Gene therapy for SCID associated with leukemia risk

Long-term follow-up of 9 patients with X-linked severe combined immunodeficiency disease (SCID-Xl) who underwent gene therapy shows that the gene therapy corrected the immunodeficiency responsible for the disease.

However, the research team also found that the treatment confers an increased risk of acute leukemia. Four of the 9 patients (44%) developed T-cell acute lymphoblastic leukemia. (ALL)

Salima Hacein-Bey-Abina, PharmD, PhD, from the Necker-Enfants Malades Hospital in Paris, and colleagues reported the results in the July 22 issue of The New England Journal of Medicine.

Between 1999 and 2002, 9 patients with gamma-chain deficiency who did not have an HLA-identical donor for hematopoietic stem cell transplant underwent ex vivo gamma-chain retrovirus-mediated gene transfer to CD34+ bone marrow cells. The patients were a median age of 7 months.

The patients remained in a sterile unit between 45 and 90 days. None had any severe opportunistic infections after leaving the unit. All patients developed varicella-zoster virus that did not require hospitalization; 3 patients had recurrent rhinitis, and 2 patients had transient warts.

Of the 4 patients who developed ALL, 1 died. The other 3 received chemotherapy and recovered. The immunodeficiency induced by the chometherapy in the 3 survivors resolved without requiring additional therapy.

Patients achieved normal T-cell counts between 2 and 5 months after gene therapy. Researchers observed a trend (P=0.11) for higher T-cell counts at 1 year post therapy in patients who developed leukemia than in those who did not.

Patients’ B-cell counts decreased to normal levels after gene therapy. At presentation, the counts had been elevated in the infants.

All surviving patients but one, including those who recovered from T-cell ALL, could live in a normal, nonprotected environment and experienced normal growth during the follow-up period of almost 10 years. And all attended regular schools.

The researchers said the study confirmed that ex vivo gene therapy could result in long-term correction of the SCID phenotype. However, they admitted that the “risk of the development of a malignant condition related to the treatment...cannot be ignored.”

They noted that alternatives to gene therapy, including transplantation from unrelated donors, from cord blood, or from haploidentical parents, also have associated risks. Graft-versus-host disease and related infections are a major cause of death in transplant patients.

They concluded that gene therapy may be another option for patients with SCID-Xl and other inherited diseases of the hematopoietic system who lack an HLA-identical donor.