配型相合同胞供者与单倍体相合造血干细胞移植治疗恶性血液病的单中心临床研究

Single-center clinical research of matched sibiling donor and haploidentical hematopoietic stem cell transplantation for treatment of malignant hematopathy

目的通过与配型相合同胞供者造血干细胞移植（MSD-HSCT）比较，评估单倍体相合造血干细胞移植（haplo-HSCT）治疗恶性血液病的安全性与疗效。方法选取2011年1月至2015年5月于重庆医科大学附属第一医院血液内科行血缘相关造血干细胞移植（HSCT）的恶性血液病患者共计68例作为研究对象。按照接受血缘相关HSCT类型的不同，将其分为MSD-HSCT组（n=33）与haplo—HSCT组（n=35）。所有患者疾病诊断均符合《血液病诊断及疗效标准》（3版）中相应恶性血液病的诊断标准，本研究纳入标准；患者诊断符合恶性血液病诊断标准；临床资料完整。排除标准：临床资料不全者。对两组患者及供者的一般临床资料进行回顾性分析；检测HSCT后两组患者造血干细胞的植入情况；比较两组患者HSCT方案、输入造血干细胞数及移植相关并发症发生率、总体生存（OS）率、无病生存（DFS）率、复发率、死亡率，并进行统计学分析。本研究遵循的程序符合重庆医科大学附属第一医院人体试验委员会所制定的伦理学标准，得到该委员会批准。两组患者性别构成比、预处理方案类型及干细胞移植类型、供者年龄等一般临床资料相比，差异均无统计学意义（P〉O005）。结果①MSD-HSCT组与haplo—HSCT组患者疾病种类分布，疾病状态分布，供、受者间血型匹配程度相比，差异均无统计学意义（x^2=2．313、2．809、3．420，P=0．678、0．094、0．331）；但MSD-HSCT组患者年龄大于haplo-HSCT组，且差异有统计学意义（t=2．534，P=0．010）。②MSD-HSCT组患者输入单个核细胞（MNC）数为（15．0±3．8）×10^8／kg，haplo—HSCT组为（16．3±4．2）×10^8／kg，两组相比，差异无统计学意义（t=1．277，P=0．206）。MSD-HSCT组患者输入CD34^＋细胞数为（5．8±3．1）×10^6／kg，haplo—HSCT组为（6．8±2．7）×10^6／kg，两组相比，差异亦无统计学意义（t=1．062，P=0．294）。③MSD-HSCT组患者中性粒细胞植活平均时间为（12．7±2．9）d，早于haplo—HSCT组的（16．1±4．8）d，且差异有统计学意义（t=3．510，P=0．001）；MSD-HSCT组患者血小板植活平均时间为（12．7±4．9）d亦早于haplo-HSCT组的（16．1±7．9）d，且差异亦有统计学意义（t=2．094，P=0．016）。本研究68例患者移植后均获得造血功能重建。MSD-HSCT组与haplo—HSCT组供、受者嵌合度均为完全嵌合。④两组患者急性移植物抗宿主病（aGVHD）累积发生率（18．2％比22．9％）、慢性移植物抗宿主病（cGVHD）累积发生率（39．3％比26．9％）、植入综合征（ES）发生率（0比2．9％）、出血性膀胱炎（HC）发生率（24．2％比45．7％）、血栓性微血管病变（TMA）发生率（3．0％比2．9％）、肝静脉阻塞性疾病（VOD）发生率（3．0％比2．9％）、毛细血管渗漏综合征（CLS）发生率（O比2．9％）、疱疹发生率（24．2％比14．3％）、细菌感染发生率（33．3％比20．0％）、真菌感染发生率（12．1％比20．0％）、巨细胞病毒（CMV）感染发生率（9．1％比5．7％）、继发肿瘤发生率（3．0％比O）、可逆性脑后部白质综合征（RPLS）发生率（O比2．9％）相比，差异均无统计学意义（x^2=0．227、1．551、0．957、3．429、0．002、0．002、0．957、1．089、1．551、0．778、0．284、1．076、0．957，P=0．634、0．336、0．328、0．064、0．966、0．966、0．328、0．297、0．213、0．378、0．594、0．299、0．328）。⑤截至2015年9月1日，MSD-HSCT组共计21例患者存活，本组患者的死亡率为36．4％，复发率为18．2％，平均生存时间为（34．7±4．2）个月，3年OS率及DFS率分别为60．6％、56．0％。haplo—HSCT组23例存活，本组患者的死亡率为34．3％，复发率为5．7％，平均生存时间为（27．3±3．2）个月，3年OS率及DFS率分别为61．9％、58．5％。两组患者的复发率、死亡率相比，差异均无统计学意义（x^2=2．543、0．032，P=0．111、0．858）；两组患者平均生存时间比较，差异亦无统计学意义（t=1．537，P=0．129）；两组患者3年0S率及DFS率比较，差异无统计学意义（x^2=0．137、0．032，P=0．706、0．694）。结论恶性血液病患者接受MSD-HSCT后，造血重建时间早于接受haplo-HSCT者，但二者的OS率、DFS率、复发率、死亡率及移植物抗宿主病（GVHD）发生率相近。haplo—HSCT治疗恶性血液病的安全性及疗效与MSD-HSCT相似。

Objective To evaluate the safety and efficacy of haploidentical hematopoietic stem cell transplantation （haplo-HSCT） in the treatment of malignant hematopathy, through comparison with matched sibling donor hematopoietic stem cell transplantation （MSD-HSCT）. Methods From January 2011 to May 2015,a total of 68 patients who had accepted related donor hematopoietic stem cell transplantation （HSCT） in Department of Hematology, First Affiliated Hospital of Chongqing Medical University were enrolled into this retrospective study as study subjects. According to different types of related donor HSCT, 68 cases of patients were divided into MSD-HSCT group （n=33） and haplo-HSCT group （n=35）. All the cases were conformed to the diagnostic criteria of Standard of Diagnosis and Curative Effect of Hematology （3rd edition）. The inclusion criteria of this study： patientsp diagnosis were conformed to the diagnostic criteria of malignant hematopathy and clinical data were complete. Exclusion criteria： clinical data were not complete. Clinical data of donors and patients of the two groups were retrospectively analyzed. Implantations of hematopoietic stern cells in two groups after HSCT were tested. HSCT schemes, the number of input hematopoietic stem cells and outcome of engraftment, transplant related complications, overall survival （OS） rate, disease free survival （DFS） rate, incidence of relapse and mortality were compared and analyzed statistically. The study protocol was approved by the Ethical Review Board of Investigation in Human at First Affiliated Hospital of Chongqing Medical University. There were no statistically significant differences of patientsr clinical data, such as gender ratio, preprocessing solution type, type of stem cell transplantation and donorsr age between two groups （P〉0.05）. Results OThere were no statistical differences of patientsr disease, disease status, blood type between donors and recipients between the two groups （x^2 =2. 313, 2. 809, 3. 420; P=0. 678, 0. 094, 0. 331）. But the patients in MSD- HSCT group were older than haplo-HSCT group with statistical significance （t = 2. 534, P = 0. 010）. （2）There were no statistical differences of the input of mononuclear cells （MNC）E（15.0 ± 3.8） × 10^8/kg vs （16.3±4.2） × 10^8/kg）] and the CD34＋ cells [（5.8±3.1） × 106/kg vs （6.8± 2.7） × 10^6/kg] between the two groups （t=1. 277, 1. 062; P=0. 206, 0. 294）. OIn MSD-HSCT group, average time of neutrophils count over 0.5 × 10^9/L [-（12.7±2.9） d] was significantly earlier than that of hapto-HSCT group [（16.1± 4.8） d] （t=3. 510,P=0. 001）. Average time of platelets count over 20×10^9/L [（12.7±4. 9] d] was also significantly earlier than that of haplo-HSCT group -（16.1 ±7.9） d] （t= 2. 094, P = 0. 016）. All of the 68 patients obtained hematopoietic reconstruction and achieved chimeric state. （4）There were no statistical differences of cumulative incidence of acute graft versus host disease （aGVHD） （18. 2% vs 22. 9%）, cumulative incidence of chronic graft versus host disease （cGVHD） （39. 3% vs 26. 9%）, incidence of engraftment syndrome （ES） （0 vs 2. 9%）, hemorrhagic cystitis （HC） （24. 2% vs 45. 7%）, thrombotic microangiopathy （TMA） （3. 0% vs 2. 9%）, hepatic veno-occlusive disease （VOD） （3. 0% vs 2. 9%）, capillary leak syndrome （CLS） （0 vs 2.9%）, herpes （24.2% vs 14. 3%）, bacterial infection （33.3% vs 20.0%）, fungal infection （12. 1% vs 20. 0%）, cytomegalovirus （CMV） infection （9. 1% vs 5. 7%）, secondary tumors （3.0% vs 0）, reversible posterior leukoeneephalopathy syndrome （RPLS） （0 vs 2.9%） between the two groups （x^2=0. 227, 1. 551, 0. 957, 3. 429, 0. 002, 0. 002, 0. 957, 1. 089, 1. 551, 0. 778, 0.284, 1.076, 0.957; P=0. 634, 0.336, 0.328, 0.064, 0.966, 0.966, 0. 328, 0.297, 0.213, 0. 378, 0. 594, 0. 299, 0. 328）. （5）Up to September 1st, 2015, there were 21 patients survived in MSD-HSCT group, and the mortality was 36.4%, relapse rate was 18.2%. Mean survival time was （34. 7±4. 2） months, and OS and DFS rate of 3 years were 60. 6%, 56. 0%, respectively. Twenty-three patients survived in haplo-HSCT group, and the mortality was 34.3 %, relapse rate was 5.7 %. Mean survival time was （27.3±3.2） months, and OS and DFS rate of 3 years were 61.9%, 58.5% respectively. There were no statistical differences between relapse rate and mortality between two groups （x^2 = 2. 543, 0. 032; P=0. 111, 0.858）. There was also no statistical difference of mean survival time between two groups （t= 1. 537, P〈0. 129）. There were no statistical differences between OS and DFS rate of 3 years （x^2= 0. 137, 0. 032; P=0. 706, 0. 694）. Conclusions The hematopoietic reconstruction time of neutrophiIs and platelets in malignant hematopathy patients who received MSD-HSCT treatment were earlier than those malignant hematopathy patients who received haplo-HSCT treatment, but they got a similar rate of OS, DFS, relapse, mortality and graft versus host disease （GVHD）. Safety and efficacy of haplo-HSCT in treatment of malignant hematopathy is similar with MSD-HSCT.