Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.
BACKGROUND
Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease.


METHODS
Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward.


RESULTS
All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (+/-SE) donor-recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3+/-8.6% and 83.3+/-10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0+/-0.3 and 12.6+/-0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient.


CONCLUSIONS
A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor-recipient chimerism and reverse the sickle cell phenotype. (ClinicalTrials.gov number, NCT00061568.)
Hsieh
Matthew M
MM
Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
Kang
Elizabeth M
EM
Fitzhugh
Courtney D
CD
Link
M Beth
MB
Bolan
Charles D
CD
Kurlander
Roger
R
Childs
Richard W
RW
Rodgers
Griffin P
GP
Powell
Jonathan D
JD
Tisdale
John F
JF
D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D000755:Anemia, Sickle Cell / Q000628:therapy*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D018952:Antigens, CD34; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006454:Hemoglobins / Q000032:analysis; D006650:Histocompatibility Testing; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009294:Narcotics / Q000009:adverse effects; D009504:Neutrophils; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D013375:Substance Withdrawal Syndrome; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D006454:Hemoglobins; D009294:Narcotics; D000074323:Alemtuzumab; D020123:Sirolimus