Allogeneic Hematopoietic Stem Cell Transplant Reverses The Phenotype Of DOCK8 Deficiency

Abstract

BackgroundDOCK8 deficiency— a combined immunodeficiency characterized by recurrent sinopulmonary infections and severe cutaneous DNA viral infections, eczema, food and drug allergies, and increased risk of viral driven malignancies— results from homozygous or compound heterozygous mutations in the dedicator of cytokinesis 8 protein. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potential curative therapy for DOCK8 deficiency. MethodsWe treated 4 patients with DOCK8 deficiency with allogeneic HSCT using a reduced toxicity, myeloablative-conditioning regimen consisting of busulfan 3.2 mg/kg/day IV for 4 days and fludarabine 40 mg/m2/day for 4 days. Two patients received matched related donor allogeneic HSCT, and 2 received 10/10 HLA matched unrelated donor allogeneic HSCT. All patients received tacrolimus, and short methotrexate on days 1,3, 6, and 11, for graft-versus-host-disease (GVHD) prophylaxis. Indication for transplant was severe recurrent infections with end organ damage in three patients, and a refractory EBV-virus driven lymphoma at the time of unrelated donor PBSC transplant in the fourth patient. ResultsThe ages of the patients at the time of transplant were 27, 25, 18, and 16. The median follow-up for patients was 7 months (range 5-18 months). All 4 patients engrafted at a median of 12 days, and all 4 had complete reconstitution of the CD3/CD4 and CD3/CD8 compartments with donor cells. Clinical correction of the DOCK8 clinical phenotype occurred within 3-6 months of engraftment and correlated with lymphocyte reconstitution. Mucositis was the major side effect of the transplant-conditioning regimen. All had transient worsening of their pre-transplant infections 1-3 months post-transplant. In the patient with an EBV-virus driven lymphoma that had been refractory to chemotherapy, there was complete resolution of the disease on PET scanning at 100 days post-transplant. One patient, who received unrelated donor bone marrow cells, had skin GVHD that responded to a short course of steroids. There was no chronic GVHD. ConclusionsAllogeneic HSCT in DOCK8 deficiency results in reconstitution of the deficient lymphocyte compartments that are present pre-transplant and complete reversal of the infection susceptibility phenotype. There was minimal regimen-related toxicity, and the incidence of GVHD was low despite complete donor chimerism. With genetic testing for DOCK8 deficiency now more widely available, we anticipate that earlier diagnosis will enable patients to be transplanted earlier in their clinical course, before significant organ damage or the development of viral-driven malignancies Disclosures:No relevant conflicts of interest to declare.