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

• Published in: The journal of allergy and clinical immunology. Global 2023-08, Vol.2 (3), p.100106-100106, Article 100106
• Main Authors: Pandrowala, Ambreen, Sharma, Ajay Narayan, Kakunje, Manasa, Bodhanwala, Minnie, Hiwarkar, Prashant
• Format: Article
• Language: English
• Subjects: bone marrow transplantation; chimerism; DOCK8 deficiency; HSCT
• ISSN: 2772-8293; 2772-8293
• DOI: 10.1016/j.jacig.2023.100106

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. Here we have sought to devise a strategy for reducing the possibility of mixed chimerism without increasing the risk of transplant-related mortality. 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. 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. High CD34+ cell dose and reduced toxicity conditioning can achieve full donor chimerism in DOCK8 deficiency.