Wang Ling, Wang Li-Ning, Zhou Ji-Fang, Gao Wen-Hui, Jiang Chuan-He, Tang Wei, Zhao Wei-Li, Hu Jiong, Jiang Jie-Ling
Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.
Front Med (Lausanne). 2021 Feb 23;8:627946. doi: 10.3389/fmed.2021.627946. eCollection 2021.
T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
异基因造血干细胞移植（allo-HSCT）后采用清髓性预处理治疗血液系统恶性肿瘤时出现的T细胞混合嵌合状态（MC），可能预示着植入失败或疾病复发。免疫调节，如供体淋巴细胞输注（DLI）或快速减量或停用免疫抑制治疗，可使MC逆转至完全供体嵌合状态（FDC）。然而，移植物抗宿主病（GvHD）的发生或加重以及相关死亡率仍是免疫调节的主要关注点。在这项前瞻性单臂研究（NCT03663751）中，我们测试了低剂量地西他滨（LD-DAC，每日5 mg/m²，共5天，每6 - 8周重复一次）在不进行免疫调节的情况下治疗MC患者以预防MC相关复发和/或移植失败的疗效和安全性。共纳入14例患者。所有患者均接受了清髓性预处理方案，在allo-HSCT后第30天至第180天记录到MC，供体嵌合水平为59%至97%，无可检测的微小残留病（MRD）。11例患者（78.6%）对治疗反应良好，供体嵌合水平升高（≥95%），其中9例实现了FDC。所有这些患者的反应持续了中位数11个月（3 - 22个月）。3例反应不佳的患者最终要么复发要么出现移植失败。这3例患者在第二次allo-HSCT后的最后一次随访时均存活且病情缓解。LD-DAC单药治疗耐受性良好，血液学和非血液学毒性有限。仅2例患者出现了新发GvHD症状。总体而言，allo-HSCT后估计的2年总生存率（OS）和无事件生存率（EFS）分别为90.9 ± 8.7%和67.0 ± 13.7%。总之，单独使用LD-DAC可使大多数接受清髓性预处理的allo-HSCT后患者的MC逆转，而实现FDC的患者可享有长期EFS且无重大并发症。需要进一步开展更大样本量的前瞻性研究以证实LD-DAC的益处。
