Allogeneic Hematopoetic 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.)




As the authors note in their abstract, the myeloablative transplantation of allogeneic stem cells has been extremely successful (90-95%) in curing children with sickle cell disease. However, the myeloablation process has shown unacceptable toxicity in human adult patients, preventing clinicians from successfully treating these patients. The authors thus tested a nonmyeloablative procedure on a murine model to determine safety and efficacy, then progressed to this study on 10 adult human patients. Instead of attempting to block T cell activation as in normal myeloablative procedures, the drug combination used by this team inhibits T cell proliferation. The inhibition of T cell proliferation causes anergy in the host’s Tcells, limiting their reactivity to antigens, promoting T cell tolerance to the new graft tissue. With this treatment, the authors were successful at reversing the sickle cell disease phonotype in 9 out of 10 patients, and managed to prevent GVHD in all patients. This is promising research into being able to reverse the disease state in adults.

1. Hsieh, M. M.; Kang, E. M.; Fitzhugh, C. D.; Link, M. B.; Bolan, C. D.; Kurlander, R.; Childs, R. W.; Rodgers, G. P.; Powell, J. D.; Tisdale, J. F., Allogeneic Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease. N Engl J Med 2009, 361 (24), 2309-2317.