亲缘单倍体造血干细胞移植治疗急性巨核细胞白血病的疗效及安全性分析
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摘要
目的探讨单倍型异基因造血干细胞移植(Haplo-HSCT)治疗急性巨核细胞白血病(AMKL)的疗效及安全性分析。方法回顾性分析2013年2月-2018年4月我院收治14例AMKL患儿进行Haplo-HSCT的临床资料并复习相关文献。男性9例,女性5例,中位年龄2(1. 4～3)岁,13例为第一次Haplo-HSCT,1例为非血缘全相合无关供者移植半年后复发挽救性二次移植。HLA配型均为父母亲单倍型。使用清髓性预处理方案,同时兼顾患儿个体实际情况制定的个体化方案。移植物为骨髓和/或外周血干细胞,输注单个核细胞中位数为10. 2(2.3～12.7)×10~8/kg,CD34+细胞中位数为6.2(2.0～11.5)×10~6/kg,非血缘脐带血做为第三方细胞辅助治疗。结果中性粒细胞、血小板重建的中位天数分别为14d和15d。28d评价供受者间基因嵌合率完全供者型占92%(12/13),1例移植后排斥,1例移植11d尚未植活,死于弥漫性肺出血。Ⅰ～Ⅳ度aGVHD发生率为61%(8/13),其中Ⅲ～Ⅳ度aGVHD3例,其中1例因aGVHD死亡,cGVHD累积发生率53%(7/13),其中广泛型cGVHD为0。CMV/EBV病毒激活率30%(4/13)。3例移植后早期复发(100d内),复发率为23%(3/13),9例患儿免疫残留持续阴性,为供者型完全嵌合,无病生存至今,存活的9例患者中位随访时间21(8～61)个月,总生存率为64%(9/14)。结论 AMKL单纯依靠化疗预后差,Haplo-HSCT可以改善AMKL患儿预后,提高生存率,但仍有部分患儿早期复发,减少复发的手段值得进一步探讨。
Objective To investigate the efficacy of haplotype allogeneic hematopoietic stem cell transplantation( Haplo-HSCT) in the treatment of acute megakaryocytic leukemia( AMKL). Methods Clinical data about Haplo-HSCT of 14 children with AMKL admitted in Bayi Children's Hospital Affiliated to Army General Hospital from February 2013 to April 2018 were analyzed retrospectively and related literatures were reviewed. There were 9 males and 5 females, the median age was 2(ranged 1. 4-3) years old. 13 cases were treated with Haplo-HSCT for the first time. One case is recurrent rescue secondary transplantation of a non-blood matched unrelated donor after six months. All HLA matching types were parental haplotypes. The actual situation of the individual program was taken into account when myeloablative preconditioning regimen was used. The transplant was bone marrow and/or peripheral blood stem cell. The median of mononuclear cells infused was 10.2( 2.3-12.7) × 10~8/kg.The median of CD34 + cells was 6.2(2. 0-11.5) × 10~6/kg. Unrelated cord blood was used as a thirdparty cell adjuvant therapy. Results The median days of neutrophil and platelet reconstruction were 14 days and 15 days, respectively. Complete donor type of gene chimerism rate among donor recipients within 28 days accounted for 92%(12/13). There was 1 case of rejection after transplantation. One case which had not been alive after being transplanted for 11 days died of diffuse pulmonary hemorrhage. The incidence of Ⅰ-Ⅳ aGVHD was 61%, among which 3 cases were Ⅲ-Ⅳ severe aGVHD. One case died from aGVHD. Cumulative incidence of chronic GVHD was 53%(7/13). The prevalence of chronic GVHD was 0. The activation rate of CMV/EBV virus was 30%(4/13). There were 3 cases of early recurrence after transplantation(within 100 days). The recurrence rate was 23%(3/13). There are now9 children with persistent negative immune residue which was donor complete chimerism. They survived till now. The median follow-up time of 9 surviving patients was 21(8-61) months, and the overall survival rate was 64%(9/14). Conclusions AMKL has poor prognosis only be treated by chemotherapy. Haplo-HSCT can improve prognosis of patients with AMKL and improve survival rate.However, there are still some patients with early recurrence, the method of reducing recurrence is worth further exploring.
Objective To investigate the efficacy of haplotype allogeneic hematopoietic stem cell transplantation( Haplo-HSCT) in the treatment of acute megakaryocytic leukemia( AMKL). Methods Clinical data about Haplo-HSCT of 14 children with AMKL admitted in Bayi Children's Hospital Affiliated to Army General Hospital from February 2013 to April 2018 were analyzed retrospectively and related literatures were reviewed. There were 9 males and 5 females, the median age was 2(ranged 1. 4-3) years old. 13 cases were treated with Haplo-HSCT for the first time. One case is recurrent rescue secondary transplantation of a non-blood matched unrelated donor after six months. All HLA matching types were parental haplotypes. The actual situation of the individual program was taken into account when myeloablative preconditioning regimen was used. The transplant was bone marrow and/or peripheral blood stem cell. The median of mononuclear cells infused was 10.2( 2.3-12.7) × 10~8/kg.The median of CD34 + cells was 6.2(2. 0-11.5) × 10~6/kg. Unrelated cord blood was used as a thirdparty cell adjuvant therapy. Results The median days of neutrophil and platelet reconstruction were 14 days and 15 days, respectively. Complete donor type of gene chimerism rate among donor recipients within 28 days accounted for 92%(12/13). There was 1 case of rejection after transplantation. One case which had not been alive after being transplanted for 11 days died of diffuse pulmonary hemorrhage. The incidence of Ⅰ-Ⅳ aGVHD was 61%, among which 3 cases were Ⅲ-Ⅳ severe aGVHD. One case died from aGVHD. Cumulative incidence of chronic GVHD was 53%(7/13). The prevalence of chronic GVHD was 0. The activation rate of CMV/EBV virus was 30%(4/13). There were 3 cases of early recurrence after transplantation(within 100 days). The recurrence rate was 23%(3/13). There are now9 children with persistent negative immune residue which was donor complete chimerism. They survived till now. The median follow-up time of 9 surviving patients was 21(8-61) months, and the overall survival rate was 64%(9/14). Conclusions AMKL has poor prognosis only be treated by chemotherapy. Haplo-HSCT can improve prognosis of patients with AMKL and improve survival rate.However, there are still some patients with early recurrence, the method of reducing recurrence is worth further exploring.
引文
1. Garderet L, Labopin M, Gorin N C, et al. Hematopoietic stem cell transplantation for de novo acute megakaryocytic leukemia in first complete remission:a retrospective study of the European Group for Blood and Marrow Transplantation(EBMT). Blood, 2005, 105:405-409.
2.张之南.血液病诊断及疗效标准第二版.科学出版社,1998.
3.罗荣牡,达万明,胡波,等.清肿瘤化疗方案联合低强度改良预处理方案用于异基因造血干细胞移植治疗30例恶性血液病的安全性和疗效初探.中国实验血液学杂志,2014, 22:1047-1052.
4.杜振兰,陈鹏,罗荣牡,等.第三方脐血辅助输注的单倍型造血干细胞移植36例疗效分析.中华全科医师杂志,2014, 8:1200-1203.
5. Bourquin J P, Subramanian A, Langebrake C, et al. Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci U S A,2006, 103:3339-3344.
6. Savasan S, Buck S, Raimondi S C,et al. CD36(thrombospondin receptor)expression in childhood acute megakaryoblastic leukemia:in vitro drug sensitivity and outcome]. Leukemia&Lymphoma,2006, 47:2076-2083.
7. Athale UH, Razzouk BI, Raimondi SC, et al. Biology and outcome of childhood acute megakaryoblastic leukemia:a single institution's experience. Blood, 2001, 97:3727-3732.
8.金眉,吴润晖.儿童急性巨核细胞白血病9例分析.中国小儿血液与肿瘤杂志,2008, 13:224-227.
9.杨文钰,陈晓娟,李梅,等.儿童急性巨核细胞白血病临床生物学特征分析.中国小儿血液与肿瘤杂志,2008, 13:121-124.
10.安琪,方代华,徐淑梅,等.儿童急性巨核细胞白血病MICM分型诊断.中国小儿血液与肿瘤杂志,2015, 20:145-150.
11. Hama A, Yagasaki H, Takahashi Y, et al. Acute megakaryoblastic leukaemia(AMKL)in children:a comparison of AMKL with and without Down syndrome. Bri J Haematol, 2008, 140:552-561.
12. Tandonnet J, Clavel J, Baruchel A, et al. Myeloid leukaemia in children with down syndrome:Report of the registry-based French experience between 1990 and 2003. Pediatric Blood&Cancer,2010, 54:927-933.
13.周进,王婧,刘辉,等.含地西他滨方案桥接异基因造血干细胞移植治疗MDS/AML的效果评估.中华医学杂志,2015, 95:920-924.
14.程龙灿,刘娜,陈健琳,等.地西他滨强化预处理方案造血干细胞移植治疗难治复发急性髄性白血病的临床研究.军事医学,2017.
15.曹翊雄,李君君,罗泽宇,等.HHT联合CAG治疗复发难治性急性髄系白血病的疗效观察.中国现代医学杂志,2016, 18:8-11.
16.王涛,马梁明,朱秋娟,等.氟达拉滨联合中剂量阿糖胞苷治疗复发难治性急性髄系白血病效果观察.白血病·淋巴瘤,2014,23:216-222.
17.南虎松,金春姬,刘红,等.地西他滨联合减量FLAG方案治疗复发难治型急性髓系白血病的疗效分析.中国现代医学杂志,2015,28:78-81.
18. Daihong Liu, Xiaojun Huang, Kaiyan Liu, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematologic malignancies in children. Biol Blood Marrow Transplant, 2008, 14:469-477.
19.黄晓军.构建有中国特色的造血干细胞移植体系.中华血液学杂志,2012, 33:601-602.
2.张之南.血液病诊断及疗效标准第二版.科学出版社,1998.
3.罗荣牡,达万明,胡波,等.清肿瘤化疗方案联合低强度改良预处理方案用于异基因造血干细胞移植治疗30例恶性血液病的安全性和疗效初探.中国实验血液学杂志,2014, 22:1047-1052.
4.杜振兰,陈鹏,罗荣牡,等.第三方脐血辅助输注的单倍型造血干细胞移植36例疗效分析.中华全科医师杂志,2014, 8:1200-1203.
5. Bourquin J P, Subramanian A, Langebrake C, et al. Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci U S A,2006, 103:3339-3344.
6. Savasan S, Buck S, Raimondi S C,et al. CD36(thrombospondin receptor)expression in childhood acute megakaryoblastic leukemia:in vitro drug sensitivity and outcome]. Leukemia&Lymphoma,2006, 47:2076-2083.
7. Athale UH, Razzouk BI, Raimondi SC, et al. Biology and outcome of childhood acute megakaryoblastic leukemia:a single institution's experience. Blood, 2001, 97:3727-3732.
8.金眉,吴润晖.儿童急性巨核细胞白血病9例分析.中国小儿血液与肿瘤杂志,2008, 13:224-227.
9.杨文钰,陈晓娟,李梅,等.儿童急性巨核细胞白血病临床生物学特征分析.中国小儿血液与肿瘤杂志,2008, 13:121-124.
10.安琪,方代华,徐淑梅,等.儿童急性巨核细胞白血病MICM分型诊断.中国小儿血液与肿瘤杂志,2015, 20:145-150.
11. Hama A, Yagasaki H, Takahashi Y, et al. Acute megakaryoblastic leukaemia(AMKL)in children:a comparison of AMKL with and without Down syndrome. Bri J Haematol, 2008, 140:552-561.
12. Tandonnet J, Clavel J, Baruchel A, et al. Myeloid leukaemia in children with down syndrome:Report of the registry-based French experience between 1990 and 2003. Pediatric Blood&Cancer,2010, 54:927-933.
13.周进,王婧,刘辉,等.含地西他滨方案桥接异基因造血干细胞移植治疗MDS/AML的效果评估.中华医学杂志,2015, 95:920-924.
14.程龙灿,刘娜,陈健琳,等.地西他滨强化预处理方案造血干细胞移植治疗难治复发急性髄性白血病的临床研究.军事医学,2017.
15.曹翊雄,李君君,罗泽宇,等.HHT联合CAG治疗复发难治性急性髄系白血病的疗效观察.中国现代医学杂志,2016, 18:8-11.
16.王涛,马梁明,朱秋娟,等.氟达拉滨联合中剂量阿糖胞苷治疗复发难治性急性髄系白血病效果观察.白血病·淋巴瘤,2014,23:216-222.
17.南虎松,金春姬,刘红,等.地西他滨联合减量FLAG方案治疗复发难治型急性髓系白血病的疗效分析.中国现代医学杂志,2015,28:78-81.
18. Daihong Liu, Xiaojun Huang, Kaiyan Liu, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematologic malignancies in children. Biol Blood Marrow Transplant, 2008, 14:469-477.
19.黄晓军.构建有中国特色的造血干细胞移植体系.中华血液学杂志,2012, 33:601-602.