304: Effect of Substituting Fludarabine and Thymoglobulin for Cyclophosphamide in Busulfan-based Conditioning Regimens on T-cell Chimerism and outcomes after Allogeneic Hematopoietic Cell Transplantation (HCT) (2008)

Substitution of cyclophosphamide by agents such as fludarabine and thymoglobulin in busulfan-based conditioning regimens has been used to reduce complications after allogeneic HCT. We performed a retrospective analysis of outcomes among 348 patients who had HCT since 2001 with the use of 5 myeloablative conditioning regimens: BuCY ± Thymoglobulin, FluBu, or FluBu + Thymoglobulin with different doses of Flu designated Flu[1(120 mg/m2)]BuThy and Flu[2(250 mg/m2)]BuThy. Grafts consisted of unmanipulated bone marrow or growth factor-mobilized blood cells from related or unrelated donors, except for 9 patients who received BuCY and mobilized blood cells from related donors that were 90% depleted of T-cells. Donor chimerism in recipient blood T-cells (CD3) and granulocytes (CD33+) was measured at day 80 after HCT.Patient characteristics in the 5 groups were similar: median age 49, 91% MDS or AML (64% high-risk), 51% unrelated donors, 88% PBSC, 59% HCT-CI ≥1. Donor chimerism of granulocytes was complete by day +80 in all groups, but persistent mixed T-cell chimerism was observed in certain groups. Compared to patients who received BuCY with unmanipulated allografts, the incidence of mixed chimerism with >50% recipient T-cells was higher among patients who received Flu, bone marrow grafts or T-cell depleted grafts (e.g., Flu[1]BuThy: OR 14.5, p < 0.0001). Most patients with mixed chimerism at day 80 had full donor T-cell chimerism at 1 yr after HCT, but some patients with malignancy in complete remission at 3 yr continue to have persistent mixed T-cell chimerism.Compared to BuCY controls, improved outcomes with reduced regimen-related toxicity were observed in the 22 patients who received Flu[1]BuThy. After adjustment for age, disease risk, donor type, HCT-CI and prior CMV infection in the recipient, the Flu[1]BuThy group had significantly lower rates of acute GvHD (HR 0.50, p = 0.02), chronic GvHD (HR 0.31, p = 0.003) and NRM (HR 0.25, p = 0.05), although relapse was not significantly increased (HR 1.13, p = 0.87) and overall survival was not significantly improved (HR = 0.60, p = 0.19). In contrast, NRM and survival in the Flu[2]BuThy and BuCY groups showed no statistically significant differences. In general, addition of thymoglobulin for GvHD prophylaxis significantly reduced the incidence of chronic GvHD. A prospective, randomized trial is needed to determine whether superior outcomes can be achieved after conditioning with Flu[1]BuThy as compared with BuCy. Substitution of cyclophosphamide by agents such as fludarabine and thymoglobulin in busulfan-based conditioning regimens has been used to reduce complications after allogeneic HCT. We performed a retrospective analysis of outcomes among 348 patients who had HCT since 2001 with the use of 5 myeloablative conditioning regimens: BuCY ± Thymoglobulin, FluBu, or FluBu + Thymoglobulin with different doses of Flu designated Flu[1(120 mg/m2)]BuThy and Flu[2(250 mg/m2)]BuThy. Grafts consisted of unmanipulated bone marrow or growth factor-mobilized blood cells from related or unrelated donors, except for 9 patients who received BuCY and mobilized blood cells from related donors that were 90% depleted of T-cells. Donor chimerism in recipient blood T-cells (CD3) and granulocytes (CD33+) was measured at day 80 after HCT. Patient characteristics in the 5 groups were similar: median age 49, 91% MDS or AML (64% high-risk), 51% unrelated donors, 88% PBSC, 59% HCT-CI ≥1. Donor chimerism of granulocytes was complete by day +80 in all groups, but persistent mixed T-cell chimerism was observed in certain groups. Compared to patients who received BuCY with unmanipulated allografts, the incidence of mixed chimerism with >50% recipient T-cells was higher among patients who received Flu, bone marrow grafts or T-cell depleted grafts (e.g., Flu[1]BuThy: OR 14.5, p < 0.0001). Most patients with mixed chimerism at day 80 had full donor T-cell chimerism at 1 yr after HCT, but some patients with malignancy in complete remission at 3 yr continue to have persistent mixed T-cell chimerism. Compared to BuCY controls, improved outcomes with reduced regimen-related toxicity were observed in the 22 patients who received Flu[1]BuThy. After adjustment for age, disease risk, donor type, HCT-CI and prior CMV infection in the recipient, the Flu[1]BuThy group had significantly lower rates of acute GvHD (HR 0.50, p = 0.02), chronic GvHD (HR 0.31, p = 0.003) and NRM (HR 0.25, p = 0.05), although relapse was not significantly increased (HR 1.13, p = 0.87) and overall survival was not significantly improved (HR = 0.60, p = 0.19). In contrast, NRM and survival in the Flu[2]BuThy and BuCY groups showed no statistically significant differences. In general, addition of thymoglobulin for GvHD prophylaxis significantly reduced the incidence of chronic GvHD. A prospective, randomized trial is needed to determine whether superior outcomes can be achieved after conditioning with Flu[1]BuThy as compared with BuCy.