ORIGINAL ARTICLE Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML B Horn 1 , L-A Baxter-Lowe 2 , L Englert 1 , A McMillan 1 , M Quinn 1 , K DeSantes 3 and M Cowan 1 1 Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA; 2 Department of Surgery, University of California San Francisco, San Francisco, CA, USA and 3 Department of Pediatrics, University of Wisconsin, Madison, WI, USA The major problems with busulfan/cyclophosphamide (Bu/Cy)-containing conditioning regimens are acute toxicities and graft failure. To decrease acute toxicities, we have prospectively evaluated a reduced intensity conditioning (RIC) regimen using targeted dosing of i.v. busulfan, fludarabine, and rabbit ATG (Bu/Flu/rATG) in children with diagnoses that historically would have been conditioned with Bu/Cy regimens. Nineteen pediatric patients were enrolled in the study. The donors included HLA-matched and one antigen-mismatched unrelated volunteers (n ¼ 11), unrelated cord blood (n ¼ 1), and related donors (n ¼ 7). Four patients developed graft failure, which occurred between 1 and 8.5 months post transplant. All four of them underwent a second transplantation and 3/4 are alive without evidence of disease. The mean follow-up of living patients is 29.57s.d. 11 months. Despite excellent 2-year post-transplant overall survival (897s.d.7%) and event-free survival (747s.d.10%), the study was closed prematurely due to high graft failure rate (21%). Receiving a transplant from a mismatched unrelated donor was identified as a risk factor for graft failure. The Bu/Flu/rATG RIC regimen was very well tolerated, resulted in excellent overall survival, and provided sustained engraftment in patients undergoing transplant from matched sibling and unrelated donors. However, it did not provide sustained engraftment in the majority of children with nonmalignancies under- going mismatched unrelated donor transplants. Bone Marrow Transplantation (2006) 37, 263–269. doi:10.1038/sj.bmt.1705240; published online 5 December 2005 Keywords: reduced intensity conditioning; children; nonmalignant disorders; rATG Introduction Hematopoietic stem cell transplantation is the treatment of choice for nonmalignant disorders, such as congenital cytopenias, hemoglobinopathies, immune deficiencies, and metabolic disorders, such as Hurler’s syndrome. 1–4 Estab- lishment of normal donor hematopoiesis in these disorders reverses the disease or halts disease progression. However, limitations of transplant include toxicities of conditioning regimens, graft rejection, and GVHD. Although reduced intensity conditioning (RIC) regimens have been studied extensively in adults with a variety of disorders, the reports on their use in children with nonmalignant disorders are scarce. With the goal of avoiding TBI and its deleterious effects on growth and neurocognitive development in young children, in the past, Bu/Cy was used as a back- bone in the conditioning of children with nonmalignant disorders and myeloid malignancies. 1,2,5,6 The main com- plications of Bu/Cy conditioning included toxicities, such as veno-occlusive liver disease (VOD), mucositis, long-term effects on gonads and hair, and failure of engraftment, in particular in an unrelated donor setting. 7–10 In a previous study, we showed that oral busulfan, when targeted to the level 4600 ng/ml, with Cy and horse ATG resulted in engraftment rate of more than 90%; however, with significant hepatic and mucosal toxicity. 11 In an effort to minimize toxicity, we combined targeted intravenous busulfan with a new immunosuppressive antimetabolite (fludarabine) and a more potent anti-thymocyte globulin – rATG (Thymoglobulin, SangStat), and studied it prospec- tively in a pediatric patient population. 12,13 We describe the engraftment rate, chimerism, immune reconstitution, and toxicities of this reduced intensity conditioning regimen when used in children with a variety of nonmalignant disorders, myelodysplastic syndrome (MDS) and CML. Study design Between September 2000 and June 2004, 19 pediatric patients with nonmalignant disorders, CML and MDS, were enrolled in a prospective phase II study conducted at the University of California, San Francisco and University of Wisconsin, Madison. The study was approved by the Committee on Human Research and Cancer Center Received 1 August 2005; revised 3 October 2005; accepted 23 October 2005; published online 5 December 2005 Correspondence: Dr B Horn, Department of Pediatrics, University of California San Francisco, UCSF Medical Center, 505 Parnassus Avenue, M-659, San Francisco, CA 94143-1278, USA. E-mail: hornb@peds.ucsf.edu Bone Marrow Transplantation (2006) 37, 263–269 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt