Reduced toxicity conditioning and a high CD34(+) cell dose can achieve full donor chimerism in DOCK8 deficiency

BACKGROUND: Biallelic mutations in the dedicator of cytokinesis 8 (DOCK8) gene were identified as the cause of combined immunodeficiency in 2009. Survival rates without hematopoietic stem cell transplant in patients with DOCK8 deficiency decline from 87% at 10 years to 33% at 30 years. Hematopoietic stem cell transplant is therefore the recommended treatment for cure of DOCK8 deficiency. However, patients with DOCK8 deficiency have multiple infectious comorbidities; hence, they cannot tolerate myeloablative conditioning. Reduced intensity conditioning reduces the risk of transplant-related mortality but increases the possibility of mixed chimerism. Mixed chimerism in children with immunodeficiency increases the risk of autoimmunity and the need for long-term immunoglobulin infusion. OBJECTIVE: Here we have sought to devise a strategy for reducing the possibility of mixed chimerism without increasing the risk of transplant-related mortality. METHODS: To balance the risk of transplant-related mortality and mixed chimerism, we used treosulfan-based reduced toxicity conditioning with a high CD34(+) cell dose and differential T-cell capping for HLA-matched and haploidentical transplants. RESULTS: We are able to report that by using the aforementioned novel strategy, we achieved excellent transplant outcomes in the first cohort of high-risk patients with DOCK8 deficiency from India. CONCLUSION: High CD34(+) cell dose and reduced toxicity conditioning can achieve full donor chimerism in DOCK8 deficiency.