造血干细胞移植治疗重型再生障碍性贫血:血小板生成素促血小板植入的有效性和安全性
|
摘要
背景:研究表明,异基因造血干细胞移植后应用血小板生成素在造血调控、造血重建等方面有一定作用,为临床推广应用提供理论基础。目的:分析血小板生成素在异基因造血干细胞移植治疗重型再生障碍性贫血中促进血小板植入的临床疗效和安全性。方法:2012年1月至2017年1月共入选50例接受异基因造血干细胞移植治疗的重型再生障碍性贫血患者,分为治疗组和对照组各25例,其中男28例,女22例,平均年龄27.8(16-48)岁,治疗组在移植后7 d起应用血小板生成素300 U/kg,连续14 d,比较两组患者血小板植入后在≥20×10~9 L~(-1)、50×10~9 L~(-1)和100×10~9 L~(-1)的时间节点及血小板中位输注次数。该治疗方案得到解放军陆军总医院伦理委员会批准和患者知情同意。结果与结论:两组患者均获造血重建,治疗组和对照组血小板≥20×10~9 L~(-1)、50×10~9 L~(-1)和100×10~9 L~(-1)的中位时间分别为16.2,19.3,30.2 d和18.8,25.8,38.5 d,治疗组血小板植入时间比对照组分别提前2.6,6.5,8.3 d,辐照血小板中位输注次数分别为6.8次和9.5次,两组数据结果显示差异有显著性意义(P <0.05)。随访至2017年7月,两组患者无病生存率分别为80%,72%。结果表明,血小板生成素能够促进异基因造血干细胞移植后血小板植入及恢复,且患者耐受性好,值得临床进一步推广应用。
BACKGROUND: Studies have shown that the use of thrombopoietin after allogeneic hematopoietic stem cell transplantation has a certain role in hematopoietic regulation and hematopoietic reconstitution, providing a theoretical basis for clinical application. OBJECTIVE: To analyze the clinical efficacy and safety of thrombopietin in the treatment of severe aplastic anemia after hematopoietic stem cell transplantation. METHODS: Fifty patients receiving allogeneic hematopoietic stem cell transplantation from January 2012 to January 2017 including 28 males and 22 females with the mean age of 27.8(16-48) years were enrolled. Patients received 300 U/kg thrombopietin(treatment group, n=25) subcutaneously, which began at 7 days after transplantation, or were only treated with symptomatic treatment(control group, n=25). Time node of platelet implantation in two groups of patients ≥ 20×10~9/L, 50×10~9/L, and 100×10~9/L and median Infusion times of platelet were compared between two groups. The study protocol was approved by the Ethics Committee of Army General Hospital, and enrolled patients signed informed consent prior to the inception of the trial. RESULTS AND CONCLUSION: The median time of platelet implantation ≥ 20×10~9/L, 50×10~9/L, and 100×10~9/L was 16.2, 19.3, and 30.2 days in the treatment group and 18.8, 25.8, and 38.5 days in the control group, respectively. The time of platelet implantation time in the treatment group was 2.6, 6.5, and 8.3 days earlier than that in the control group. The median number of irradiated platelet implantation was 6.8 times in the treatment group and 9.5 times in the control group. There was a significant difference between the two groups(P < 0.05). All the patients were followed up to July 2017, and the disease-free survival rates were 80% in the treatment group and 72% in the control group. These findings indicate that thrombopietin can promote platelet implantation and recovery after allogeneic hematopoietic stem cell transplantation, and is well tolerated, which is worthy of further clinical application.
BACKGROUND: Studies have shown that the use of thrombopoietin after allogeneic hematopoietic stem cell transplantation has a certain role in hematopoietic regulation and hematopoietic reconstitution, providing a theoretical basis for clinical application. OBJECTIVE: To analyze the clinical efficacy and safety of thrombopietin in the treatment of severe aplastic anemia after hematopoietic stem cell transplantation. METHODS: Fifty patients receiving allogeneic hematopoietic stem cell transplantation from January 2012 to January 2017 including 28 males and 22 females with the mean age of 27.8(16-48) years were enrolled. Patients received 300 U/kg thrombopietin(treatment group, n=25) subcutaneously, which began at 7 days after transplantation, or were only treated with symptomatic treatment(control group, n=25). Time node of platelet implantation in two groups of patients ≥ 20×10~9/L, 50×10~9/L, and 100×10~9/L and median Infusion times of platelet were compared between two groups. The study protocol was approved by the Ethics Committee of Army General Hospital, and enrolled patients signed informed consent prior to the inception of the trial. RESULTS AND CONCLUSION: The median time of platelet implantation ≥ 20×10~9/L, 50×10~9/L, and 100×10~9/L was 16.2, 19.3, and 30.2 days in the treatment group and 18.8, 25.8, and 38.5 days in the control group, respectively. The time of platelet implantation time in the treatment group was 2.6, 6.5, and 8.3 days earlier than that in the control group. The median number of irradiated platelet implantation was 6.8 times in the treatment group and 9.5 times in the control group. There was a significant difference between the two groups(P < 0.05). All the patients were followed up to July 2017, and the disease-free survival rates were 80% in the treatment group and 72% in the control group. These findings indicate that thrombopietin can promote platelet implantation and recovery after allogeneic hematopoietic stem cell transplantation, and is well tolerated, which is worthy of further clinical application.
引文
[1]Park SS,Kwak DH,Jeon YW,et al.Beneficial Role of Low-Dose Antithymocyte Globulin in Unrelated Stem Cell Transplantation for Adult Patients with Acquired Severe Aplastic Anemia:Reduction of Graft-versus-Host Disease and Improvement of Graft-versusHost Disease-Free,Failure-Free Survival Rate.Biol Blood Marrow Transplant 2017;23(9):1498-1508.
[2]Mori T,Onishi Y,Ozawa Y,et al.Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with hepatitis-associated aplastic anemia.Int J Hematol.2019;109(6):711-717.
[3]Kim H,Im HJ,Koh KN,et al.Comparable Outcome with a Faster Engraftment of Optimized Haploidentical Hematopoietic Stem Cell Transplantation Compared with Transplantations from Other Donor Types in Pediatric Acquired Aplastic Anemia.Biol Blood Marrow Transplant.2019;25(5):965-974.
[4]郭智,刘晓东,杨凯,等.allo-HSCT并使用高剂量环磷酰胺诱导免疫耐受治疗重型再生障碍性贫血[J].中华器官移植杂志,2015,36(6):356-361.
[5]Ghanem KM,Kharfan-Dabaja MA,El-Solh H,et al.Fludarabine-based reduced intensity regimen for matched related donor hematopoietic stem cell transplantation in acquired severe aplastic anemia.Curr Res Transl Med.2017;65(3):115-119.
[6]Shin SH,Jeon YW,Yoon JH,et al.Comparable outcomes between younger(?40 years)and older(>40 years)adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning.Bone Marrow Transplant.2016;51(11):1456-1463.
[7]郭智,陈惠仁.单倍体造血干细胞移植后高剂量环磷酰胺诱导免疫耐受治疗再生障碍性贫血的研究[J].中华器官移植杂志,2015,36(12):753-755.
[8]童春,郭智,楼金星,等.单倍型异基因造血干细胞移植治疗重型再生障碍性贫血:回顾性分析[J].中国组织工程研究,2015,19(36):5821-5826.
[9]Yahng SA,Park SS,Jeon YW,et al.Successful outcomes of second hematopoietic stem cell transplantation with total nodal irradiation and ATG conditioning for graft failure in adult patients with severe aplastic anemia.Bone Marrow Transplant.2018;53(10):1270-1277.
[10]Rodeghiero F,Ruggeri M.Treatment of immune thrombocytopenia in adults:the role of thrombopoietin-receptor agonists.Semin Hematol.2015;52(1):16-24.
[11]Elmahdi S,Muramatsu H,Narita A,et al.Markedly High Plasma Thrombopoietin(TPO)Level is a Predictor of Poor Response to Immunosuppressive Therapy in Children With Acquired Severe Aplastic Anemia.Pediatr Blood Cancer.2016;63(4):659-664.
[12]Zhang Y,Lin CHS,Kaushansky K,et al.JAK2V617FMegakaryocytes Promote Hematopoietic Stem/Progenitor Cell Expansion in Mice Through Thrombopoietin/MPL Signaling.Stem Cells.2018;36(11):1676-1684.
[13]徐云华,成柏君,陆舜,等.短程间歇预防性给予重组人血小板生成素治疗肺癌化疗诱导的严重血小板减少的疗效[J].中华肿瘤杂志,2011,33(5):395-399.
[14]Bosch-Vilaseca A,García-Cadenas I,Roldán E,et al.Usefulness of thrombopoietin receptor agonists for persistent clinically relevant thrombocytopenia after allogeneic stem cell transplantation.Eur J Haematol.2018;101(3):407-414.
[15]Zhang Y,Guo Z,Liu XD,et al.Comparison of Haploidentical Hematopoietic Stem Cell Transplantation and Immunosuppressive Therapy for the Treatment of Acquired Severe Aplastic Anemia in Pediatric Patients.Am J Ther.2017;24(2):e196-e201.
[16]Guo Z,Gao HY,Zhang TY,et al.Analysis of allogeneic hematopoietic stem cell transplantation with high-dose cyclophosphamide-induced immune tolerance for severe aplastic anemia.Int J Hematol.2016;104(6):720-728.
[17]郭智,童春,刘晓东,等.单倍型异基因造血干细胞移植后大剂量环磷酰胺诱导免疫耐受治疗儿童重型再生障碍性贫血[J].中国组织工程研究,2016,20(32):4818-4824.
[18]郭智,陈惠仁,杨凯,等.免疫耐受新方法单倍型造血干细胞移植治疗重型再生障碍性贫血[J].中国组织工程研究,2015,19(41):6683-6687.
[19]Yang S,Yuan X,Ma R,et al.Comparison of Outcomes of Frontline Immunosuppressive Therapy and Frontline Haploidentical Hematopoietic Stem Cell Transplantation for Children with Severe Aplastic Anemia Who Lack an HLA-Matched Sibling Donor.Biol Blood Marrow Transplant.2019;25(5):975-980.
[20]郭智,陈惠仁,刘晓东,等.低强度预处理联合移植后诱导免疫耐受的单倍体相合Allo-HSCT治疗重型再生障碍性贫血的临床疗效研究[J].中国实验血液学杂志,2016,24(6):1811-1816.
[21]郭智,任骅,胡亮钉,等.重型再生障碍性贫血移植后合并肺部侵袭性真菌感染6例临床分析[J].解放军医学杂志,2017,42(12):1097-1101.
[22]Barbieri D,Elvira-Matelot E,Pelinski Y,et al.Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response.J Exp Med.2018;215(5):1463-1480.
[23]程莹,孙延庆,张雯洁,等.重组人血小板生成素促进异基因造血干细胞移植后血小板恢复的Meta分析[J].现代肿瘤医学,2015,23(10):1446-1451.
[24]孙明玲,王新有,江明,等.重组人血小板生成素联合大剂量地塞米松治疗初治原发性免疫性血小板减少症的临床分析[J].中华内科杂志,2016,55(3):202-205.
[25]Lakhwani S,Perera M,Fernández-Fuertes F,et al.Thrombopoietin receptor agonist switch in adult primary immune thrombocytopenia patients:A retrospective collaborative survey involving 4 Spanish centres.Eur J Haematol.2017;99(4):372-377.
[26]Taylor A,Westwood JP,Laskou F,et al.Thrombopoetin receptor agonist therapy in thrombocytopenia:ITP and beyond.Br JHaematol.2017;177(3):475-480.
[27]Gudbrandsdottir S,Ghanima W,Nielsen CH,et al.Effect of thrombopoietin-receptor agonists on circulating cytokine and chemokine levels in patients with primary immune thrombocytopenia(ITP).Platelets.2017;28(5):478-483.
[28]Blair TA,Moore SF,Walsh TG,et al.Phosphoinositide 3-kinase p110αnegatively regulates thrombopoietin-mediated platelet activation and thrombus formation.Cell Signal.2018;50:111-120.
[29]Barbieri D,Elvira-Matelot E,Pelinski Y,et al.Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response.J Exp Med.2018;215(5):1463-1480.
[30]苗瞄,吴德沛,曹祥山,等.血小板生成素在异基因造血干细胞移植后促进血小板植入的临床研究[J].中华血液学杂志,2012,33(5):362-365.
[31]江岷,潘欣,徐晨,等.重组人血小板生成素促进异基因造血干细胞移植血小板恢复的随机对照临床试验[J].血栓与止血学,2011,17(6):247-253.
[32]Rodeghiero F,Carli G.Beyond immune thrombocytopenia:the evolving role of thrombopoietin receptor agonists.Ann Hematol.2017;96(9):1421-1434.
[2]Mori T,Onishi Y,Ozawa Y,et al.Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with hepatitis-associated aplastic anemia.Int J Hematol.2019;109(6):711-717.
[3]Kim H,Im HJ,Koh KN,et al.Comparable Outcome with a Faster Engraftment of Optimized Haploidentical Hematopoietic Stem Cell Transplantation Compared with Transplantations from Other Donor Types in Pediatric Acquired Aplastic Anemia.Biol Blood Marrow Transplant.2019;25(5):965-974.
[4]郭智,刘晓东,杨凯,等.allo-HSCT并使用高剂量环磷酰胺诱导免疫耐受治疗重型再生障碍性贫血[J].中华器官移植杂志,2015,36(6):356-361.
[5]Ghanem KM,Kharfan-Dabaja MA,El-Solh H,et al.Fludarabine-based reduced intensity regimen for matched related donor hematopoietic stem cell transplantation in acquired severe aplastic anemia.Curr Res Transl Med.2017;65(3):115-119.
[6]Shin SH,Jeon YW,Yoon JH,et al.Comparable outcomes between younger(?40 years)and older(>40 years)adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning.Bone Marrow Transplant.2016;51(11):1456-1463.
[7]郭智,陈惠仁.单倍体造血干细胞移植后高剂量环磷酰胺诱导免疫耐受治疗再生障碍性贫血的研究[J].中华器官移植杂志,2015,36(12):753-755.
[8]童春,郭智,楼金星,等.单倍型异基因造血干细胞移植治疗重型再生障碍性贫血:回顾性分析[J].中国组织工程研究,2015,19(36):5821-5826.
[9]Yahng SA,Park SS,Jeon YW,et al.Successful outcomes of second hematopoietic stem cell transplantation with total nodal irradiation and ATG conditioning for graft failure in adult patients with severe aplastic anemia.Bone Marrow Transplant.2018;53(10):1270-1277.
[10]Rodeghiero F,Ruggeri M.Treatment of immune thrombocytopenia in adults:the role of thrombopoietin-receptor agonists.Semin Hematol.2015;52(1):16-24.
[11]Elmahdi S,Muramatsu H,Narita A,et al.Markedly High Plasma Thrombopoietin(TPO)Level is a Predictor of Poor Response to Immunosuppressive Therapy in Children With Acquired Severe Aplastic Anemia.Pediatr Blood Cancer.2016;63(4):659-664.
[12]Zhang Y,Lin CHS,Kaushansky K,et al.JAK2V617FMegakaryocytes Promote Hematopoietic Stem/Progenitor Cell Expansion in Mice Through Thrombopoietin/MPL Signaling.Stem Cells.2018;36(11):1676-1684.
[13]徐云华,成柏君,陆舜,等.短程间歇预防性给予重组人血小板生成素治疗肺癌化疗诱导的严重血小板减少的疗效[J].中华肿瘤杂志,2011,33(5):395-399.
[14]Bosch-Vilaseca A,García-Cadenas I,Roldán E,et al.Usefulness of thrombopoietin receptor agonists for persistent clinically relevant thrombocytopenia after allogeneic stem cell transplantation.Eur J Haematol.2018;101(3):407-414.
[15]Zhang Y,Guo Z,Liu XD,et al.Comparison of Haploidentical Hematopoietic Stem Cell Transplantation and Immunosuppressive Therapy for the Treatment of Acquired Severe Aplastic Anemia in Pediatric Patients.Am J Ther.2017;24(2):e196-e201.
[16]Guo Z,Gao HY,Zhang TY,et al.Analysis of allogeneic hematopoietic stem cell transplantation with high-dose cyclophosphamide-induced immune tolerance for severe aplastic anemia.Int J Hematol.2016;104(6):720-728.
[17]郭智,童春,刘晓东,等.单倍型异基因造血干细胞移植后大剂量环磷酰胺诱导免疫耐受治疗儿童重型再生障碍性贫血[J].中国组织工程研究,2016,20(32):4818-4824.
[18]郭智,陈惠仁,杨凯,等.免疫耐受新方法单倍型造血干细胞移植治疗重型再生障碍性贫血[J].中国组织工程研究,2015,19(41):6683-6687.
[19]Yang S,Yuan X,Ma R,et al.Comparison of Outcomes of Frontline Immunosuppressive Therapy and Frontline Haploidentical Hematopoietic Stem Cell Transplantation for Children with Severe Aplastic Anemia Who Lack an HLA-Matched Sibling Donor.Biol Blood Marrow Transplant.2019;25(5):975-980.
[20]郭智,陈惠仁,刘晓东,等.低强度预处理联合移植后诱导免疫耐受的单倍体相合Allo-HSCT治疗重型再生障碍性贫血的临床疗效研究[J].中国实验血液学杂志,2016,24(6):1811-1816.
[21]郭智,任骅,胡亮钉,等.重型再生障碍性贫血移植后合并肺部侵袭性真菌感染6例临床分析[J].解放军医学杂志,2017,42(12):1097-1101.
[22]Barbieri D,Elvira-Matelot E,Pelinski Y,et al.Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response.J Exp Med.2018;215(5):1463-1480.
[23]程莹,孙延庆,张雯洁,等.重组人血小板生成素促进异基因造血干细胞移植后血小板恢复的Meta分析[J].现代肿瘤医学,2015,23(10):1446-1451.
[24]孙明玲,王新有,江明,等.重组人血小板生成素联合大剂量地塞米松治疗初治原发性免疫性血小板减少症的临床分析[J].中华内科杂志,2016,55(3):202-205.
[25]Lakhwani S,Perera M,Fernández-Fuertes F,et al.Thrombopoietin receptor agonist switch in adult primary immune thrombocytopenia patients:A retrospective collaborative survey involving 4 Spanish centres.Eur J Haematol.2017;99(4):372-377.
[26]Taylor A,Westwood JP,Laskou F,et al.Thrombopoetin receptor agonist therapy in thrombocytopenia:ITP and beyond.Br JHaematol.2017;177(3):475-480.
[27]Gudbrandsdottir S,Ghanima W,Nielsen CH,et al.Effect of thrombopoietin-receptor agonists on circulating cytokine and chemokine levels in patients with primary immune thrombocytopenia(ITP).Platelets.2017;28(5):478-483.
[28]Blair TA,Moore SF,Walsh TG,et al.Phosphoinositide 3-kinase p110αnegatively regulates thrombopoietin-mediated platelet activation and thrombus formation.Cell Signal.2018;50:111-120.
[29]Barbieri D,Elvira-Matelot E,Pelinski Y,et al.Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response.J Exp Med.2018;215(5):1463-1480.
[30]苗瞄,吴德沛,曹祥山,等.血小板生成素在异基因造血干细胞移植后促进血小板植入的临床研究[J].中华血液学杂志,2012,33(5):362-365.
[31]江岷,潘欣,徐晨,等.重组人血小板生成素促进异基因造血干细胞移植血小板恢复的随机对照临床试验[J].血栓与止血学,2011,17(6):247-253.
[32]Rodeghiero F,Carli G.Beyond immune thrombocytopenia:the evolving role of thrombopoietin receptor agonists.Ann Hematol.2017;96(9):1421-1434.