Stem cell transplantation for Nijmegen breakage syndrome--experience in 6 patients

Nijmegen breakage syndrome (NBS) is a autosomal recessive disorder characterized by immunodeficiency, characteristic facial appearance, chromosomal instability, X-ray hypersensitivity, and predisposition to malignancy. Patients harbour mutations in NBS1 which encodes for nibrin, a protein critically important in DNA double strand repair. About 40% of patients develop malignancy mostly of lymphoid origin before age 21. Traditionally NBS patients have not undergone HSCT owing to concerns about chromosomal instability and increased toxicity. Only 2 cases have been reported, both included in this series. We therefore attempted to summarize the limited transplant experience in NBS patients in Europe. A total of six patients could be included. All carried homozygous NBS1 mutations. Median age at diagnosis was 7.6 years (range 1-18) and 14.5 years (2.3-20.3) at transplant. The reason to attempt SCT was resistant or secondary malignancy in four cases. The other two were transplanted because of severe immunodeficiency or suspected Fanconi anaemia (FA) with immunodeficiency. All had a T-cell defect and 4/6 had deficient humoral immunity before transplant. As expected the conditioning regimes varied widely, however 5 patients received reduced intensity regimens with in vivo T-cell depleting agents. The donors were matched family members in 3 patients, one haploidentical parent and two matched unrelated donors. At a median follow up of 2.2 years (1.6-8.1) five of six patients are alive and well. Three patients had no relevant transplant related complications. Three had severe mucositis and infectious complications, one of whom died on day +5 from sepsis. The latter one was the patient who had received BMT from a matched sibling after a myeloablative, busulfan containing conditioning regimen. Acute GVHD grade I-II occurred in 3/5 patients, mild chronic GVHD in one. Four patients are either complete or nearly complete donor chimeras, one has mixed chimerism, all five exhibit restored T-cell immunity. Four patients have normal humoral immunity and one remains on IVIG at 1.6 years post transplant. Although very limited, the experience in these six patients suggests that SCT in NBS is feasible, can correct the immunodeficiency and effectively treat malignancy. Acute toxicity seems to be reasonable with reduced intensity conditioning regimens. However, valid concerns remain about increasing the risk for subsequent malignancy through cytotoxic agents in these patients.