Liposomal mitoxantrone demonstrates superiority to traditional mitoxantrone in the treatment of AML

Abstract Background Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy with poor prognosis, faces significant therapeutic challenges despite the standard “7+3” induction therapy. Mitoxantrone (MIT), an anthraquinone derived antitumor drug that combats leukemia by inducing apoptosis and inhibiting topoisomerase II to disrupt DNA processes. However, its clinical application is limited due to side effects, including myelosuppression and cardiotoxicity. Liposomal mitoxantrone (Lipo-MIT), an innovative anthracycline nano-drug, has demonstrated improved pharmacokinetic properties and preliminary efficacy in AML. Research exploring the unique roles and mechanisms of Lipo-MIT compared to MIT in AML treatment remains scarce. Aims This study aims to comprehensively compare the antitumor activities and pharmacological effects of Lipo-MIT and MIT in the treatment of AML. Additionally, we seek to explore the unique advantages of Lipo-MIT and elucidate its potential molecular mechanisms, including drug delivery and alterations in the immune microenvironment. Furthermore, we aim to explore potential optimizable combination regimens, with the Lipo-MIT plus venetoclax and azacitidine (VA-Lipo-MIT) protocol serving as a case in point. Methods In vivo tumor suppression performance of single-dose Lipo-MIT versus MIT We evaluated the therapeutic effects of single-dose Lipo-MIT compared to MIT on overall survival (OS) and leukemic burden across multiple organ compartments (peripheral blood, bone marrow, liver, spleen, and lymph nodes) in two distinct AML murine bone marrow transplantation models: NUP98-HOXA9 and MLL-AF9-driven leukemogenesis. Through comprehensive flow cytometric analysis, we further quantified treatment-induced apoptosis in bone marrow-resident leukemia cells and monitored dynamic changes in immune cell populations. The in vivo biodistribution ofLipo-MIT versus MIT The biological distribution of the drug in model mice, encompassing peripheral blood, bone marrow, and spleen, was detected via high-performance liquid chromatography (HPLC). In vivo antitumor performance of combination therapy Building on the characteristics of venetoclax resistance of the MLL-AF9 model, we explored the anti-tumor performance and overall survival of the VAM regimen. Results Compared with conventional MIT, Lipo-MIT demonstrated superior efficacy in reducing leukemic burden across critical hematopoietic compartments-peripheral blood, bone marrow, and spleen-in AML murine models. This therapeutic advantage translated into significant survival benefits: In the MLL-AF9 model, Lipo-MIT treatment extended median OS to 44 days versus 35 days with MIT and 22 days in vehicle control (p<0.01). A similar pattern emerged in the NUP98-HOXA9 model, with median OS durations of 37 days (Lipo-MIT), 28 days (MIT), and 20 days (vehicle) respectively (p<0.01). Mechanistically, Lipo-MIT induced more potent and sustained apoptosis in bone marrow-resident leukemia cells compared to MIT owing to its longer sustained-release effect in vivo. Compared to MIT, peak drug concentration of bone marrow occured later, and the levels were markedly elevated for Lipo-MIT. Furthermore, flow cytometric analysis revealed enhanced immunomodulatory effects of Lipo-MIT, characterized by significantly increased proportions of CD3+ T lymphocytes and their CD4+/CD8+ subsets in peripheral blood, bone marrow, and splenic compartments. These immunophenotypic alterations were both quantitatively greater and temporally sustained compared to MIT. In the venetoclax-resistant MLL-AF9 model, the initial results of VA-LIpo-MIT regimen showed better efficacy manifested as significantly prolonged survival compared with the VA regimen. Summary/Conclusion Lipo-MIT demonstrates superior performance compared to traditional MIT in AML models, improving survival and leukemic clearance through a dual mechanism: robust induction of apoptosis facilitated by a prolonged in vivo sustained-release profile, and amplified T cell immunity. The VAM regimen demonstrates superior efficacy in prolonging survival compared to the VA regimen in the venetoclax-resistant MLL-AF9 model. These results support Lipo-MIT as a promising strategy combining direct antileukemic effects and immune modulation.