Allogeneic hematopoietic stem-cell transplantation for sickle cell disease

Abstract

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.)

Figure 1. Conditioning Regimen and Screening of Patients

Panel A shows the conditioning regimen used before hematopoietic stem-cell transplantation (HSCT). The regimen consisted of alemtuzumab, at a total dose of 1 mg per kilogram of body weight, given over a period of 5 days in gradually increasing doses: 0.03 mg per kilogram (test dose) on day −7, 0.1 mg per kilogram on day −6, and then 0.3 mg per kilogram per day on days −5 through −3. A single dose of 300 cGy of total-body irradiation (TBI) was administered on day −2 (with gonadal shielding applied for men). Treatment with oral sirolimus was initiated on day −1 at a dose of 5 mg every 4 hours for three doses, then 5 mg daily starting on day 0, modified to achieve target trough levels of 10 to 15 ng per milliliter of whole blood. Panel B shows the numbers of patients and their siblings who were screened, the number of eligible patients, and the number of patients who underwent transplantation. Among a total of 24 eligible patients, 6 of 6 HLA-matched siblings were identified. Four patients were excluded owing to major ABO incompatibility and a previously reported high incidence of pure red-cell aplasia from residual recipient lymphoid cells in nonmyeloablative HSCT,^, and one patient died of suspected sudden arrhythmia from severe iron overload 1 month before the planned HSCT. Eight patients are currently undergoing optimization of their medical therapy, including hydroxyurea therapy, iron chelation, and pain management, and one patient is currently undergoing evaluation for HSCT.

Figure 2. Neutrophil Counts after Hematopoietic Stem-Cell Transplantation (HSCT)

Each circle represents the mean neutrophil count for all patients after the transplantation procedure. I bars indicate standard errors.

Figure 3. Donor-Cell Chimerism and Laboratory Measurements after Hematopoietic Stem-Cell Transplantation

Panel A shows the mean (±SE) percentage of donor cells after hematopoietic stem-cell transplantation (HSCT). Donor chimerism among CD3+ T cells and CD14+15+ myeloid cells was assessed by means of a polymerase-chain-reaction assay to determine minisatellite polymorphisms between patient and donor. Panel B shows the laboratory measurements obtained one month before HSCT and those obtained at the most recent follow-up (median, 30 months; range, 15 to 54). The bar graphs in Panel B show mean values for total hemoglobin before, during (Exch), and after HSCT for male and female recipients; T bars indicate standard errors. For the reticulocyte count, total bilirubin level, and lactate dehydrogenase (LDH) level shown in Panel C, the horizontal lines within the box plots indicate the mean values, the lower and upper ends of the boxes represent the 25th and 75th percentiles, and the I bars represent the 10th and 90th percentiles; the dashed lines represent the upper limits of the reference ranges.