Hematopoietic stem cell transplantation outcomes for 11 patients with dedicator of cytokinesis 8 deficiency

Abstract

Background Dedicator of cytokinesis 8 (DOCK8) deficiency can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Reports of outcome are still limited. Objective To analyze the results of HSCT in patients with DOCK8 deficiency and report whether approaches resulting in mixed chimerism result in clinically relevant immune reconstitution. Methods We performed retrospective chart review of 11 patients with DOCK8 deficiency, and measured DOCK8 expression and cytokine production. Results Of 11 patients, 7 received HSCT from related and 4 from unrelated donors; nine patients received busulfan-based conditioning regimens. Survival was excellent (10/11 patients alive, 91%), including a patient who had undergone liver transplantation. Patients showed significant improvements in the frequency and severity of infections. While eczema resolved in all, food allergies and high IgE levels persisted in some patients. Lymphopenia, eosinophilia, low numbers of naïve CD8+ T cells and switched memory B cells, and Th1/Th2 cytokine imbalance improved in most patients. While the 8 matched related or unrelated donor recipients had full donor chimerism, all 3 recipients of mismatched unrelated donor HSCT had high levels of donor T cell chimerism, and low B and myeloid chimerism (0–46%). Almost all switched memory B cells were of donor origin. All patients including those with mixed chimerism mounted robust antibody responses to vaccination. Conclusion Allogeneic HSCT ameliorated the infectious and atopic symptoms of DOCK8 deficiency. In patients with mixed chimerism, selective advantage for donor-derived T cells and switched memory B cells promoted restoration of cellular and humoral immunity and protection against opportunistic infection.

Haploidentical Related Donor Hematopoietic Stem Cell Transplantation for Dedicator-of-Cytokinesis 8 Deficiency Using Post-Transplantation Cyclophosphamide

“…Regarding the extent of donor chimerism necessary to reverse the disease phenotype, a retrospective study of 11 patients with DOCK8 deficiency who underwent HSCT was recently reported [14]. Although the 7 patients receiving matched related donors all had high levels of donor chimerism, several of the mismatched patients, who received a nonmyeloablative regimen, had high levels of donor CD3 + chimerism but low levels of myeloid and B cell chimerism.…”

“…DOCK8 deficiency is associated with a high degree of morbidity and mortality—including life-threatening infections and virus-driven malignancies—with an estimated overall survival of 50% at 20 years [3]. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a curative therapy for DOCK8 deficiency [6-14]. …”

“…However, there are only a few reports of transplantations using haploidentical related donors in DOCK8 deficiency [9,14,15]. The success of haploidentical transplantation in other primary immunodeficiency syndromes suggested the feasibility of this approach in patients with DOCK8 deficiency [16-19].…”

DOCK8 Deficiency Presenting as an IPEX-Like Disorder

“…She was started on antimicrobial prophylaxis and monthly IVIG infusion with good clinical improvement. Currently, the patient is being evaluated for hematopoietic stem cell transplantation (HSCT) from her full-matched healthy sibling (23). …”

“…Finally, and in terms of therapy, the definitive treatment of DOCK8 deficiency is bone marrow transplantation (23). The emergence of immune dysregulation in the context of an immunodeficiency disorder presents challenges in terms of therapy.…”