Hematopoietic Cell Transplant for Patients with NEMO Defect: A Single Center Experience

Background: NF-kappa B essential modulator (NEMO) is an important activator of NF-kappa B, which regulates numerous genes involved in immune responses and ectodermal development. Hypomorphic mutations in NEMO have been associated with a spectrum of disorder such as X linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID), X- liked immunodeficiency without ectodermal dysplasia and isolated susceptibility to atypical mycobacteria. Currently, allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for patients with NEMO defects. However, there are only few case reports of successful HCT for this disorder. Here we report our experience of allogeneic HCT for patients with NEMO defect.

Methods:  We retrospectively analyzed the outcomes of 4 patients with NEMO defect who had undergone allogeneic HCT between January 2005 and September 2012 in our institution. Hypomorphic mutations in NEMO were identified in all 4 patients. Three had XL-EDA-ID and one had X- liked immunodeficiency without ectodermal dysplasia. Prior to transplant all of them had recurrent bacterial infections and two of them had disseminated atypical mycobacterial infection. Autoimmune hemolytic anemia was noted in two patients. The median age at transplantation was 10.5 years (range: 3.3-18.2). All of them underwent myeloablative preparative regimen consisting of busulfan, cyclophosphamide, and ATG, and busulfan kinetics were used to dose busulfan. Two patients received matched (8/8) unrelated donor (URD) bone marrow transplant and two received single locus mismatch (7/8) URD bone marrow transplant. In all patients cyclosporine and prednisone was used as GvHD prophylaxis.

Result: Overall survival was 75% (3/4) at a median follow-up of 59 months post-transplant (range: 12 -70). The median time for neutrophil engraftment was 12.5 days (range: 11-15). Grade II to III acute GVHD developed in two patients and one patient developed chronic skin GVHD. Mixed donor chimerism was noted in one patient needing stem cell boost 4 years after HCT. Death in one patient was due to HSV pneumonitis and disseminated mycobacterial infection with multi-organ failure. All surviving patients    immune reconstituted with normal lymphocyte subpopulation, normal distribution of CD45RA/RO, normal NK cell function and mitogen response.  Two patients are currently off immunoglobulin replacement with good specific antibody response to both protein and polysaccharide antigens.

Conclusion: HCT is effective in correction of innate and adaptive immune defects associated with NEMO deficiency. Further follow-up and larger multi-institutional studies are needed to better understand the role of HCT in this disorder.