Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT

Abstract

Peripheral blood stem cell transplantation (PBSCT) offers a curative option for sickle cell disease (SCD). Although HLA-matched sibling transplantation is promising, the vast majority of patients lack such a donor. We sought to develop a novel nonmyeloablative HLA-haploidentical PBSCT approach that could safely be used for patients with severe organ damage. Based on findings in our preclinical model, we developed a phase 1/2 trial using alemtuzumab, 400 cGy total body irradiation, and escalating doses of posttransplant cyclophosphamide (PT-Cy): 0 mg/kg in cohort 1, 50 mg/kg in cohort 2, and 100 mg/kg in cohort 3. A total of 21 patients with SCD and 2 with β-thalassemia received a transplant. The mean hematopoietic cell transplant-specific comorbidity index of 6 reflected patients with cirrhosis, heart failure, and end-stage renal disease. The engraftment rate improved from 1 (33%) of 3 in cohort 1 to 5 (63%) of 8 in cohort 2 and 10 (83%) of 12 in cohort 3. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. There was no transplant-related mortality, and overall survival was 87%. At present, 0% in cohort 1, 25% in cohort 2, and 50% in cohort 3 remain free of their disease. There was no grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). Therefore, PT-Cy improves engraftment and successfully prevents severe GVHD after nonmyeloablative conditioning in patients with SCD who are at high risk for early mortality. Additional strategies are necessary to decrease the graft rejection rate and achieve a widely available cure for all patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT00977691.

Graphical abstract

Figure 1.

Conditioning regimen. All patients received alemtuzumab, 400 cGy TBI, and sirolimus. Cohort 1 patients received no PT-Cy, cohort 2 patients received 50 mg/kg PT-Cy, and cohort 3 patients received 100 mg/kg PT-Cy. Sirolimus target level was 10 to 15 ng/dL. Sirolimus was started 1 day before PBSC infusion in patients 4 through 9 and 4 days posttransplant in patients 10 and 11. IV, intravenous; N/A, not applicable.

Figure 2.

Donor chimerism levels in the 3 patient cohorts posttransplant over time. Percentage of (A) donor myeloid chimerism and (B) donor CD3 chimerism. Chimerism levels are reported only for patients who initially engrafted. Data are reported as mean plus standard error of the mean for each time point.