Baseline TP53 mutations in Adults with SCD developing Myeloid Malignancy following Hematopoietic Cell Transplantation

Sickle cell disease (SCD) is associated with severe morbidity and early mortality. Allogeneic hematopoietic cell transplantation (AlloHCT) is currently the only widely used curative therapy for SCD patients. While population-based studies report an increased incidence of hematologic malignancies in SCD patients, there is particular concern for an increased risk of development of myeloid malignancy following AlloHCT. Between September 2004 and April 2018 a total of 76 adult patients received an AlloHCT for SCD at the NIH Clinical Center. We report here on the three SCD patients who developed myeloid malignancy, all two to five years after unsuccessful nonmyeloablative allogeneic HCT. We show, in two cases, that TP53 mutations present at the time of post-transplant myeloid malignancy diagnosis were also detectable prior to transplantation and increased in frequency over time. Development of myeloid malignancy is a potential complication for SCD patients undergoing hematopoietic cell therapy and may be associated with detectable mutations prior to transplantation.

镰状细胞病（Sickle cell disease, SCD）与严重发病及早期死亡风险升高密切相关。异基因造血细胞移植（Allogeneic hematopoietic cell transplantation, AlloHCT）是目前唯一广泛应用于SCD患者的治愈性治疗手段。既往基于人群的研究显示，SCD患者血液系统恶性肿瘤的发病率升高，学界尤其担忧接受AlloHCT后髓系恶性肿瘤的发病风险增加。2004年9月至2018年4月期间，美国国立卫生研究院（NIH）临床中心共76名成人SCD患者接受了针对该病的AlloHCT治疗。本文报告了3例发生髓系恶性肿瘤的SCD患者，其发病均发生于非清髓性异基因造血细胞移植失败后的2至5年。研究发现，在2例患者中，移植后髓系恶性肿瘤确诊时检出的TP53基因突变，在移植前即可被检测到，且突变频率随时间推移逐渐升高。对于接受造血细胞治疗的SCD患者而言，髓系恶性肿瘤是一种潜在并发症，且该并发症可能与移植前即可检出的基因突变存在关联。