Better Leukemia-Free and Overall Survival in AML in First Remission With Cyclophosphamide Plus Busulfan vs Total-Body Irradiation
Myeloablative conditioning with cyclophosphamide combined with intravenous busulfan (Busulfex) was associated with better leukemia-free and overall survival than conditioning with cyclosphosphamide and total-body irradiation in patients with acute myeloid leukemia (AML) who were in first complete remission after receiving a first hematopoietic cell transplant from a human-leukocyte antigen–matched sibling or unrelated donor. The results were reported in Blood.
Cyclophosphamide combined with either total-body irradiation or busulfan “are the most widely used myeloablative conditioning regimens for allotransplants,” but comparisons of the effectiveness of the regimens have been lacking, noted the international team of researchers, led by Edward A. Copelan, MD, of Levine Cancer Institute in Charlotte, North Carolina.
The authors also noted that in studies using oral busulfan, fixed doses are associated with substantial individual variation in plasma levels, with low levels associated with relapse and rejection and high levels with hepatic veno-occlusive disease and other toxicities. Intravenous busulfan has been reported to decrease toxicities and mortality. “Thus, while molecular HLA-typing and better supportive care have improved survival generally after [hematopoietic cell transplant], improvements in its administration might differentially improve results using [busulfan].”
For this study, the patient population consisted of all patients reported to the Center for International Blood and Marrow Transplant Research, a working group of more than 500 transplant centers worldwide, who had a first allogeneic hematopoietic cell transplant with an HLA-identical sibling or unmatched related donor between 2000 and 2006 and received conditioning with cyclophosphamide and total-body irradiation (nonfractionated dose ≥ 5.5 Gy, fractionated dose ≥ 9 Gy) or with cyclophosphamide and busulfan ( ≥ 9 mg/kg) without additional chemotherapeutic agents.
‘Remarkably Low’ Rates of Nonrelapse Mortality With Busulfan
Multivariate analysis of data from 1,230 patients found significantly lower nonrelapse mortality among patients receiving intravenous busulfan (relative risk = 0.58; 95% confidence interval [CI] = 0.39–0.86; P = .0066) compared to total-body irradiation. “The incidence of relapse within the first year following transplant did not differ among the groups; however, relapse beyond the first year occurred significantly less frequently in those receiving [intravenous], but not oral, busulfan compared to [total-body irradiation] ([relative risk] = 0.23; 95% CI = 0.08–0.65; P = .006),” the authors reported. Leukemia-free survival and overall survival were significantly higher in patients receiving intravenous busulfan than those receiving total-body irradiation.
The rates of nonrelapse mortality with busulfan in this study “are remarkably low,” the authors noted. Overall and leukemia-free survival “also clearly favor the use of [busulfan], as do ease of administration and previous evidence of a lower incidence of some delayed complications, including cataracts, impaired growth and some second malignancies, compared to [total-body irradiation].”
In the absence of a prospective randomized comparison of cyclophosphamide with either total-body irradiation or busulfan using contemporary administration, dosing, and supportive care, the authors concluded that intravenous busulfan should be used in preference to total-body irradiation in patients with AML in first complete response undergoing hematopoietic cell transplant from matched related or matched unrelated donors.
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