Allogeneic stem cell transplantation for Severe Combined Immunodeficiency Syndromes

Therapy, Course, and Prognosis of Severe Combined Immunodeficiency Syndromes

SCID is a medical emergency and is inevitably fatal if untreated. Confirmation of diagnosis by appropriate laboratory assays, referral to a tertiary care center, and aggressive treatment of infections should be immediately initiated in infants with possible SCID. High-dose intravenous sulfamethoxazole/trimethoprim (20 mg/kg) is effective in treating P. jiroveci pneumonia. CMV or adenoviral infections should be treated with ganciclovir or cidofovir, respectively. Infants who have received bacillus Calmette-Guerin vaccination at birth should receive isoniazid and rifampicin, regardless of the presence of overt signs of mycobacteriosis. Administration of intravenous immunoglobulins and antimicrobial prophylaxis are necessary to reduce the risk of infections. Parenteral nutrition may be necessary, especially if chronic diarrhea and failure to thrive are present.

Allogeneic stem cell transplantation for Severe Combined Immunodeficiency Syndromes

Survival, however, is ultimately dependent on immune reconstitution. Allogeneic stem cell transplantation was first performed in 1968 in an infant with X-linked SCID,76 and is the treatment of choice. Survival following stem cell transplantation from an human leukocyte antigen (HLA)-identical sibling is currently as high as 90 percent.27,77,78 T-cell–depleted transplantation from haploidentical donors results in excellent results if the transplantation is performed in the neonatal period79 or in the first 3.5 months of life,27 but survival is only 50 to 65 percent if performed at a later age.77 Haploidentical transplantation is more successful in B+ SCID than in B– SCID,77 but is problematic in patients with the Artemis gene mutation or ADA deficiency, or with reticular dysgenesis. Although graft rejection should in theory be impossible in patients with SCID (making the use of pretransplantation chemotherapy unnecessary), full and durable immune reconstitution is more easily achieved following pretransplantation nonmyeloablative conditioning, which favors engraftment of donor stem cells. Promising results have been achieved with stem cell transplantation from matched-unrelated donors and unrelated cord blood.78,80

Failure to achieve sufficient T- and B-cell reconstitution is associated with prolonged morbidity after transplantation, but most patients with SCID enjoy good quality of life after transplantion,81 except for those with ADA or PNP deficiency and SCID with increased cellular radiosensitivity, who often develop neurologic deterioration and developmental problems even after transplantation.82–84

Enzyme replacement therapy offers rapid normalization of the toxic metabolites in ADA deficiency in those who do not have a matched donor, and may result in immune reconstitution and significant clinical improvement in patients with ADA deficiency,85 although T-cell counts often remain low.86

A proof of principle that gene therapy may cure SCID has been achieved in X-linked SCID87,88; however, some of the patients have developed leukemia because of insertional mutagenesis.89,90 In contrast, efficacy of gene therapy without adverse events has been reported in ADA deficiency.91