Allogeneic cellular gene therapy in hemoglobinopathies--evaluation of hematopoietic SCT in sickle cell anemia.

Many patients with thalassemia have been cured with BMT since the first successful transplant in 1981. Allogeneic stem cell gene therapy is the only treatment option for patients with sickle cell anemia (SCA). A total of 11 patients with a median age of 12 years (range, 2-16), affected by SCA, received hematopoietic SCT from HLA-identical, related donors following a myeloablative-conditioning regimen. Indications for transplantation were vaso-occlusive crisis, acute chest syndrome, avascular bone necrosis, chronic RBC transfusions, or hemorrhagic stroke. All patients had sustained engraftment. One patient became a stable mixed chimera with 25% of donor cells at 4 years after transplantation. One patient died at 1 year after transplantation. The probability of survival, SCA-free survival and TRM at 5 years after transplant were 90, 90 and 10%, respectively. All 10 surviving patients remained free of any SCA-related events after transplantation. In conclusion, these data confirm SCT from a suitable HLA-matched, related donor should become the primary option for curing children with SCA. There is an excellent survival rate and a return to normal life, free of SCA-related events.

Higher CD3(+) and CD34(+) cell doses in the graft increase the incidence of acute GVHD in children receiving BMT for thalassemia.

We evaluated the incidence of GVHD, risk factors and the impact of graft composition on acute GVHD (aGVHD) in 92 children who underwent BMT for thalassemia following busulfan/cyclophosphamide (BUCY)-based conditioning regimens and GVHD prophylaxis with CSA/short-MTX and methylprednisolone. The incidence of grade 2-4 and 3-4 aGVHD was 35% (95% confidence interval (CI) 25-44) and 9% (95% CI 4-16), respectively. We found that CD3(+) and CD34(+) cell doses above the median were associated with high incidence of grade 2-4 aGVHD (49 vs 20%, P=0.005 and 46 vs 23%, P=0.021, respectively). In multivariate analysis, high CD3(+) (hazard ratio (HR) 4.6; 95% CI 1.4-14.7; P=0.010) and CD34(+) (HR 4.3; 95% CI 1.4-12.7; P=0.011) cell doses were associated with grade 2-4 aGVHD. We further examined the effect of CD3(+) and CD34(+) cell doses on aGVHD using quartile cutoff points and found a minimum threshold for CD3(+) (38 × 10(6)/kg) and CD34(+) (4 × 10(6)/kg) cells above which the incidence of grade 2-4 aGVHD is significantly increased. This study shows for the first time a positive correlation between the number of CD3(+) and CD34(+) cells and aGVHD in children receiving sibling BMT, and indicates that using tailored and more intensive post transplant immunosuppression may permit to better control aGVHD.

Second hematopoietic SCT in patients with thalassemia recurrence following rejection of the first graft.

There is a substantial incidence of graft failure in patients with thalassemia after myeloablative conditioning regimens especially in class 3 patients in whom its incidence could be as high as 8-38.5%. Most patients with graft failure have recurrence of thalassemic marrow. Historically, results of second transplants for thalassemia were poor because of a high rejection rate and/or increased TRM. Sixteen patients with thalassemia recurrence following rejection of the first graft and with a median age of 9 years (range, 4-20) were given second transplants using BM (n=7) or PBSC (n=9) after preparation with a new treatment protocol. All but two patients received stem cells from the same donor. The median interval between two transplants was 28 months (range, 8-204). The sustained engraftment rate was high (94%) with only one patient having primary graft failure. The probability of overall survival, event-free survival, TRM and graft failure were 79, 79, 16 and 6%, respectively. There were three transplant-related deaths. Thirteen patients are alive with Lansky/Karnofsky score of 100. This intensified treatment protocol was well tolerated with no significant increase in toxicity. The excellent results obtained with this new preparative regimen allow us to recommend it for second transplantation for patients with thalassemia recurrence.