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

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.

Reply to M. Shibusawa et al

“…Shibusawa et al 1 expressed interest in our work 2 and provided helpful comments about whether mean fluorescence intensity (MFI) and proportion of CD20 on leukemic cells at the baseline were well balanced between the two groups in the current study. 2 However, the information on MFI of CD20 was not routinely provided in our reports, and the characteristics of MFI and proportion of CD20 on leukemic cells were not taken into account when the patients were enrolled in this study.…”

PASS‐ALL study of paediatric‐inspired versus adult chemotherapy regimens on survival of high‐risk Philadelphia‐negative B‐cell acute lymphoblastic leukaemia with allogeneic haematopoietic stem cell transplantation

“…Donor selection was based on patients' biological characteristics and patients or guardians consent 18 . Conditioning regimens consist of BuCy (busulphan and cyclophosphamide) and TBI/Cy (total body irradiation, cyclophosphamide) as previously reported 19 . Generally, TBI/Cy regimen was performed in the patients with MRD‐positive or CNSL pretransplantation.…”

“…18 Conditioning regimens consist of BuCy (busulphan and cyclophosphamide) and TBI/Cy (total body irradiation, cyclophosphamide) as previously reported. 19 Generally, TBI/Cy regimen was performed in the patients with MRD-positive or CNSL pretransplantation. For the patients with MSD donor, the conditioning regimens were performed according to the clinical trial (NCT02670252).…”

Conditioning Regimen in Patients With Adult Acute B Lymphoblastic Leukemia

“…2 Thus, we are concerned whether MFI and proportion of CD20 on leukemic cells at the baseline were well balanced between the two groups in the current study. We would be grateful if the authors 1 could provide details on these matters.…”

“…Zhang et al 1 conducted a randomized trial among adult patients with acute B lymphoblastic leukemia (B-ALL) comparing busulfan plus cyclophosphamide regimen versus total body irradiation plus cyclophosphamide regimen. The authors 1 observed that the busulfan plus cyclophosphamide regimen had noninferior survival to total body irradiation plus cyclophosphamide regimen. However, it should be noted that mean fluorescence intensity (MFI) and proportion of CD20 at the baseline have a prognostic impact among B-ALL.…”