Safety and Efficacy of VA Combined with Modified BuCy Conditioning Regimen Followed By Allo-HSCT for High-Risk or Refractory/Relapsed Acute Lymphoblastic Leukemia : A Prospective, Single-Center, Single-Arm Clinical Trial
Authors: Chen Xiaoqian , Cui Wei , Cui Qingya , Li Zheng , Chen Sifan , Li Mengyun , Li Xuekai , Chen Juan , Yu Yan , Zhang Xin , Wu Depei , Tang Xiaowen 
Published: December 2024

Background : Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for high-risk or refractory/relapsed (r/r) acute lymphoblastic leukemia (ALL). However, relapse remains a leading cause of death post allo-HSCT, with a cumulative incidence of relapse (CIR) of approximately 30%-50%. Therefore, prevention of relapse is of great importance to improve the outcome of allo-HSCT in high-risk ALL patients. Intensive myeloablative conditioning is a primary therapeutic option that can maximize the reduction of the residual leukemia burden in order to reduce disease recurrence post transplantation. Venetoclax combined with azacytidine (the VA regimen) has demonstrated synergistic anti-tumor activity against several hematological malignancies, particularly newly diagnosed and high-risk ALL (data unpublished). Furthermore, the VA regimen can disrupt energy metabolism and eliminate leukemia stem cells. Therefore, we aim to evaluate the safety and efficacy of the VA regimen combined with modified BuCy for high-risk or r/r ALL patients undergoing allo-HSCT.
Method : From Dec 2021 to Apr 2024, 20 patients diagnosed with high-risk or r/r ALL were enrolled. All patients received 7-day courses of venetoclax (200mg/d on days -17 to -11) and 7-day courses of azacytidine (75mg/m2/d on days -17 to -11) combined with mBuCy conditioning regimen consisting of 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. For matched sibling and unrelated donors, cytarabine was given at a dose of 2 g/m2 /d on day -9. Rabbit antithymocyte globulin was given at 2.5mg/kg/d on days -5 to -2 except for matched sibling donors.
Results : As of April 2024, 20 patients, with a median age of 30.5 years (ranging from 12 to 56 years)，were enrolled in this study. High risk cytogenetic or molecular factors were detected in 100% patients, such as KMT2A rearrangement, Ph-like ALL, hypodiploidy and testicular leukemia. ALL patients achieved morphological complete remission prior to transplantation, with 19 (95%) patients maintaining minimal residual disease (MRD)-negative remission. The majority (85%) received transplantation from haploidentical donors. Hematopoietic recovery was achieved for all patients, with a median time to absolute neutrophil counts (ANC) engraftment of 12 days (range: 9-13 days) and platelet (PLT) engraftment of 17 days (range: 8-30 days). During a median follow-up period of 14.5 months (range: 2.6-31.1 months), 1 patient experienced relapse at 9 months after transplantation, while another patient died from severe sepsis on day 222 post-transplantation. Overall survival (OS) at 1 year was 94.1% (95% CI, 83.6-100%). Leukemia-free survival (LFS) at 1 year was 87.8% (95% CI, 73.4-100%). The CIR at 1 year was 6.7% (95% CI, 6.7-61.6%). The non-relapse mortality (NRM) at 1 year was 5.9% (95% CI, 0-17.4%). Grade I-II acute graft-versus-host disease (aGVHD) occurred in 30% of patients, with no case of grade III-IV aGVHD. Mild chronic graft-versus-host disease (cGVHD) was observed in 3 patients. The most common non-hematologic adverse events (AEs) were grade I-II gastrointestinal issues, with diarrhea affecting 45% and nausea affecting 30% of patients. No higher-grade AEs or hepatic veno-occlusive disease (VOD) were noted. By the end of the follow-up period, the incidences of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) activation were 25% (5 out of 20) and 40% (8 out of 20), respectively.
Conclusion : Our study suggests that the VA regimen combined with modified BuCy shows good tolerability, significantly decreases the relapse rate, and prolongs long-term survival in high-risk or refractory/relapsed ALL patients.