Busulfan Plus Cyclophosphamide Versus Total Body Irradiation Plus Cyclophosphamide for Adults Acute B Lymphoblastic Leukemia: An Open-Label, Multicenter, Phase III Trial

Haiyan Zhang, Zhiping Fan, Fen Huang, Lijie Han, Yajing Xu, Na Xu, Lan Deng, Shunqing Wang, Dongjun Lin, Xiaodan Luo, Qing Zhang, Xiaodan Liu, Xudong Li, Xinquan Liang, Shuangfeng Xie, Hong Qu, Sijian Yu, Hongsheng Zhou, Pengcheng Shi, Li Xuan, Ren Lin, Hui Liu, Hua Jin, Jing Sun, Qifa Liu, Haiyan Zhang, Zhiping Fan, Fen Huang, Lijie Han, Yajing Xu, Na Xu, Lan Deng, Shunqing Wang, Dongjun Lin, Xiaodan Luo, Qing Zhang, Xiaodan Liu, Xudong Li, Xinquan Liang, Shuangfeng Xie, Hong Qu, Sijian Yu, Hongsheng Zhou, Pengcheng Shi, Li Xuan, Ren Lin, Hui Liu, Hua Jin, Jing Sun, Qifa Liu

Abstract

Purpose: It remains controversial whether busulfan-based versus total body irradiation (TBI)-based regimens have comparable outcomes in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). We investigated the efficacy and toxicity of busulfan plus cyclophosphamide (BuCy) and TBI plus cyclophosphamide (TBI-Cy) conditioning in allo-HSCT for adult standard-risk B-cell-ALL in first complete remission (CR1).

Patients and methods: We performed an open-label, randomized phase III trial at 13 hospitals in China. Eligible patients (age 14-65 years) had standard-risk ALL in CR1. Patients were randomly assigned (1:1) to BuCy (0.8 mg/kg four times per day on days -7 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2) or TBI-Cy (4.5 Gy TBI on days -5 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2). The primary end point was 2-year overall survival. Analysis was per protocol. This trial is registered with ClinicalTrials.gov (identifier: NCT02670252) and is complete.

Results: Between January 2016 and February 2020, 275 patients were assigned to receive BuCy (273 assessed) and 275 to TBI-Cy (272 assessed). The 2-year overall survival was 76.6% (95% CI, 71.7 to 81.8) and 79.4% (74.7 to 84.4; P = .457; difference 2.9%; 95% CI, -4.1 to 9.8; P = .022), indicating noninferiority of BuCy. The 2-year relapse was 20.2% (95% CI, 15.6 to 25.1) and 18.4% (14.0 to 23.2; P = .616), and the nonrelapse mortality was 11.0% (95% CI, 7.6 to 15.0) and 11.0% (7.7 to 15.1; P = .988) in the BuCy and TBI-Cy groups, respectively. There were no differences in regimen-related toxicity, graft-versus-host disease, or late effects between the two groups.

Conclusion: The BuCy regimen has noninferior efficiency and safety as TBI-Cy (4.5 Gy × 2) for patients with adult standard-risk B cell-ALL in CR1 undergoing HLA-matched allo-HSCT.

Figures

FIG 1.
FIG 1.
CONSORT diagram. B-ALL, B-cell acute lymphoblastic leukemia; BuCy, busulfan plus cyclophosphamide; TBI-Cy, total body irradiation plus cyclophosphamide.
FIG 2.
FIG 2.
Outcomes of allogeneic-hematopoietic stem-cell transplantation with BuCy or TBI-Cy conditioning regimens: (A) survival by conditioning regimens, (B) cumulative incidence of disease relapse by conditioning regimens, (C) DFS by conditioning regimens, and (D) cumulative incidence of NRM by conditioning regimens. BuCy, busulfan plus cyclophosphamide; DFS, disease-free survival; NRM, nonrelapse mortality; OS, overall survival; TBI-Cy, total body irradiation plus cyclophosphamide.
FIG 3.
FIG 3.
Subgroup analysis of overall survival in patients receiving BuCy or TBI-Cy. BuCy, busulfan plus cyclophosphamide; CR, complete remission; HR, hazard ratio; HSCT, hematopoietic stem-cell transplantation; MRD, minimal residual disease; MSD, matched sibling donor; MUD, matched unrelated donor; OS, overall survival; TBI-Cy, total body irradiation plus cyclophosphamide.
FIG A1.
FIG A1.
Postrelapse OS according to conditioning regimens. BuCy, busulfan plus cyclophosphamide; OS, overall survival; TBI-Cy, total body irradiation plus cyclophosphamide.
FIG A2.
FIG A2.
Graft-versus-host disease incidence of allogeneic-hematopoietic stem-cell transplantation with BuCy or TBI-Cy conditioning regimens. Cumulative incidence of (A) II-IV aGVHD, (B) III-IV aGVHD, (C) cGVHD, and (D) severe cGVHD by conditioning regimens. aGVHD, acute graft-versus-host disease; BuCy, busulfan plus cyclophosphamide; cGVHD, chronic graft-versus-host disease; TBI-Cy, total body irradiation plus cyclophosphamide.

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