 (range: 0–40) and 14 (range: 0–38) days, respectively (Table 2). The most common grade 3–4 non-hematological adverse event was infection, including upper respiratory infections, pneumonia, intestinal infections, etc. None of the patients had tumor lysis syndrome.

After achieving CR or CRi, 6 patients gave up treatment for personal reasons. Thirty-three patients received Ven combined DEC (Ven 400 mg d1–7; DEC 20 mg/M2/q8h d2–3) once every 4–6 weeks as consolidation therapy. Additionally, two patients were treated with intensive chemotherapy, one patient was administered DEC alone due to severe pneumonia, and one patient remained in the clinical trial. By the end of the follow-up, 9 patients gave up continuing consolidation therapy for personal reasons, and the median consolidation cycle for VEN + DEC was 5 (1–13). The consolidation therapy was shown to be well tolerated, and most patients did not require dose adjustment. Allo-HSCT was recommended according to ELN guidelines. Until Aug 30, 2024, with a median follow-up of 11 (0.5–20) months, four patients underwent allo-HSCT. Twelve patients relapsed, and 16 patients died. The estimated 12-month OS, EFS, and DFS rates were 66.8% (95% CI: 53.5–83.4%), 58.1% (95% CI: 44.4–76.0%), and 68.4% (95% CI: 54.2–86.3%), respectively (Supplementary Fig. 2). Due to limited number of patients, there was no difference in OS, EFS, and RFS among different prognostic risk groups (Supplementary Fig. 3).

In recent years, the widespread application of Ven in AML has significantly improved the efficacy of de novo AML patients. How to combine VEN and HMA rationally, improve efficacy, and reduce myelosuppression is still being explored in elderly or IC-intolerant patients. In our study, the induction regimen DEC3-VEN demonstrated superior efficacy and tolerability. The ORR was 93.3% with a cCR (CR + CRi) rate of 86.7% and an MRD negative rate of 75.8% after one cycle of treatment. This result was significantly better than previous reports that Ven combined with AZA or 5-day DEC regimen, and comparable to Ven combined with 10-day DEC. However, DEC3-VEN exhibited significantly less myelosuppression than Ven plus 10-day DEC, with the median duration to recovery of the absolute WBC ≥ 1 × 109/L and PLT ≥ 30 × 109/L post-induction therapy was 15 (range: 0–40) and 14 (range: 0–38) days. We speculate that these may be attributed to several factors: (1) High-dose decitabine also exhibits cytotoxic properties besides demethylation effects. When Ven is combined with multi-frequency, high-dose DEC, it might exert a similar effect as Ven in conjunction with intensive chemotherapy. (2) The shortened duration of Ven administration reduced bone marrow suppression and demonstrated good tolerability. In contrast to consolidation therapy in the Viale-A study, our consolidation regimen (Ven 400 mg d1–7; DEC 20 mg/m2/q8h d2–3) also showed better tolerability. At the end of the follow-up, the number of consolidation cycles of VEN + DEC was 5 (1–13), and few patients adjusted the dose due to severe myelosuppression. Patients who gave up treatment mostly did so for personal reasons (economic, cognitive, conceptual, etc.). This may be attributed to the fact that Ven was given for only one week, and the duration and dosage of DEC were reduced.

In the cohort, the most common cause of relapse and death is discontinuation of treatment. Out of the 12 patients with relapse, 9 patients gave up treatment for personal reasons (economic, cognitive, conceptual, etc.). Due to a limited number of patients, there was no difference in OS, EFS, and RFS among different prognostic risk groups. Further exploration is required to determine whether the regimen can improve long-term survival, and prospective clinical studies are ongoing (ClinicalTrials.gov, numbers NCT06073730, NCT06285136). Preliminary results showed a significant improvement in the efficacy and tolerability of DEC3-VEN compared to VEN combined with AZA and a high CR rate after one cycle of the induction treatment in young patients with de novo AML.

In conclusion, Ven combined with three-day multi-frequency DEC (DEC3-VEN) is a highly effective and safe induction therapy regimen for the elderly or unfit for intensive chemotherapy de novo AML patients.