Examining Conditioning Regimens with Busulfan plus Fludarabine or Cyclophosphamide in Older AML Patients

Myeloablative conditioning regimens that contain busulfan plus cyclophosphamide are associated with substantial non-relapse mortality in patients with acute myeloid leukemia (AML) who are undergoing allogeneic hematopoietic cell transplantation (alloHCT). While combining busulfan with fludarabine has been proposed as an alternative preparative regimen to reduce non-relapse mortality in these patients, the two combinations have not been compared head-to-head.

A recent open-label, multicenter, randomized, phase III trial conducted by Alessandro Rambaldi, MD, from the Hematology and Bone Marrow Transplant Unit at Azienda Ospedaliera Papa Giovanni XXIII in Bergamo, Italy, and colleagues compared the safety and efficacy of busulfan + cyclophosphamide to busulfan + fludarabine in patients 40 to 65 years old with AML who had an Eastern Cooperative Oncology Group performance status of less than 3 and were in complete remission (CR).

Patients included in the study were treated at 25 hospital transplant centers in Italy and one center in Israel between January 3, 2008, and December 20, 2012. A total of 252 patients were randomized 1:1 to receive alloHCT conditioning regimens containing:

  • Two-hour intravenous (IV) infusions of busulfan 0.8 mg/kg four times per day for four consecutive days plus cyclophosphamide 60 mg/kg per day for two consecutive days (n=125)
  • Two-hour IV infusions of busulfan 0.8 mg/kg four times per day for four consecutive days plus fludarabine 40 mg/m2 per day for four consecutive days (n=127)

Randomization was conducted via a dedicated Web-based system using remote data entry, with patients stratified by donor type and CR status.

Patients were followed for a median of 27.5 months. Non-relapse mortality at one year (the study’s primary endpoint, assessed on an intention-to-treat basis) was more than doubled in the busulfan + cyclophosphamide group compared with the busulfan + fludarabine group: 17.2 percent (95% CI 11.6-25.4) vs. 7.9 percent (4.3-14.3; p=0.026).

Safety outcomes, assessed in the per-protocol population, were similar but lower in the patients treated with fludarabine between both groups. The most frequently reported grade ≥3 treatment-related adverse events included:

  • Gastrointestinal events
    • 28 patients (23%) in the busulfan + cyclophosphamide group
    • 26 patients (21%) in the busulfan + fludarabine group
  • Infections
    • 21 patients (17%) in the busulfan + cyclophosphamide group
    • 13 patients (10%) in the busulfan + fludarabine group

“The reduction of transplant toxicity is important, but leukemia relapse after transplantation remains an unmet clinical need for AML patients,” Dr. Rambaldi told ASH Clinical News. “The mortality and the overall toxicity associated with the transplant procedure have been reduced thanks to a better tolerated but still myeloablative, chemotherapy-based conditioning program. This is why this result did not come at the cost of a significantly increased incidence of relapse, as is usually the case when reduced-intensity or immunosuppressive conditioning regimens are employed.”

“In older patients with AML, the myeloablative busulfan + fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan + cyclophosphamide, but retains potent anti-leukemic activity,” Dr. Rambaldi and colleagues concluded. “Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients.”

Future studies, they noted, should be focused on innovative post-engraftment treatments based either on drugs or donor cells. “These post-transplant treatments should be planned as an integral part of the allogeneic hematopoietic cell transplantation platform, and appropriately designed clinical trials to address these new approaches are needed.”


Rambaldi A, Grassi A, Masciulli A, et al. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015;16:1525-36.