VA Combined with Mbucy Conditioning Regimen Followed By Allo-HSCT Can Improve Survival of High-Risk AML Patients: A Prospective, Single-Center, Single-Arm Clinical Trial

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for high-risk acute myeloid leukemia (AML). And relapse remains a leading cause of death post transplantation due to poor survival for high risk AML patients. Therefore, how to optimal conditioning regimens to reduce the relapse rate and improve overall survival(OS) post transplant are necessary.The combination of venetoclax and azacitidine(VA) disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia.Therefore, we evaluate the safety and efficacy of VA regimen followed by modified BuCy (VA-mBuCy) as conditioning regimen for high-risk AML.

Methods: This prospective, single-center, single-arm clinical trial enrolled patients diagnosed with high-risk AML (reference 2022-AML-ELN guideline) in the First Affiliated Hospital of Soochow University (NCT05823714). All patients received the VA regimen, comprising venetoclax 200mg from day 1 to day 7 and azacytidine 75mg/m2 from day 1 to 7, followed by the mBuCy conditioning regimen(Me-CCNU 250 mg/m2/d on day -10, cytarabine 2 g/m2 every 12 h on days -9 to -8, busulfan 0.8 mg/kg every 6 h on days -7 to -5, and cyclophosphamide 1.8 g/m2/d on days -4 to -3).

Results: From Jan 2022 to Mar 2024, a total of 20 patients were enrolled, with a median age of 47 years (range: 16 to 62 years) at the time of transplantation. All patients achieved morphological complete remission(CR).16 of the 20 patients (80%) did not achieve molecular MRD-negative CR prior to transplantation, including 5 patients with KMT2A rearrangement, 2 patients with TP53 mutations, 2 patients with Mutated NPM1 with FLT3-ITD,1 patient with CBFB-MYH11 transcript,1 patient with NUP98-HOXCB transcript,1 patient with extramedullary disease. The median time for neutropenia and thrombocytopenia recovery were 12(10-15)and 13 (10-36) days. Among the 20 patients, 4 patients developes grade Ⅰ-Ⅱacute graft-versus-host disease (GVHD) and 2 patients developed mild chronic GVHD. There were no cases of veno-occlusive disease and hemorrhagic cystitis. The incidence rates for active CMV and EBV infections were 30% (6 out of 20) and 20% (4 out of 20), respectively. However, bloodstream infections (10 out of the 20 cases) occurred frequently,which responded to antibiotics soon.There were no transplantation-related mortality. The median follow-up time was 16.5 months (3-30 months). One-year overall survival (OS) rate and leukemia-free survival (LFS) rate was 94.4% and 62.6% respectively. Two-year OS rate and LFS rate was 79.3% and 46.4% respectively.

Conclusion: In conclusion, our results suggest that VA-mBuCy conditioning regimen followed by allo-HSCT represented a valid regimen, able to provide better OS of high-risk AML patients, especially with MRD-positive status.