异基因造血干细胞移植后慢性肝脏移植物抗宿主病的危险因素及预后分析
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摘要
目的:探讨异基因造血干细胞移植(allo-HSCT)后并发肝脏cGVHD患者的危险因素及预后。方法:总结2013年1月至2016年12月期间在本院接受allo-HSCT的147例患者临床资料,回顾性分析患者性别、年龄、移植前疾病状态、HLA相合程度、供者性别、干细胞类型、GVHD预防方案中是否加用ATG、预处理期间肝功能异常、移植前HBsAg、急性GVHD与肝脏cGVHD发生的关系,并分析肝脏cGVHD与患者预后关系。结果:32例患者发生肝脏cGVHD,累积发生率26.4%。单因素分析移植前HBsAg~+及预处理期间肝功能异常均与肝脏cGVHD无明显相关(P>0.05),多因素分析显示,早期出现aGVHD(HR=2.087,P=0.045)是肝脏cGVHD的独立危险因素,加用ATG显著降低肝脏cGVHD的发生率(HR=0.231,P=0.000)。单因素分析发生肝脏cGVHD与未发生组相比患者移植后2年复发率较低(P=0.038)。结论:移植早期出现aGVHD是肝脏cGVHD发生的独立危险因素,ATG可以减少肝脏cGVHD的发生率。肝脏cGVHD患者移植后2年复发率相对低。
Objective: To analyze the risk factors and prognosis of hepatic chronic GVHD after allogeneic hematopoietic stem cell transplantation( allo-HSCT). Methods: The clinical data of 147 patients undergoing allo-HSCT from January 2013 to December 2016 were analyzed,the correlation between recipient age and sex,disease state,matched degree of HLA,donor sex,stem cell sources,ATG in GVHD prophylaxis,liver dysfunction during conditioning period,pre-transplant HBsAg,prior aGVHD and hepatic cGVHD were studied,and the correlation between hepatic cGVHD and prognosis were analysed. Results: Thirty-two patients had hepatic cGVHD,cumulative incidence of 26. 4%. In univariate analysis,pre-transplant HBsAg + and liver dysfunction during conditioning period were not significantly related with hepatic cGVHD( P > 0. 05). In multivariate analysis,prior acute GVHD( HR = 2. 087,P =0. 045) was the independent risk factor for hepatic cGVHD,ATG( HR = 0. 231,P = 0. 000) was significantly related with a lower incidence of hepatic cGVHD. In univariate analysis,patients with hepatic cGVHD had a lower 2 years relapse rate( P = 0. 038). Conclusion: Prior acute GVHD is the independent risk factor for hepatic cGVHD,the ATG can significantly reduce the incidence of hepatic cGVHD. Hepatic cGVHD has been found to relate with a lower 2 years relapse rate.
Objective: To analyze the risk factors and prognosis of hepatic chronic GVHD after allogeneic hematopoietic stem cell transplantation( allo-HSCT). Methods: The clinical data of 147 patients undergoing allo-HSCT from January 2013 to December 2016 were analyzed,the correlation between recipient age and sex,disease state,matched degree of HLA,donor sex,stem cell sources,ATG in GVHD prophylaxis,liver dysfunction during conditioning period,pre-transplant HBsAg,prior aGVHD and hepatic cGVHD were studied,and the correlation between hepatic cGVHD and prognosis were analysed. Results: Thirty-two patients had hepatic cGVHD,cumulative incidence of 26. 4%. In univariate analysis,pre-transplant HBsAg + and liver dysfunction during conditioning period were not significantly related with hepatic cGVHD( P > 0. 05). In multivariate analysis,prior acute GVHD( HR = 2. 087,P =0. 045) was the independent risk factor for hepatic cGVHD,ATG( HR = 0. 231,P = 0. 000) was significantly related with a lower incidence of hepatic cGVHD. In univariate analysis,patients with hepatic cGVHD had a lower 2 years relapse rate( P = 0. 038). Conclusion: Prior acute GVHD is the independent risk factor for hepatic cGVHD,the ATG can significantly reduce the incidence of hepatic cGVHD. Hepatic cGVHD has been found to relate with a lower 2 years relapse rate.
引文
1 Arnaout K,Patel N,Jain M,et al.Complications of allogeneic hematopoietic stem cell transplantation.Cancer Invest,2014;32(7):349-362.
2 Paczesny S,Hakim FT,Pidala J,et al.National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease:Ⅲ.The 2014 biomarker working group report.Biol Blood Marrow Transplant,2015;21(5):780-792.
3 Flowers ME,Inamoto Y,Carpenter PA,et al.Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graftversushost disease according to National Institutes of Health consensus criteria.Blood,2011;117(11):3214-3219.
4 Kanda J,Nakasone H,Atsuta Y,et al.Risk factors and organ involvement of chronic GVHD in Japan.Bone Marrow Transplant,2014;49(2):228-235.
5 Yang F,Lu D,Hu Y,et al.Risk factors for graft-versus-host disease after transplantation of hematopoietic stem cells from unrelated donors in the China marrow donor program.Ann Transplant,2017;22:384-401.
6 Abdul Wahid SF,Ismail NA,Mohd-Idris MR,et al.Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia:a metaanalysis.Stem Cells Dev,2014;23(21):2535-2552.
7 Sakamoto S,Kawabata H,Kanda J,et al.Differing impacts of pretransplant serum ferritin and C-reactive protein levels on the incidence of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.Int J Hematol,2013;97(1):109-116.
8 McDonald GB,Frieze D.A problem-oriented approach to liver disease in oncology patients.Gut,2008;57(7):987-1003.
9 Przepiorka D,Weisdorf D,Martin P,et al.1994 Consensus Conference on Acute GVHD Grading.Bone Marrow Transplant,1995;15(6):825-828.
10 Filipovich AH,Weisdorf D,Pavletic S,et al.National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease:I.Diagnosis and staging working group report.Biol Blood Marrow Transplant,2005;11(12):945-956.
11 King PD.Hepatotoxicity of chemotherapy.The oncologist,2001;6(2):162-176.
12 El-Sayed MH,El-Haddad A,Fahmy OA,et al.Liver disease is a major cause of mortality following allogeneic bone-marrow transplantation.Eur J Gastroenterol Hepatol,2004;16(12):1347-1354.
13 Lee SJ,Flowers ME.Recognizing and managing chronic graft-versushost disease.Hematology Am Soc Hematol Educ Program,2008:134-141.doi:10.1182/asheducation-2008.1.134
14 Grube M,Holler E,Weber D,et al.Risk factors and outcome of chronic graft-versus-host disease after allogeneic stem cell transplantation-results from a single-center observational study.Biol Blood Marrow Transplant,2016;22(10):1781-1791.
15 Arai Y,Jo T,Matsui H,et al.Efficacy of antithymocyte globulin for allogeneic hematopoietic cell transplantation:a systematic review and meta-analysis.Leuk Lymphoma,2017;58(8):1840-1848.
16 Soiffer RJ,Lerademacher J,Ho V,et al.Impact of immune modulation with anti-T-cell antibodies on the outcome of reducedintensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies.Blood,2011;117(25):6963-6970.
17 Wang Y,Fu HX,Liu DH,et al.Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation:a randomized trial.Bone Marrow Transplant,2014;49(3):426-433.
18赵珺,任汉云,邱志祥,等.移植前及预处理期间肝功能异常对异基因造血干细胞移植效果的影响.中华内科杂志,2014;53(2):99-103.
19 Nordlander A,Mattsson J,Ringdén O,et al.Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia.Biol Blood Marrow Transplant,2004;10(3):195-203.
20 Passweg JR,Tiberghien P,Cahn JY,et al.Graft-versusleukemia effects in T lineage and B lineage acute lymphoblastic leukemia.Bone Marrow Transplant,1998;21(2):153-158.
2 Paczesny S,Hakim FT,Pidala J,et al.National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease:Ⅲ.The 2014 biomarker working group report.Biol Blood Marrow Transplant,2015;21(5):780-792.
3 Flowers ME,Inamoto Y,Carpenter PA,et al.Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graftversushost disease according to National Institutes of Health consensus criteria.Blood,2011;117(11):3214-3219.
4 Kanda J,Nakasone H,Atsuta Y,et al.Risk factors and organ involvement of chronic GVHD in Japan.Bone Marrow Transplant,2014;49(2):228-235.
5 Yang F,Lu D,Hu Y,et al.Risk factors for graft-versus-host disease after transplantation of hematopoietic stem cells from unrelated donors in the China marrow donor program.Ann Transplant,2017;22:384-401.
6 Abdul Wahid SF,Ismail NA,Mohd-Idris MR,et al.Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia:a metaanalysis.Stem Cells Dev,2014;23(21):2535-2552.
7 Sakamoto S,Kawabata H,Kanda J,et al.Differing impacts of pretransplant serum ferritin and C-reactive protein levels on the incidence of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.Int J Hematol,2013;97(1):109-116.
8 McDonald GB,Frieze D.A problem-oriented approach to liver disease in oncology patients.Gut,2008;57(7):987-1003.
9 Przepiorka D,Weisdorf D,Martin P,et al.1994 Consensus Conference on Acute GVHD Grading.Bone Marrow Transplant,1995;15(6):825-828.
10 Filipovich AH,Weisdorf D,Pavletic S,et al.National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease:I.Diagnosis and staging working group report.Biol Blood Marrow Transplant,2005;11(12):945-956.
11 King PD.Hepatotoxicity of chemotherapy.The oncologist,2001;6(2):162-176.
12 El-Sayed MH,El-Haddad A,Fahmy OA,et al.Liver disease is a major cause of mortality following allogeneic bone-marrow transplantation.Eur J Gastroenterol Hepatol,2004;16(12):1347-1354.
13 Lee SJ,Flowers ME.Recognizing and managing chronic graft-versushost disease.Hematology Am Soc Hematol Educ Program,2008:134-141.doi:10.1182/asheducation-2008.1.134
14 Grube M,Holler E,Weber D,et al.Risk factors and outcome of chronic graft-versus-host disease after allogeneic stem cell transplantation-results from a single-center observational study.Biol Blood Marrow Transplant,2016;22(10):1781-1791.
15 Arai Y,Jo T,Matsui H,et al.Efficacy of antithymocyte globulin for allogeneic hematopoietic cell transplantation:a systematic review and meta-analysis.Leuk Lymphoma,2017;58(8):1840-1848.
16 Soiffer RJ,Lerademacher J,Ho V,et al.Impact of immune modulation with anti-T-cell antibodies on the outcome of reducedintensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies.Blood,2011;117(25):6963-6970.
17 Wang Y,Fu HX,Liu DH,et al.Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation:a randomized trial.Bone Marrow Transplant,2014;49(3):426-433.
18赵珺,任汉云,邱志祥,等.移植前及预处理期间肝功能异常对异基因造血干细胞移植效果的影响.中华内科杂志,2014;53(2):99-103.
19 Nordlander A,Mattsson J,Ringdén O,et al.Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia.Biol Blood Marrow Transplant,2004;10(3):195-203.
20 Passweg JR,Tiberghien P,Cahn JY,et al.Graft-versusleukemia effects in T lineage and B lineage acute lymphoblastic leukemia.Bone Marrow Transplant,1998;21(2):153-158.