Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS

Borje S Andersson, Marcos de Lima, Peter F Thall, Xuemei Wang, Daniel Couriel, Martin Korbling, Soonja Roberson, Sergio Giralt, Betty Pierre, James A Russell, Elizabeth J Shpall, Roy B Jones, Richard E Champlin, Borje S Andersson, Marcos de Lima, Peter F Thall, Xuemei Wang, Daniel Couriel, Martin Korbling, Soonja Roberson, Sergio Giralt, Betty Pierre, James A Russell, Elizabeth J Shpall, Roy B Jones, Richard E Champlin

Abstract

We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with i.v. busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. Sixty-seven patients received BuCy2, and subsequently, 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these nonrandomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 versus 39 years, P < .01), more often had unrelated donors (47.3% versus 20.9%, P < .0003), and had shorter median follow-up (39.7 versus 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome ("period" effects), 78 acute myelogenous leukemia (AML) patients receiving Melphalan-Flu (MF), treated in parallel during this time (1997-2004) were used to estimate the period effect. The MF patients' outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in the first complete remission (CR1) had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, whereas CR1 patients younger than age 41 had a 3-year EFS of 83%. These results support replacing BuCy +/- ATG with Bu-Flu +/- rabbit-antithymocyte globulin (ATG), and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1.

Figures

Figure 1
Figure 1
Kaplan-Meier Estimates for the probabilities of (a) Overall Survival, and (b) Event-Free Survival by treatment Group in 215 patients treated with BuCy2 (----) and Bu-Flu (––) (the numbers within parenthesis indicate number of events and cohort size).
Figure 1
Figure 1
Kaplan-Meier Estimates for the probabilities of (a) Overall Survival, and (b) Event-Free Survival by treatment Group in 215 patients treated with BuCy2 (----) and Bu-Flu (––) (the numbers within parenthesis indicate number of events and cohort size).
Figure 2
Figure 2
Kaplan-Meier Estimates for the probabilities of (a) Non-Relapse Related Survival, and (b) Relapse-Free Survival, by treatment Group in 215 patients treated with BuCy2 (----) and Bu-Flu (––) (the numbers within parenthesis indicate number of events and cohort size).
Figure 2
Figure 2
Kaplan-Meier Estimates for the probabilities of (a) Non-Relapse Related Survival, and (b) Relapse-Free Survival, by treatment Group in 215 patients treated with BuCy2 (----) and Bu-Flu (––) (the numbers within parenthesis indicate number of events and cohort size).
Figure 3
Figure 3
Survival of patients transplanted in CR1, “early disease” with BuCy2 (----) and Bu-Flu (––); (a) Overall Survival, and (b) Event-Free Survival in all CR1 patients. In graphs (c) Overall Survival, and (d) Event-Free Survival is depicted for patients up to and including 40 years of age (the numbers within parenthesis indicate number of events and cohort size).
Figure 4
Figure 4
Posterior distribution under the lognormal regression model for (a) Overall Survival, and (b) Event-Free Survival of the corrected Bu-Flu vs. BuCy2 treatment effect. In these plots, p denotes the probability of a beneficial effect of Bu-Flu versus Bu Cy2, and is represented by the area of the shaded region in the respective figure.
Figure 4
Figure 4
Posterior distribution under the lognormal regression model for (a) Overall Survival, and (b) Event-Free Survival of the corrected Bu-Flu vs. BuCy2 treatment effect. In these plots, p denotes the probability of a beneficial effect of Bu-Flu versus Bu Cy2, and is represented by the area of the shaded region in the respective figure.
Figure 5
Figure 5
Posterior distributions under the lognormal regression model for (a) Non-Relapse Related Survival, and (b) Relapse-Free Survival of the corrected Bu-Flu vs. BuCy2 treatment effect within the 215 Bu-treated patients. In the plot, p denotes the probability of beneficial effect of Bu-Flu versus BuCy2, and is represented by the area of the shaded region in the respective figure.
Figure 5
Figure 5
Posterior distributions under the lognormal regression model for (a) Non-Relapse Related Survival, and (b) Relapse-Free Survival of the corrected Bu-Flu vs. BuCy2 treatment effect within the 215 Bu-treated patients. In the plot, p denotes the probability of beneficial effect of Bu-Flu versus BuCy2, and is represented by the area of the shaded region in the respective figure.

Source: PubMed

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