Defects in
DNA cross-link repair 1C (DCLRE1C),
protein kinase DNA activated catalytic
polypeptide (PRKDC),
ligase 4 (LIG4), NHEJ1, and NBS1 involving the nonhomologous end-joining (NHEJ) DNA repair pathway result in radiation-sensitive
severe combined immunodeficiency (SCID). Results of hematopoietic
cell transplantation for radiation-sensitive SCID suggest that minimizing exposure to
alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of preconditioning with
alkylating agents is associated with a greater likelihood of full T- and B-cell reconstitution compared with no conditioning or immunosuppression alone. A reduced-intensity regimen using
fludarabine and low-dose
cyclophosphamide might be effective for patients with LIG4, NHEJ1, and NBS1 defects, although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose-
alkylating agents without significant late effects. Until nonchemotherapy agents, such as anti-CD45 or anti-CD117, become available, options include minimizing exposure to
alkylators, such as single-agent low-dose targeted
busulfan, or achieving T-cell reconstitution, followed several years later with a conditioning regimen to restore B-cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and
graft-versus-host disease. Prospective multicenter studies are needed to evaluate these approaches in this rare but highly vulnerable patient population.