Bhoopalan Senthil Velan, Suryaprakash Shruthi, Sharma Akshay, Wlodarski Marcin W
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, United States.
Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, United States.
Front Oncol. 2023 Sep 11;13:1236038. doi: 10.3389/fonc.2023.1236038. eCollection 2023.
Diamond-Blackfan anemia (DBA) is one of the most common inherited causes of bone marrow failure in children. DBA typically presents with isolated erythroid hypoplasia and anemia in infants. Congenital anomalies are seen in 50% of the patients. Over time, many patients experience panhematopoietic defects resulting in immunodeficiency and multilineage hematopoietic cytopenias. Additionally, DBA is associated with increased risk of myelodysplastic syndrome, acute myeloid leukemia and solid organ cancers. As a prototypical ribosomopathy, DBA is caused by heterozygous loss-of-function mutations or deletions in over 20 ribosomal protein genes, with being involved in 25% of patients. Corticosteroids are the only effective initial pharmacotherapy offered to transfusion-dependent patients aged 1 year or older. However, despite good initial response, only ~20-30% remain steroid-responsive while the majority of the remaining patients will require life-long red blood cell transfusions. Despite continuous chelation, iron overload and related toxicities pose a significant morbidity problem. Allogeneic hematopoietic cell transplantation (HCT) performed to completely replace the dysfunctional hematopoietic stem and progenitor cells is a curative option associated with potentially uncontrollable risks. Advances in HLA-typing, conditioning regimens, infection management, and graft-versus-host-disease prophylaxis have led to improved transplant outcomes in DBA patients, though survival is suboptimal for adolescents and adults with long transfusion-history and patients lacking well-matched donors. Additionally, many patients lack a suitable donor. To address this gap and to mitigate the risk of graft-versus-host disease, several groups are working towards developing autologous genetic therapies to provide another curative option for DBA patients across the whole age spectrum. In this review, we summarize the results of HCT studies and review advances and potential future directions in hematopoietic stem cell-based therapies for DBA.
钻石黑范贫血（DBA）是儿童骨髓衰竭最常见的遗传性病因之一。DBA通常表现为婴儿期单纯性红系造血发育不全和贫血。50%的患者有先天性异常。随着时间的推移，许多患者会出现全血细胞生成缺陷，导致免疫缺陷和多系血细胞减少。此外，DBA与骨髓增生异常综合征、急性髓系白血病和实体器官癌症的风险增加有关。作为一种典型的核糖体病，DBA是由20多个核糖体蛋白基因的杂合功能丧失突变或缺失引起的，25%的患者与之相关。对于1岁及以上依赖输血的患者，皮质类固醇是唯一有效的初始药物治疗。然而，尽管初始反应良好，但只有约20%-30%的患者对类固醇仍有反应，而其余大多数患者将需要终身红细胞输血。尽管持续进行螯合治疗，但铁过载及其相关毒性构成了一个严重的发病问题。进行异基因造血细胞移植（HCT）以完全替代功能失调的造血干细胞和祖细胞是一种治愈性选择，但存在潜在的无法控制的风险。HLA分型、预处理方案、感染管理和移植物抗宿主病预防方面的进展已使DBA患者的移植结果得到改善，不过对于有长期输血史的青少年和成人以及缺乏匹配良好供体的患者，生存率仍不理想。此外，许多患者缺乏合适的供体。为了填补这一空白并降低移植物抗宿主病的风险，几个研究小组正在努力开发自体基因疗法，为全年龄段的DBA患者提供另一种治愈性选择。在这篇综述中，我们总结了HCT研究的结果，并回顾了基于造血干细胞的DBA治疗的进展和潜在的未来方向。
