Venetoclax plus mitoxantrone hydrochloride liposome and Azacitidine As first-line treatment for adults with Acute Myeloid Leukemia

Abstract

Abstract Background The standard “3+7” regimen (idarubicin/daunorubicin combined with cytarabine, IA/DA) remains the cornerstone of first-line induction therapy for acute myeloid leukemia (AML), excluding acute promyelocytic leukemia (APL). While this protocol achieves complete remission in 60-80% of newly diagnosed AML patients, its clinical utility is limited by significant treatment-related toxicities, particularly in elderly patients and those with comorbidities. These adverse effects encompass prolonged myelosuppression, cumulative cardiotoxicity, and life-threatening infections that frequently necessitate treatment discontinuation. Recent advancements in targeted therapies and novel combination strategies have revolutionized AML management, particularly for patients ineligible for intensive chemotherapy. To explore more appropriate combination regimens, we prompted a promising combination involves the use of venetoclax (VEN), mitoxantrone hydrochloride liposome (MITO) and azacitidine (AZA). Aims To evaluate characteristics, outcomes and safety of AML patients treated with first line VEN-MITO-AZA. Methods This was a single-arm, prospective, multi-center clinical study (ChiCTR 2400093555). We enrolled 51 patients aged 18–80 years with newly diagnosed and previously untreated AML patients (except APL) and an Eastern Cooperative Oncology Group performance status of 0–2. Patients had induction treatment with intravenous MITO (20 mg/m² on days 1), oral venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3–14, and subcutaneous AZA (100 mg/m² on days 1–7) , MVA regimen. For induction therapy, the length of the treatment was 28–35 days per cycle and the number of treatment cycles was one or two, patients with FLT3-ITD/TKD could combined with FLT3 inhibitors in the second induction treatment. The primary research endpoint was the composite complete remission rate (cCR (complete remission (CR) plus complete remission with incomplete blood cell count recovery (CRi))) after one cycle of induction treatment. Secondary endpoints were overall remission rate (ORR), minimal residual disease (MRD) conversion negative rate, event-free survival time, overall survival time and safety. Results Between April 17, 2024 and May 1st, 2025, 51 patients were enrolled (aged 18-75 years; median 50 years, of which 21/51(42.3%) cases were in favorable risk group, 13/51(25.5%) cases were in intermediate risk group, and 17/51(33.3%) cases were in adverse risk group. 31 (60.8%) patients were women and 20 (39.2%) were men. DNMT3A was the most common mutated gene of 24.0%, M2 subtype of acute myeloid leukemia is the most common subtype, accounting for 64.7% of cases.Efficacy observation: The overall CRc rate was 38/51(74.5%) and ORR was 44/51(86.3%) after first induction therapy. 24/46(52.2%) of patients who achieve a positive response achieved MRD negativity. With a median follow-up of 5.8 months, 32/51(62.7%) patients remain in CR, the median EFS and OS is not reached. In the subgroup analysis, we found that the ORR of MVA in favorable, intermediate, and adverse-risk subgroups is 71.4%, 100%, and 94.1%, respectively. However, in patients with the RUNX1-RUNX1T1 fusion gene, the ORR of MVA as first-line induction therapy was 14.3% (1/7), while in patients without the RUNX1-RUNX1T1 fusion gene, the ORR was 97.7% (43/44). This suggests that patients with the RUNX1-RUNX1T1 fusion gene may not be suitable for first-line induction therapy with this regimen. (2) Safety observation: The median unit of red blood cell transfusions during first induction was 6.0 U, while the median unit of platelet transfusions was only 3.0 U. with particularly fewer platelet transfusions and lower volumes of transfusion compared to the conventional 3+7 regimen. During the MVA regimen induction treatment, no patients experienced fatal complications due to chemotherapy toxicity. Furthermore, in a uremic patient, no significant organ toxicity was observed with this regimen, indicating the safety and efficacy of MVA strategy. None patients experienced adverse reactions and complications including cardiotoxicity, liver and renal dysfunctions, and febrile neutropenia. The adverse reactions were tolerated or controlled. Overall, the regimen was well tolerated in patients with AML at the initial diagnosis. Conclusion As a promising treatment, MVA regimen is effective and safe in newly diagnosed AML patients. Disclosures No relevant conflicts of interest to declare.