Although allogeneic hematopoietic progenitor cell transplantation (HPCT) can be curative for sickle cell anemia (SCA), most patients lack an HLA matched sibling donor or matched unrelated donor. A 2002 multidisciplinary conference held at St. Jude Children’s Research Hospital reached consensus that pilot studies using parental donors were reasonable and ethical. Subsequently, eight children with a history of clinically overt stroke were transplanted on two sequential pilot studies. Peripheral blood progenitor cells were obtained from parents with sickle cell trait. Conditioning was i.v. busulfan (targeted to Css 900 ng/ml) q 6 hours x 4 days, fludarabine 150–200 mg/m2, and OKT3/methylprednisolone and infusion of CD34+ HPCT for 3 patients. Five patients received i.v. busulfan (targeted to Css 900 ng/ml) x 4 days, cyclophosphamide 200 mg/kg, thiotepa 10 mg/kg, OKT3/methylprednisolone, and infusion of both CD34+ cells and CD3+ cells with a fixed T-cell addback of 1.0–1.5 x 105 CD3+ cells/kg. Six children received pre-transplant immunosuppression with hydroxyurea and azathioprine. The median follow-up of eight patients is 1.4 years (range 2 months–4 years). Five of eight had durable donor engraftment,4 of whom are alive and free of SCA post-HPCT. Rejection occurred in 4 patients and was successfully reversed with additional CD34+ cells in one of three patients. GVHD occurred in patients receiving a fixed T-cell addback or DLI: two patients had grade II acute graft-versus-host disease (aGVHD), one grade III aGVHD, and three patients developed chronic GVHD, including a fatal case of bronchiolitis obliterans organizing pneumonia (BOOP) and fungal sepsis. One engrafted patient developed medulloblastoma 2 years post-HPCT and is in remission after treatment. Further investigation revealed that this child inherited a novel germline p53 mutation. In this preliminary experience, haploidentical HPCT for children with SCA and stroke was associated with significant graft rejection and chronic GVHD. The addition of pre-transplant hydroxyurea and azathioprine, increased intensity of conditioning, and the use of T-cell addback to the graft did not improve engraftment in the second cohort. While offering the possibility of cure, haploidentical HPCT for SCA as performed in this experience is associated with significant toxicity and should only be pursued in the context of a rigorously designed and controlled prospective clinical trial.

Disclosure:Employment: Paul Woodard, MD is now an employee of PDL Biopharma, Inc. Research Funding: Gregory Hale has received research funding from PDL Biopharma, Inc. Membership Information: Gregory Hale is part of the Speakers Bureau of PDL Biopharma, Inc. Off Label Use: This presentation includes information on the off-label use of i.v. busulfan (Busulfex).