Clinical and Immunological Correction of DOCK8 Deficiency by Allogeneic Hematopoietic Stem Cell Transplantation Following a Reduced Toxicity Conditioning Regimen

Abstract

Dedicator of cytokinesis 8 protein (DOCK8) deficiency is a combined immunodeficiency disorder characterized by an expanding clinical picture with typical features of recurrent respiratory or gastrointestinal tract infections, atopic eczema, food allergies, chronic viral infections of the skin, and blood eosinophilia often accompanied by elevated serum IgE levels. The only definitive treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). We report a patient with early severe manifestation of DOCK8 deficiency, who underwent unrelated allogeneic HSCT at the age of 3 years following a reduced toxicity conditioning regimen. The transplant course was complicated by pulmonary aspergilloma pretransplantation, adenovirus (ADV) reactivation, and cytomegalovirus (CMV) pneumonitis 4 weeks after transplantation. With antifungal and antiviral treatment the patient recovered. Seven months after transplantation the patient is in excellent clinical condition. Eczematous rash, chronic viral skin infections, and food allergies have subsided, associated with normalization of IgE levels and absolute numbers of eosinophils. Chimerism analysis shows stable full donor chimerism. DOCK8 deficiency can be successfully cured by allogeneic HSCT. This treatment option should be considered early after diagnosis, as opportunistic infections and malignancies that occur more frequently during the natural course of the disease are associated with higher morbidity and mortality.

Recent Advances in DOCK8 Immunodeficiency Syndrome

“…In contrast, the only form of definitive therapy, borne out through the experience of multiple centers, has been hematopoietic stem cell transplantation (HSCT) (24-31). HSCT for DIDS has been successfully performed using reduced intensity myeloablative conditioning regimens with matched related or matched unrelated allogeneic donor cells (24-26, 29, 30). In one case, engraftment of matched related allogeneic donor cells, sufficient for development of severe GVHD, occurred even without any conditioning, emphasizing the intrinsic survival advantage of DOCK8-expressing cells (32).…”

“…HSCT also cures the eczematous dermatitis, as well as food allergies in some but not all patients (26-29, 33, 34). Whether HSCT also cures the autoimmune complications and reduces the risk of cancers are as yet undetermined.…”

Food allergies can persist after myeloablative hematopoietic stem cell transplantation in dedicator of cytokinesis 8–deficient patients

“…4,5,9 Thus, we prospectively studied food allergies in the next six DOCK8-deficient patients transplanted at the NIH (Patients 7–12 in Table 1). This second group included two patients (patients 9 and 12) who had undergone related donor haploidentical transplants and had systemic allergic reactions to foods that they were already allergic to before transplant.…”

Primary immunodeficiency update

“…38–40 Cutaneous viral infections and dermatitis have shown dramatic improvement in the first 6 months after transplant. 31, 40 …”