Efficacy and Safety of Dose-Tailored Mitoxantrone Liposomes Combined with Cytarabine and Venetoclax in Newly Diagnosed Acute Myeloid Leukemia (Non-M3) Based on Marrow Leukemic Cellularity
Authors: Hui Li , JIyi FU , Zheng Boyue , HU Lianjie , LI Yaqiong , WANG Xin , HU Qing , Wei Li , Yi Hai , Yuan Ying , Huan Wang , Haiqing Yang , Yang Xi , Zheng Hong , Jia Yongqian 
Published: December 2024

Background: Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hematologic malignancy. The standard “3+7” treatment often brings remission but relapse was common, 2- year and 5-year survival rates were 32% and 24%. New therapeutic strategies, such as the ‘3+7+X’ incorporating targeted therapies, offer renewed hope for improved outcomes. Mitoxantrone liposomes, due to their unique pharmacokinetic properties, can accumulate in the bone marrow for an extended period, exerting a prolonged toxicity against leukemic cells. Multiple studies have validated the anticancer effect of Lipo-MIT in AML. However, AML patients exhibit diverse bone marrow proliferative states, and varying dosages can significantly affect both treatment outcomes and safety. To achieve a harmonious balance between efficacy and safety, particularly in mitigating chemotherapy-related complications, it is imperative to optimize the therapeutic regimen.

Objective: explore the efficacy and safety of individualized doses of Lipo-MIT in combination with cytarabine (A) and venetoclax (V) (MAV regimen) for AML treatment, with dosing tailored specifically to each patient's bone marrow leukemic cellularity and peripheral blood leukemic cell count.

Methods: We conducted a multicenter retrospective analysis of 11 pts with newly diagnosed AML who received MAV regimen between December 2023 and June 2024. Pts aged 18 years and above with a confirmed diagnosis of AML according to the 2016-revised WHO criteria, excluding acute promyelocytic leukemia (APL), were eligible for inclusion. High-dose group, for pts with extremely active or significantly active bone marrow proliferation (with bone marrow blasts ≥50%; or bone marrow blasts &lt;50% and peripheral white blood cell count ≥100×109/L), The median dose of Lipo-MIT in the regimen was 26mg/m2 (range 20.0-26.0 mg/m2). Low-dose group, For pts with markedly active bone marrow proliferation (bone marrow blast cells &lt;50%, and peripheral white blood cell count &lt;100×109/L), or those with active or decreased bone marrow proliferation, The median dose of Lipo-MIT in the regimen was 16.4 mg/m2 (range 13.4-19.4 mg/m2).Efficacy was assessed by composite complete remission (CRc) rate, minimal residual disease (MRD) negative rate,relapse-free survival (RFS), overall survival (OS)and correlative analyses.Adverse events were assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Results: At the data cut-off of 30 June 2024, 11 pts who received induction therapy with the MAV regimen were enrolled. The median age was 52.0 years (range 30.0-60.0), 63.6% were female, and 81.8% were assigned to the high-dose group. The median white blood cell (WBC) count was 19.0x109/L(range 0.8-190.2x109/L). Risk stratification based on cytogenetic and molecular abnormalities were ailable for all 11 pts: 3 pts (27.3%) favorable risk, 3 pts (27.3%) intermediate risk, and 5 pts (45.4%) adverse risk. Gene-sequencing was performed on 100% of patients (11/11). NPM1 was most frequently mutated (36.4%, 4/11), followed by IDH2 and DNMT3A (each 27.3%, 3/11). FLT3-ITD and TET2 mutated in 18.2% (2/11), while CEBPA and BCOR each mutated in 9.1% (1/11) of patients. The composite complete remission rate（CRc） was 100% (11/11) after one cycle of the MAV regimen. Among the pts with CRc, flow cytometric MRD-negativity was achieved in 10 (90.9%) of pts. Other efficacy indicators such as RFS (relapse-free survival) and OS (overall survival) will be reported after long-term follow-up. The most common grade 3-4 non-haematological adverse events were pulmonary infection (18.2%), vomiting (9.1%). No tumour lysis syndrome events were observed. The most common grade 3-4 hematological toxicities were leukopenia (72.7%), neutropenia (90.9%), anemia (90.9%), thrombocytopenia (63.6%), and febrile neutropenia (27.3%).

Conclusions: A dose-tailored MAV regimen for the treatment of newly diagnosed AML, based on the degree of bone marrow leukemic cellularity and peripheral blood leukemic cell counts, resulted in a high complete remission rate and was well tolerated. It deserves further large-sample, prospective studies.

Disclosures No relevant conflicts of interest to declare.