Nonmyeloablative HSCT feasible in adults with SCD

Sickle cell

Myeloablative allogeneic hematopoietic stem cell transplant (HSCT) can cure children with sickle cell disease (SCD). However, the conditioning regimen is frequently much too toxic to use in adults with severe SCD.

Researchers tried a nonmyeloablative regimen in adults and found it to be feasible. Corresponding author John F. Tisdale, MD, and colleagues primarily from the National Institutes of Health reported their findings in the December 10, 2009, issue of The New England Journal of Medicine.

The investigators recruited 24 eligible patients over the past 5 years. To date, 10 have received transplants. All recipients had to have an HLA-identical family donor, be 16 years of age or older, and homozygous for hemoglobin S or compound heterozygous for hemoglobin S and C.

Recipients had severe end-organ complication, such as a previous cerebrovascular event or sickle-cell nephropathy, or a potentially reversible complication that was not responding to hydroxyurea treatment.

The conditioning regimen consisted of alemtuzumab, 1 mg/kg total dose given in gradually increasing doses on days 7 to 3 prior to transplant; a single dose of 300 cGy of total body irradiation; and oral sirolimus starting the day before transplant. The investigators intended to taper the sirolimus when recipients attained T-cell donor chimerism of 100%.

Ten patients ranging in age from 16 to 45 years (median, 26 years) received allogeneic HSCT. They were alive at a median 30 months posttransplant (range, 15 to 54 months). Nine of them had lymphohematopoietic engraftment at levels that that reversed the sickle cell disease phenotype.

One patient, who inadvertently received a lesser dose of radiation, lost the graft. A year later, he received a second transplant with a conditioning regimen that included 400 cGy, and the transplant was successful.

In the patients with successful grafts, mean donor-recipient chimerism for CD3+ cells was 53.3+8.6%, and for CD14+15+, 83.3+10.3%.

Dr Tisdale reported that no patient had attained 100% donor chimerism, and so patients continued to receive sirolimus therapy.

Patients’ hemoglobin levels gradually increased after transplant to a mean of 12.6+0.6 g/dL for women and 12.7+1.1 g/dL for men. And markers of increased hemolysis declined after transplant.

No patient developed acute or chronic graft-versus-host disease, a major contributor to morbidity and mortality in transplant recipients.

One patient had reactivation of cytomegalovirus infection, 6 patients had minor ankle arthralgia, and 2 patients had ankle arthralgia that interfered with normal activities. Two patients had exertional dypsnea, which was diagnosed as sirolimus-associated pneumonitis. The investigators switched 1 patient to cyclosporine and reduced the sirolumus dose for the other, and the pneumonitis resolved.

Dr Tisdale and colleagues believe this transplant approach is feasible for use at most transplant centers because of its simplicity, low toxicity, and high efficacy.