Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial

J Clin Oncol. 2023 Oct 10;41(29):4632-4642. doi: 10.1200/JCO.23.00101. Epub 2023 Jun 19.

Abstract

Purpose: The busulfan plus fludarabine (BuFlu) conditioning regimen has lower transplant-related mortality (TRM) than busulfan plus cyclophosphamide (BuCy) in HLA-matched transplantation. We aimed to compare outcomes of the BuFlu regimen with those of the BuCy regimen in HLA-haploidentical hematopoietic cell transplantation (haplo-HCT).

Methods: We performed an open-label, randomized phase III trial at 12 hospitals in China. Eligible patients with AML (18-65 years) were randomly assigned 1:1 to receive BuFlu (busulfan 0.8 mg/kg four times per day on days -6 to -3; fludarabine 30 mg/m2 once daily on days -7 to -3) or BuCy (same dose of busulfan; cyclophosphamide 60 mg/kg once daily on days -3 and -2). The primary end point was 1-year TRM in the intention-to-treat population and safety in the per-protocol population. This trial is registered with ClinicalTrials.gov (identifier: NCT02487069) and is complete.

Results: From November 20, 2015, to September 30, 2019, 386 patients were randomly assigned to receive the BuFlu (n = 194) or BuCy (n = 192) regimen. The median follow-up was 55.0 (IQR, 46.5-69.0) months after random assignment. The 1-year TRM was 7.2% (95% CI, 4.1 to 11.4) and 14.1% (95% CI, 9.6 to 19.4; hazard ratio [HR], 0.51; 95% CI, 0.27 to 0.97; P = .041), the 5-year relapse was 17.9% (95% CI, 9.6 to 28.3) and 14.2% (95% CI, 9.1 to 20.5; HR, 1.12; 95% CI, 0.65 to 1.95; P = .670), and the 5-year overall survival was 72.5% (95% CI, 62.2 to 80.4) and 68.2% (95% CI, 58.9 to 75.9; HR, 0.84; 95% CI, 0.56 to 1.26; P = .465) in two groups, respectively. Grade 3 regimen-related toxicity (RRT) was reported for 0 of 191 patients following the BuFlu regimen and 9 (4.7%) of 190 patients following the BuCy regimen (P = .002). At least one type of grade 3-5 adverse event was reported for 130 (68.1%) of the 191 patients and 147 (77.4%) of the 190 patients in two groups, respectively (P = .041).

Conclusion: The BuFlu regimen has a lower TRM and RRT and similar relapse for patients with AML undergoing haplo-HCT compared with the BuCy regimen.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Busulfan / therapeutic use
  • Cyclophosphamide
  • Drug Therapy, Combination / adverse effects
  • Graft vs Host Disease* / etiology
  • Hematopoietic Stem Cell Transplantation* / adverse effects
  • Hematopoietic Stem Cell Transplantation* / methods
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Middle Aged
  • Recurrence
  • Transplantation Conditioning / methods
  • Vidarabine
  • Young Adult

Substances

  • Busulfan
  • Cyclophosphamide
  • fludarabine
  • Vidarabine

Associated data

  • ClinicalTrials.gov/NCT02487069