title: Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia.
abstract: We describe previously transfused patients with sickle cell disease (n = 6) and thalassemia (n = 1) who received nonmyeloablative hematopoietic stem cell transplantation (HCT) to induce stable (full or partial) donor engraftment. Patients were 3 to 20 years (median, 9 years) old. All 7 received pretransplantation fludarabine and 200 cGy of total body irradiation; 2 patients also received horse antithymocyte globulin. Patients received bone marrow (n = 6) or peripheral blood stem cells (n = 1) from HLA-identical siblings, followed by a combination of mycophenolate mofetil and cyclosporine or tacrolimus for postgrafting immunosuppression. After nonmyeloablative HCT, absolute neutrophil counts were <0.5 x 10(9)/L and <0.2 x 10(9)/L for a median of 5 days (range, 0-13 days) and 0 days (range 0-13 days), respectively. A median of 0 (range, 0-9) platelet transfusions were administered. No grade IV nonhematologic toxicities were observed. One patient experienced grade II acute graft-versus-host disease. Two months after transplantation, 6 of 7 patients had evidence of donor chimerism (range, 25%-85%). Independent of red blood cell transfusions, these 6 patients initially had increased total hemoglobin and hemoglobin A concentrations and a reduction of reticulocytosis and transfusion requirements. There were no complications attributable to sickle cell disease during the interval of transient mixed chimerism. However, after posttransplantation immunosuppression was tapered, there was loss of the donor graft, and all patients experienced autologous hematopoietic recovery and disease recurrence. One patient did not engraft. The duration of transient mixed chimerism ranged from 97 to 441 days after transplantation in patients 4 and 6, respectively, and persisted until immunosuppressive drugs were discontinued after transplantation. In summary, the nonmyeloablative HCT regimens described here produced minimal toxicity and resulted in transient donor engraftment in 6 of 7 patients with hemoglobinopathies. Although complications from the underlying hemoglobinopathies did not occur during the period of mixed chimerism, these results suggest that stable (full or partial) donor engraftment after nonmyeloablative HCT is more difficult to achieve among immunocompetent pediatric patients with hemoglobinopathies than among adults with hematologic malignancies, perhaps in part because recipients may have been sensitized to minor histocompatibility antigens of their donor by preceding blood transfusions.
authors.affiliation: Department of Pediatrics, Johns Hopkins Hospital and Oncology Center, Baltimore, Maryland, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Iannone
authors.forename: James F
authors.initials: JF
authors.lastname: Casella
authors.forename: Ephraim J
authors.initials: EJ
authors.lastname: Fuchs
authors.forename: Allen R
authors.initials: AR
authors.lastname: Chen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Ann
authors.initials: A
authors.lastname: Woolfrey
authors.forename: Michael
authors.initials: M
authors.lastname: Amylon
authors.forename: Keith M
authors.initials: KM
authors.lastname: Sullivan
authors.forename: Rainer F
authors.initials: RF
authors.lastname: Storb
authors.forename: Mark C
authors.initials: MC
authors.lastname: Walters
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications / Q000628:therapy*; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006085:Graft Survival; D006410:Hematopoiesis; D006801:Humans; D007121:Immunocompetence; D007700:Kinetics; D008297:Male; D010865:Pilot Projects; D035781:Siblings; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014916:Whole-Body Irradiation; D017086:beta-Thalassemia / Q000150:complications / Q000628:therapy*
chemical_list: D014740:Vidarabine; C024352:fludarabine