强烈预处理异基因造血干细胞移植治疗高危难治性白血病

Successful treatment of high risk/refractory leukemia by tumor-ablative individualized conditioning allogeneic hematopoietic stem cell transplantation

目的 研究强烈预处理异基因造血干细胞移植（allo-HSCT）治疗高危难治白血病患者的临床疗效.方法 根据患者移植前状态设计①HDAra-C＋Bu/Cy;②HDAra-C＋Bu/Flud;③G-CSF primed HDAa-C＋Bu/Cy;④FLAG/RICBuCy 4组强烈预处理方案,对57例高危难治患者进行alloHSCT,分析移植后患者造血重建、总生存（OS）率、无病生存（DFS）率、移植物抗宿主病（GVHD）、感染及复发率等临床指标.结果 57例患者中除1例未植活,56例稳定植入.中位随访时间17.5（2～34）个月,OS率为（74.7±6.1）%,无白血病生存（LFS）率为（62.4±6.7）%.高危组OS及LFS率分别为（74.2±7.1）%及（58.8±8.1）%,进展期组OS及LFS率分别为（77.0±11.8）%及（72.7±11.7）%.57例患者中29例发生急性GVHD（Ⅰ度18例,Ⅱ度4例,Ⅲ度2例,Ⅳ度5例）,累计发生率为（50.9±6.6）%,其中,Ⅱ～Ⅳ度和Ⅲ～Ⅳ度急性GVHD累计发生率分别为（19.3±5.2）%和（12.3±4.3）%.在可评估的56例患者中,36例发生慢性GVHD,累计发生率为（64.3±6.4）%.39例（68.42%）发生巨细胞病毒（CMV）血症.13例（22.8%）发生病毒性膀胱炎.38例（66.67%）发生细菌感染.16例（28.07%）发生真菌感染.57例患者中14例复发,其中血液学复发11例,髓外复发3例,累计复发率为（24.6±5.7）%.其中,高危组累计复发率为（28.1±7.7）%,进展期组累计复发率为（15.6±10.2）%.死亡15例,均发生在移植第100天后,移植相关死亡率为（26.3±5.8）%.死于复发6例,细菌、真菌感染5例,慢性GVHD 4例.结论 清肿瘤性个体化allo-HSCT是治疗高危难治性白血病的安全有效手段.

Objective To explore the efficacy of tumor-ablative individualized allogeneic hematopeietic stem cell transplantation for the treatment of patients with high risk/refractory leukemia. Methods Fivety-seven patients with high risk/refractory leukemia were enrolled. Tumor-ablative individualized conditioning regimens included HDAra-C ＋ Bu/Cy, Ara-C ＋ Bu/Fludarabine , G-CSF primed HDAra-C ＋ Bu/Cy,and FLAG followed by reduced-intensified BuCy. Overall survival （OS）, disease free survival （DIS）, graft versus host disase, infection and relapse pest grafting were analyzed. Results Fifty-six patients attained durable engraftment. The median follow-up duration was 17.5 （2- 34）months. The 18 months probabilities of OS and DFS were （ 74.7±6.1 ） % and （ 62.4±6.7 ） %, respectively. In addition, the 18 months probabilities of OS and DFS in patients who attained complete remission （ CR ） before transplantation were （ 74.2±7.1 ） % and （58.8±8. 1 ） %, respectively, while in those not attained CR were （ 77.0±11.8 ） % and （72.7±11.7）%, respectively. Twenty nine patients developed acute GVHD （aGVHD）（grade I in 18,grade Ⅱ in 4, grade Ⅲ in 2 and grade IV in 5 ）. The probabilities of aGVHD was （50.9±6.6） % by Kaplan-Meier curve analysis. The probabilities of grades 2-4 and grades 3 - 4 aGVHD were （ 19.3±5.2 ） % and （ 12.3±4.3 ）% respectively. Extensive chronic GVHD（cGVHD） was observed in 36 patients. The probabilities of cGVHD was （ 64. 3±6.4 ） % by Kaplan-Meier curve analysis. Cytomegaloviremia （ CMV ） was observed in 39 （68.42%） patients, hemorrhagic cystitis in 13 （22.8%） patients, fungous infection in 16 （28.07%） patients and bacterial infection in 38（66.67% ） patients. Relapse occurred in 14 patients （ hematologic relapse in 11 and extramedullary relapse in 3 ）, probabilities of relapse being （24.6±5.7） %. The 17.5-month probability of relapse in patients who attained CR before transplantation was （ 28. 1±7.7 ） %,while in those not attained CR was （ 15.6±10.2 ） %. Fifteen patients died （6 from hematological relapse,5 from infection of bacterial and fungous, 4 from cGVHD） after 100 days. Conclusion Tumor-ablative individualized allogeneic hematopoietic stem cell transplantation is a promising and safe choice for treatment of high risk/refractory leukemia, even with high leukemia burden.