Efficacy and Safety of Mitoxantrone Hydrochloride Liposome in Combination with Thiotepa-Busulfan-Fludarabine As an Intensive Conditioning Regimen Preceding Salvage Allogeneic Stem Cell Transplantation in Relapsed or Refractory Acute Myeloid Leukemia

Background:Patients with relapsed and refractory acute myeloid leukemia (R/R AML) especially those in non-remission have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Mitoxantrone hydrochloride liposome (Lipo-MIT) is a pegylated liposomal mitoxantrone formulation with promising efficacy and an acceptable safety profile in rescue treatment of R/R AML.There was no report of Lipo-MIT combination with thiotepa- busulfan-fludarabine（TBF）as an intensive conditioning regimen prior to allo-HSCT. This study aimed to explore the efficacy and safety of Lipo-MIT in combination with TBF as an intensive conditioning regimen before salvage allo-HSCT in R/R AML patients. Methods:This is a single-arm,prospective clinical trial（NCT06385808).R/R AML patients in non-remission were enrolled for salvage allo-HSCT with an intensive conditioning regimen consisted of mitoxantrone hydrochloride liposome 24mg/m² ivgtt d-7;thiotepa 5mg/kg ivgtt d-6~-5; Busulfan 0.8mg/kg q6h ivgtt d-4~-2; Fludarabine 50mg/m² ivgtt d-4~-2. The primary endpoint was the cumulative incidence of relapse. Secondary endpoints included progression-free survival (PFS), overall survival (OS), times to neutrophil engraftment and platelet engraftment, acute and chronic graft versus host disease（GVHD）and non-hematological toxicity.

Results: Thirteen patients with R/R AML who underwent salvage allo-HSCT while in non-remission or with concomitant extramedullary leukemia at the first affiliated hospital of xi'an jiaotong university were enrolled, including 6 men and 7 women with a median age of 37 (16-53) years. A total of 9 cases were refractory, and 4 cases were relapsed.Six cased with FLT3-ITD mutation, one with TP53 mutation, 2 cases transformed from myelodysplastic syndromes,and one with ASXL1, ETV6 and K-RAS mutations.Nine patients in non-remission and 4 patients with central nervous system leukemia before transplantation. The proportion of blasts in bone marrow befo re transplantation was ranged from 6% to 75%.Ten cases underwent haploidentical allo-HSCT, 3 cases underwent matched sibling allo-HSCT.

The curative effect evaluation conducted between 14 and 21 days post-transplantation showed that the complete remission rate and the minimal residual disease (MRD) negativity rate was 100%. The median engraftment time of neutrophil and platelet were 11(9-13) days and 12(11-23) days respectively. Two cases had grade II-IV acute GVHD and one with chronic GVHD, one had hemorrhagic cystitis at one month post-transplantation, and one with post-transplant lymphoproliferative diseases at 44 days post-transplantation. The median follow-up time was 6 months.So far, all patients were all alive with negative MRD .The median PFS and OS time were not determined.

The most common non-hematological adverse events of Lipo-MIT combination with TBF included diarrhea (76.9%,10/13), oral mucositis(76.9%,10/13), gastrointestinal bleeding (23.1%,3/13), drug-induced liver damage (15.4%,2/13). All of these adverse events were improved after treatment.

Conclusion:Mitoxantrone hydrochloride liposome in combination with TBF as an intensive conditioning regimen before salvage allo-HSCT shows promising results in patients with R/R AML.

Keywords:Acute myeloid leukemia,salvage allogeneic hematopoietic stem cell transplantation, relapsed，refractory

No relevant conflicts of interest to declare.