The Addition of Fludarabine to a Conventional Busulfan/Melphalan/Anti-Thymocyte Globulin (Flu/Bu/Mel/ATG) Preparative Regimen Increased Engraftment without Additional Toxicity.
Busulfan/Melphalan/ATG (Bu/Mel/ATG) have been used as a preparative regimen in children undergoing hematopoetic stem cell transplantation who are too young for or who cannot tolerate total body irradiation (TBI). While successful in a portion of patients, engraftment rates were lower than those seen in a similar patient population receiving a TBI-containing preparative regimen (Wall et al, Biol Blood Marrow Transplant.2005; 11: 637–646). We hypothesized that the addition of fludarabine, a known immunosuppressive agent used in reduced intensity transplants, to this regimen would increase engraftment without additive toxicity. Fourteen pediatric patients with hematological malignancies (acute myeloid leukemia in remission (n=5); acute myeloid leukemia in relapse (n=3), acute lymphoblastic leukemia, infant type in second remission, n=2; juvenile myelomonocytic leukemia, n=1; myelodysplastic syndrome, n=1; biphenotypic leukemia, in first remission, n=1) and non-malignant conditions (infantile myelofibrosis, n=1) were prepared with intravenous fludarabine 25mg/m2 daily × 5days from day-13 to -9, intravenous targeted busulfan 1mg/kg daily × 4 days from day-8 to -5, intravenous melphalan 45mg/m2 daily × 3 days from day-4 to -2 and intravenous equine anti-thymocyte globulin 30mg/kg daily × 3 days from day-3 to -1. Thirteen patients received unrelated donor cord blood cells and one patient received matched related marrow cells. There were 8 male, 8 Caucasian and 4 CMV seropositive patients. The median age was 1.9 years (range 7 months to 21 years). The median pre-cryopreserved total nucleated cell dose per kg for the unrelated cord blood transplant patients was 11.5 × 107/kg (range, 3.4–32.5) while the median post-thaw total nucleated cell dose per kg was 7.3 × 107/kg (range, 2.5–27.6). The median infused CD34 cells/kg was 0.2 × 105/kg (range, 0.1–0.5) and the median CD3 cells/kg was 19.6 × 106 × kg (range, 6.9–31.0). Nine patients received 4/6 HLA-matched cord blood cells, 3 received 5/6 and 2 patients received 6/6 matched grafts. The addition of fludarabine did not increase or result in any unexpected toxicity. The cumulative incidence (CINC) and median time to neutrophil and platelet engraftment, acute graft versus host disease and overall survival are shown in the table below. These data were compared to a previous published study. Engraftment of neutrophils was superior in the fludarabine/Busulfan/Melphalan/ATG group. Overall survival also improved. While these data of patients are small, these results suggest that the addition of fludarabine to a Busulfan/Melphalan/ATG regimen is safe and may facilitate engraftment with improved survival.
Comparison of outcome between Bu/Mel/ATG and Flu/Bu/Mel/ATG CINC of neutrophil engraftment at day 42 CINC of platelet engraftment 50K at day 100 CINC of GrII-IV aGVHD at 100days Overall survival at 12 months Relapse-free survival at 12 months Bu/Mel/ATG 59% (95%CI,44%–78%) 40% (95%CI,31%–69%) 41% (95%CI,25%–56%) 47% (95%CI,30%–64%) 34.4% (95%CI,18.8%–50.6%) Flu/Bu/Mel/ATG 71.4% (95%CI,46%–96.8%) 41.5% (95%CI,10.6%–72.5%) 42.9% (95%CI,29%–56.7%) 55% (95%CI, 24.6%–85.1%) 43.9% (95%CI,13%–74.8%)
Lakshminarayanan, S; Mendizabal, A; Prasad, V; Parikh, S; Szabolcs, P; Driscoll, T; Schweitzer, M; Kassmann, B; Paden, M; Robinette, D; Martin, PL; Kurtzberg, J
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