Successful Engraftment Using Varied Stem Cell Sources, Low Toxicity, and Long-Term Survival Using a Bu/Flu/ATG Reduced Intensity Allogeneic Transplantation in High Risk Pediatric Patients Ineligible for Myelablative Therapy: Results of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study ONC0313.

The role of reduced intensity conditioning (RIC) regimens in pediatric pts is unclear. To define the feasibility and toxicity of a bu/flu/ATG approach in pediatric pts ineligible for myeloablative transplant, we completed a trial at 25 North American and Australian institutions participating in the PBMTC. Forty six pediatric pts (age 2–20yrs, med 11) were enrolled with the following stem cell sources: 8 related donor (RD) BM (2 mismatched); 8 RD-PBSC; 10 unrelated donor (UD) BM; 8 UD-PBSC; 12 UD-CB. Qualifying indications included a previous allogeneic (n=22) or autologous (n=7) transplant, severe organ toxicity (n=8), invasive fungal infection (n=3), and other comorbidities (n= 6 pts, 4 with Down syndrome). Diagnoses included ALL (4 CR2; 11 CR3, 1 secondary), AML (7 CR2; 3 CR3; 3 secondary, 2 PR2+), MLL (1 CR3), CML (1 CR3), HD (3 CR3, 1 PR3), B-NHL (1 PR3), MDS (1 RA; 6 secondary), and JMML (1 PR2, 1 PR3). Patients received busulfan 0.8mg/kg/dose IV x 8 doses (target AUC 900–1100 uM/min), fludarabine 30mg/m²/d x 6 days, and thymoglobulin, 2.5 mg/m²/d x 1 day for RD and x 4 days for UD and UCB. GVHD prophylaxis consisted of cyclosporine (CSP) and mycophenylate mofetil (MMF, 15mg/kg bid). MMF was stopped at day +30 for RD and CB recipients and tapered between d +40–100 for UD recipients. CSP was tapered between d+42–100 for RD and d+100–180 for UD and UCB. Four pts rejected their grafts (9%), one after mismatched RD-BM, two after UD-BM and one after UCB. Two pts died prior to day 100 due to toxicity (4%) and the overall NRM was 11%. Acute GVHD occurred in 9/33 evaluable patients (grade I 9%, grade II 18%, no grade III-IV) and chronic GVHD occurred in 7/28 (25%) evaluable pts. Median follow up is 17 months (range 1–45 m). Two year EFS (events: rejection, relapse, death in remission) is 38% (SE 8) and 2yr OS is 51% (SE 9). No difference in outcome was noted based upon stem cell source, history of previous BMT vs. none, or ALL vs. myeloid disease vs. lymphoma. A trend toward improved survival was noted in “intermediate risk” patients (ALL CR2, AML CR2, and primary MDS without h/o previous BMT: 2yr OS 67 vs. 31%, intermediate vs. high risk, p=0.1). Patients who had undergone transplantation trended toward better survival when their previous myeloablative regimen did not contain TBI (2yr OS 82 vs. 31%, non-TBI vs. TBI, p=0.09). In conclusion, RIC using bu/flu/ATG in a cooperative group setting leads to engraftment in >90% of high risk pediatric pts using related or unrelated BM or PBSC, or unrelated CB. In spite of significant prior therapy, high risk disease, and a high rate of comorbidities in this cohort, the risk of NRM or GVHD is low. Prolonged survival has occurred not only in pts with myeloid disease (2yr OS 43% (SE 12)), but also in pts with ALL (2yr OS 49% (SE 15)), and lymphoma (2yr OS 50% (SE 35)). Flu/bu/ATG is a promising approach for pediatric pts ineligible for myeloablative transplant.