Efficacy and Safety of a Modified Conditioning Regimen Based on Mitoxantrone Hydrochloride Liposome and Busulfan/Cyclophosphamide for Patients with Refractory and Relapsed Acute Myeloid Leukemia

Background

Patients with refractory and relapsed acute myeloid leukemia (AML) face a poor prognosis, with a lack of effective treatment options available. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is usually recommended for patients with an appropriate donor, but survival remains dismal. Therefore, safer and more effective conditioning regimens are urgently needed to further reduce disease recurrence and improve the clinical outcomes.

In our preliminary work, Mitoxantrone hydrochloride liposome (Lipo-MIT)-based combined chemotherapy demonstrated a high remission rate in refractory and relapsed AML, even for patients relapsed after allo-HSCT. The liposomal formulation improved the safety profiles of Mitoxantrone and enhanced the anti-tumor effects via permeability and retention effect. In this study, we focused on the addition of Lipo-MIT to myeloablative conditioning regimens.

Aims

To evaluate the efficacy and safety of a modified conditioning regimen containing Lipo-MIT/Cladribine/Cytarabin/Busulfan and Cyclophosphamide in the treatment of refractory and relapsed AML patients underwent allo-HSCT.

Methods

Adult patients with refractory and relapsed AML underwent first allo-HSCT were enrolled in this study. Bone marrow aspirates were obtained, cytogenetic and molecular characteristics were collected at the time of diagnosis and disease relapse. HLA-haploidentical donor transplants were performed if no HLA matched sibling or unrelated donor was available. This modified myeloablative conditioning utilized Mitoxantrone hydrochloride liposome (Lipo-MIT, dose levels ranged from 24mg/m² to 36 mg/m² for 1 day), Cladribine (5mg/m² for 3 days), Cytarabin (dose levels ranged from 1g/m² to 2g/m² for 3 days), Busulfan (Bu, 3.2 mg/kg for 3 days) and Cyclophosphamide (Cy, 40mg/kg for 2 days). Patients aged over 55 years received lower dose of Lipo-MIT (24mg/m² for 1 day) and Cytarabin (1g/m² for 3 days). The therapeutic process and clinical outcomes were retrospectively analyzed.

Results

Between October 2023 and March 2024, 28 patients allografted in our clinical center were enrolled. Median age was 44 (18.0-64.0) years. Out of these patients, 11 (39.3%) had primary refractory disease and 17 (60.7%) had recurrent AML (10 patients relapsed within 12 months and 2 had relapsed ≥2 times). At the time of transplantation, 15 patients (53.6%) were found to be MRD-positive and 7 (25.0%) were transplanted with active disease. All patients engrafted successfully. The median time to neutrophil and platelet engraftment were 16 days (range 11-23) and 23 days (range 11-52), respectively. Platelet engraftment was delayed when compared with the historical controls.

At the time of this analysis, 27 patients were alive, and one patient died of secondary poor graft function and septic shock, at 4 months post-transplantation. Three patients (10.7%) experienced disease recurrence and received salvage chemotherapy and donor lymphocyte infusion (DLI). OS and RFS were 95.2% (95% CI 86.2-100%) and 83.9% (95% CI 69.2-98.6%), respectively. Three patients developed cardiac insufficiency and one developed atrial fibrillation during conditioning therapy. All patients recovered after symptomatic treatments. No severe cardiotoxicity (Grade III-IV) or transplant-related mortality occurred within 100 days, which was comparable with the historical controls.

Conclusions

In conclusion, Lipo-MIT-based combined conditioning regimen is potentially effective with acceptable tolerability in patients with refractory and relapsed AML. Further well-designed studies are required to validate the efficacy and the optimal dosage of this conditioning regimen.