Pandrowala Ambreen, Sharma Ajay Narayan, Kakunje Manasa, Bodhanwala Minnie, Hiwarkar Prashant
Department of Blood and Marrow Transplantation, Mumbai, India.
Department of Pediatrics, Bai Jerbai Wadia Hospital for Children, Mumbai, India.
J Allergy Clin Immunol Glob. 2023 Mar 28;2(3):100106. doi: 10.1016/j.jacig.2023.100106. eCollection 2023 Aug.
Biallelic mutations in the dedicator of cytokinesis 8 () 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.
2009年，胞质分裂调控蛋白8（DOCK8）基因的双等位基因突变被确定为联合免疫缺陷的病因。DOCK8缺陷患者在不进行造血干细胞移植的情况下，生存率从10岁时的87%下降到30岁时的33%。因此，造血干细胞移植是治疗DOCK8缺陷的推荐疗法。然而，DOCK8缺陷患者有多种感染合并症；因此，他们无法耐受清髓性预处理。降低强度的预处理可降低移植相关死亡率，但会增加混合嵌合体形成的可能性。免疫缺陷儿童中的混合嵌合体增加了自身免疫风险以及长期输注免疫球蛋白的必要性。
在此，我们试图设计一种策略，在不增加移植相关死亡率风险的情况下降低混合嵌合体形成的可能性。
为平衡移植相关死亡率和混合嵌合体形成的风险，我们对HLA匹配和单倍体相合移植采用了基于苏消安的低毒性预处理、高CD34细胞剂量以及差异性T细胞封帽。
我们能够报告，通过使用上述新策略，我们在印度首批高危DOCK8缺陷患者中取得了优异的移植结果。
高CD34细胞剂量和低毒性预处理可在DOCK8缺陷中实现完全供体嵌合。
