Reduced Nonrelapse Mortality With Busulfan/Fludarabine vs Busulfan/Cyclophosphamide for Stem Cell Transplantation in Acute Myeloid Leukemia
In a phase III trial reported in The Lancet Oncology, Rambaldi et al found that a myeloablative conditioning regimen of busulfan/fludarabine was associated with reduced nonrelapse mortality vs busulfan/cyclophosphamide in patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation.
Study Details
In this open-label trial, 252 patients aged 40 to 65 years in complete remission from 25 transplant centers in Italy and 1 in Israel were randomly assigned between January 2008 and December 2012 to receive busulfan plus fludarabine (n = 127) or busulfan plus cyclophosphamide (n = 125). Treatment consisted of intravenous busulfan at 0.8 mg/kg four times per day in 2-hour infusions for 4 consecutive days (days –6 through –3; total dose 12.8 mg/kg) plus fludarabine at 40 mg/m² per day for 4 consecutive days (days –6 through –3; total dose 160 mg/m²) vs the same dose of busulfan (days –9 through –6) plus cyclophosphamide at 60 mg/kg/d for 2 consecutive days (days –4 and –3; total dose 120 mg/kg). The primary endpoint was 1-year nonrelapse mortality assessed on an intention-to-treat basis.
The two groups were balanced for baseline characteristics. Donors were related for 46% of the busulfan/fludarabine group and 45% of the busulfan/cyclophosphamide group. The busulfan/fludarabine group had a lower proportion of patients with an Hematopoietic Cell Transplantation–Specific Comorbidity Index value of 1 to 2 (21% vs 335) and a greater proportion with a value of ≥ 3 (22% vs 11%).
Nonrelapse Mortality
Median follow-up was 27.5 months. One-year nonrelapse mortality was 7.9% (95% confidence interval [CI] = 4.3%–14.3%) in the busulfan/fludarabine group vs 17.2% (95% CI = 11.6%–25.4%) in the busulfan/cyclophosphamide group (P = .026). Two-year nonrelapse mortality was 9.5% vs 18.0% (P = .047). The cumulative incidence of relapse was 25.2% vs 22.1% at 1 year (P = .47) and 31.6% vs 29.6% at 2 years (P = .70).
Adverse Events
Grade ≥ 3 adverse events occurred in 37% of patients in the busulfan/fludarabine group vs 51% in the busulfan/cyclophosphamide group. The most frequently reported grade ≥ 3 adverse events were gastrointestinal events (21% vs 23%) and infections (10% vs 17%).
The investigators concluded: “In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients.”
The study was funded by Agenzia Italiana del Farmaco.
Alessandro Rambaldi, MD, of Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy, is the corresponding author of The Lancet Oncology article.
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