多药联合治疗ITP的进展
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摘要
ITP是一种主要以血小板生成减少或血小板破坏增多等为特点的复杂的、多种机制介导的自身免疫性疾病。首选治疗是糖皮质激素和静脉注射免疫球蛋白,包括很多二线治疗。但约有1/3的患者对首选治疗及随后的治疗无效或复发。近年来,通过临床实验研究提出或许可以运用多种药物联合治疗难治性或复发性ITP。现对多种药物联合治疗ITP机制和疗效综述如下
ITP is a complex,multiple mechanism of acquired autoimmune disease which are characterized by reduced platelet production and increased platelet destruction. Its first-line treatment is corticosteroids and intravenous immunoglobulin,and the secondline of treatment is splenectomy. But one-third of patients failing first and subsequent therapeutic approaches. In recent years,some investigators have suggested that combination therapy may be used to treat refractory or released ITP through clinical studies. Now,the mechanism and curative effect of the combination therapy currently used in ITP treatment are summarized as follows.
ITP is a complex,multiple mechanism of acquired autoimmune disease which are characterized by reduced platelet production and increased platelet destruction. Its first-line treatment is corticosteroids and intravenous immunoglobulin,and the secondline of treatment is splenectomy. But one-third of patients failing first and subsequent therapeutic approaches. In recent years,some investigators have suggested that combination therapy may be used to treat refractory or released ITP through clinical studies. Now,the mechanism and curative effect of the combination therapy currently used in ITP treatment are summarized as follows.
引文
[1]Rodeghiero F,Stasi R,Gernsheimer T,et al.Standardization of terminology,definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:report from an international working group[J].Blood,2009,113(11):2386.
[2]Grimaldibensouda L,Nordon C,Michel M,et al.Immune thrombocytopenia in adults:a prospective cohort study of clinical features and predictors of outcome[J].Haematologica,2016,101(9):1039-1045.
[3]唐一君,瞿文.调节性B细胞在自身免疫病中的研究进展[J].中国免疫学杂志,2015,31(7):973-976.Tang YJ,Qu W.The development of regulatory B cells in autoimmune diseases[J].Chin Immunol,2015,31(7):973-976.
[4]曾艳,韩红,陈慧.免疫性血小板减少症患者外周血Treg细胞microRNA分析[J].中国免疫学杂志,2016,32(9):1350-1353.Zeng Y,Han H,Chen H,et al.Analysis of microRNA expression profile of peripheral Treg cells in ITP[J].Chin J Immunol,2016,32(9):1350-1353.
[5]谢东杰,王爱迪,刘宝山.CD4+T细胞在原发性免疫性血小板减少症中作用机制的研究进展[J].中国免疫学杂志,2017,33(9):1415-1417.Xie DJ,Wang AD,Liu BS.The development of the mechanisms with CD4+T cells in ITP[J].Chin J Immunol,2017,33(9):1415-1417.
[6]赵淑敏,李建平,冯建明,等.树突状细胞参与免疫性血小板减少症发病机制的研究进展[J].中国免疫学杂志,2016,32(5):744-747.Zhao SM,Li JP,Feng JM,et al.The development of the mechanisms with dendritic cells in ITP[J].Chin J Immunol,2016,32(5):744-747.
[7]Provan D,Newland AC.Guidelines for immune thrombocytopenia[J].N Engl J Med,2011,364(6):580.
[8]Neunert C,Lim W,Crowther M,et al.The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia[J].Blood,2011,117(16):4190-4207.
[9]Khodadi E,Asnafi AA,Shahrabi S,et al.Bone marrow niche in immune thrombocytopenia:a focus on megakaryopoiesis[J].Ann Hematol,2016,95(11):1-12.
[10]Cines DB,Bussel JB,Liebman HA,et al.The ITP syndrome:pathogenic and clinical diversity[J].Blood,2009,113(26):6511.
[11]Norgaard M,Jensen AO,Engebjerg MC,et al.Long-term clinical outcomes of patients with primary chronic immune thrombo-cytopenia:a Danish population-based cohort study[J].Blood,2011,117(13):3514-3520.
[12]Mülfay V,Popa DP.International consensus report on the investigation and management of primary immune thrombocytopenia[J].Blood,2010,115(2):168-186.
[13]Zhao YQ,Wang QY,Zhai M,et al.A multi-center clinical trial of recombinant human thrombopoietin in chronic refractory idiopathic thrombocytopenic purpura[J].Chin J Internal Med,2004,43(8):608.
[14]Newland A,Godeau B,Priego V,et al.Remission and platelet responses with romiplostim in primary immune thrombocytopenia:final results from a phase 2 study[J].Br J Haematol,2016,172(2):262-273.
[15]Kuter DJ.The biology of thrombopoietin and thrombopoietin receptor agonists[J].Int J Hematol,2013,98(1):10.
[16]Rodeghiero F,Stasi R,Giagounidis A,et al.Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia:a pooled analysis of 13 clinical trials[J].Eur JHaematol,2013,91(5):423-436.
[17]Mazzucconi MG,Santoro C,Baldacci E,et al.TPO-RAs in pITP:description of a case series and analysis of predictive factors for response[J].Eur J Haematol,2017,98(3):242.
[18]Yoon JS,Lee YJ,Baek DW,et al.New synergistic efficacy of combination of romiplostim and steroid in refractory immune thrombocytopenia patients[J].Korean J Intern Med,2016,33(2):435-437.
[19]Matschke J,Müllerbeissenhirtz H,Novotny J,et al.A Randomized trial of daily prednisone versus pulsed dexamethasone in treatment-Na6ve adult patients with immune thrombocytopenia:EIS 2002 Study[J].Acta Haematol,2016,136(2):101.
[20]Anwer F,Yun S,Nair A,et al.Severe refractory immune thrombocytopenia successfully treated with high-dose pulse cyclophosphamide and eltrombopag[J].Case Rep Hematol,2015,2015:583451.
[21]Okazuka K,Masuko M,Matsuo Y,et al.Successful treatment of severe newly diagnosed immune thrombocytopenia involving an alveolar hemorrhage with combination therapy consisting of romiplostim,rituximab and vincristine[J].Intern Med,2013,52(11):1239-1242.
[22]Ghanima W,Khelif A,Waage A,et al.Rituximab as second-line treatment for adult immune thrombocytopenia(the RITP trial):a multicentre,randomised,double-blind,placebo-controlled trial[J].Lancet,2015,385(9978):1653-1661.
[23]Sivera P,Ruella M,Gueli A,et al.Use of the novel thrombopoietin receptor-agonist romiplostim,in combination with steroids and immunoglobulins for the increase of platelets prior to splenectomy,in refractory immune thrombocytopenia:a case report[J].Blood Coagulation Fibrinolysis,2012,23(4):331.
[24]Cheng Y,Wong RS,Soo YO,et al.Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone[J].NEngl J Med,2003,349(9):831.
[25]Garnock-Jones KP,Keam SJ.Eltrombopag[J].Drugs,2009,69(5):567-576.
[26]Gómez-Almaguer D,Herrera-Rojas MA,Jaime-Pérez JC,et al.Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults[J].Blood,2014,123(25):3906-3908.
[27]Emilia G,Luppi M,Morselli M,et al.A possible role for low-dose cyclosporine in refractory immune thrombocytopenic purpura[J].Haematologica,2008,93(7):1113.
[28]Cui ZG,Liu XG,Qin P,et al.Recombinant human thrombopoietin in combination with cyclosporin A as a novel therapy in corticosteroid-resistant primary immune thrombocytopenia[J].National Med J Chin,2013,126(21):4145-4148.
[29]Bussel JB,Lee CS,Seery C,et al.Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration[J].Haematologica,2014,99(7):1264-1271.
[30]Gudbrandsdottir S,Birgens HS,Frederiksen H,et al.Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia[J].Blood,2013,121(11):1976-1981.
[31]Zaja F,Baccarani M,Mazza P,et al.Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia[J].Blood,2016,115(14):2755-2762.
[32]Choi PY,Roncolato F,Badoux X,et al.A novel triple therapy for ITP using high-dose dexamethasone,low-dose rituximab,and cyclosporine(TT4)[J].Blood,2015,126(4):500-503.
[33]Zhou H,Xu M,Qin P,et al.A multicenter randomized open-label study of rituximab plus rh TPO vs rituximab in corticosteroid-resistant or relapsed ITP[J].Blood,2015,125(10):1541-1547.
[34]刘新光,刘晓帆,孟月生,等.重组人血小板生成素联合小剂量利妥昔单抗治疗激素无效/复发成人ITP的多中心临床研究[J].临床血液学杂志,2015,28(5):778-781.Liu XG,Liu XF,Meng YS,et al.Combination therapy with recombinant human thrombopoietin and low-dose rituximab for corticosteroid-resistant/relapsed adult ITP:a multicenter clinical trial[J].J Clin Hematol,2015,28(5):778-781.
[35]Wang S,Yang R,Zou P,et al.A multicenter randomized controlled trial of recombinant human thrombopoietin treatment in patients with primary immune thrombocytopenia[J].Int JHematol,2012,96(2):222-228.
[36]Rao VK.ITP:hematology's Cosette from Les Misérables[J].Blood,2013,121(11):1928-1930.
[2]Grimaldibensouda L,Nordon C,Michel M,et al.Immune thrombocytopenia in adults:a prospective cohort study of clinical features and predictors of outcome[J].Haematologica,2016,101(9):1039-1045.
[3]唐一君,瞿文.调节性B细胞在自身免疫病中的研究进展[J].中国免疫学杂志,2015,31(7):973-976.Tang YJ,Qu W.The development of regulatory B cells in autoimmune diseases[J].Chin Immunol,2015,31(7):973-976.
[4]曾艳,韩红,陈慧.免疫性血小板减少症患者外周血Treg细胞microRNA分析[J].中国免疫学杂志,2016,32(9):1350-1353.Zeng Y,Han H,Chen H,et al.Analysis of microRNA expression profile of peripheral Treg cells in ITP[J].Chin J Immunol,2016,32(9):1350-1353.
[5]谢东杰,王爱迪,刘宝山.CD4+T细胞在原发性免疫性血小板减少症中作用机制的研究进展[J].中国免疫学杂志,2017,33(9):1415-1417.Xie DJ,Wang AD,Liu BS.The development of the mechanisms with CD4+T cells in ITP[J].Chin J Immunol,2017,33(9):1415-1417.
[6]赵淑敏,李建平,冯建明,等.树突状细胞参与免疫性血小板减少症发病机制的研究进展[J].中国免疫学杂志,2016,32(5):744-747.Zhao SM,Li JP,Feng JM,et al.The development of the mechanisms with dendritic cells in ITP[J].Chin J Immunol,2016,32(5):744-747.
[7]Provan D,Newland AC.Guidelines for immune thrombocytopenia[J].N Engl J Med,2011,364(6):580.
[8]Neunert C,Lim W,Crowther M,et al.The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia[J].Blood,2011,117(16):4190-4207.
[9]Khodadi E,Asnafi AA,Shahrabi S,et al.Bone marrow niche in immune thrombocytopenia:a focus on megakaryopoiesis[J].Ann Hematol,2016,95(11):1-12.
[10]Cines DB,Bussel JB,Liebman HA,et al.The ITP syndrome:pathogenic and clinical diversity[J].Blood,2009,113(26):6511.
[11]Norgaard M,Jensen AO,Engebjerg MC,et al.Long-term clinical outcomes of patients with primary chronic immune thrombo-cytopenia:a Danish population-based cohort study[J].Blood,2011,117(13):3514-3520.
[12]Mülfay V,Popa DP.International consensus report on the investigation and management of primary immune thrombocytopenia[J].Blood,2010,115(2):168-186.
[13]Zhao YQ,Wang QY,Zhai M,et al.A multi-center clinical trial of recombinant human thrombopoietin in chronic refractory idiopathic thrombocytopenic purpura[J].Chin J Internal Med,2004,43(8):608.
[14]Newland A,Godeau B,Priego V,et al.Remission and platelet responses with romiplostim in primary immune thrombocytopenia:final results from a phase 2 study[J].Br J Haematol,2016,172(2):262-273.
[15]Kuter DJ.The biology of thrombopoietin and thrombopoietin receptor agonists[J].Int J Hematol,2013,98(1):10.
[16]Rodeghiero F,Stasi R,Giagounidis A,et al.Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia:a pooled analysis of 13 clinical trials[J].Eur JHaematol,2013,91(5):423-436.
[17]Mazzucconi MG,Santoro C,Baldacci E,et al.TPO-RAs in pITP:description of a case series and analysis of predictive factors for response[J].Eur J Haematol,2017,98(3):242.
[18]Yoon JS,Lee YJ,Baek DW,et al.New synergistic efficacy of combination of romiplostim and steroid in refractory immune thrombocytopenia patients[J].Korean J Intern Med,2016,33(2):435-437.
[19]Matschke J,Müllerbeissenhirtz H,Novotny J,et al.A Randomized trial of daily prednisone versus pulsed dexamethasone in treatment-Na6ve adult patients with immune thrombocytopenia:EIS 2002 Study[J].Acta Haematol,2016,136(2):101.
[20]Anwer F,Yun S,Nair A,et al.Severe refractory immune thrombocytopenia successfully treated with high-dose pulse cyclophosphamide and eltrombopag[J].Case Rep Hematol,2015,2015:583451.
[21]Okazuka K,Masuko M,Matsuo Y,et al.Successful treatment of severe newly diagnosed immune thrombocytopenia involving an alveolar hemorrhage with combination therapy consisting of romiplostim,rituximab and vincristine[J].Intern Med,2013,52(11):1239-1242.
[22]Ghanima W,Khelif A,Waage A,et al.Rituximab as second-line treatment for adult immune thrombocytopenia(the RITP trial):a multicentre,randomised,double-blind,placebo-controlled trial[J].Lancet,2015,385(9978):1653-1661.
[23]Sivera P,Ruella M,Gueli A,et al.Use of the novel thrombopoietin receptor-agonist romiplostim,in combination with steroids and immunoglobulins for the increase of platelets prior to splenectomy,in refractory immune thrombocytopenia:a case report[J].Blood Coagulation Fibrinolysis,2012,23(4):331.
[24]Cheng Y,Wong RS,Soo YO,et al.Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone[J].NEngl J Med,2003,349(9):831.
[25]Garnock-Jones KP,Keam SJ.Eltrombopag[J].Drugs,2009,69(5):567-576.
[26]Gómez-Almaguer D,Herrera-Rojas MA,Jaime-Pérez JC,et al.Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults[J].Blood,2014,123(25):3906-3908.
[27]Emilia G,Luppi M,Morselli M,et al.A possible role for low-dose cyclosporine in refractory immune thrombocytopenic purpura[J].Haematologica,2008,93(7):1113.
[28]Cui ZG,Liu XG,Qin P,et al.Recombinant human thrombopoietin in combination with cyclosporin A as a novel therapy in corticosteroid-resistant primary immune thrombocytopenia[J].National Med J Chin,2013,126(21):4145-4148.
[29]Bussel JB,Lee CS,Seery C,et al.Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration[J].Haematologica,2014,99(7):1264-1271.
[30]Gudbrandsdottir S,Birgens HS,Frederiksen H,et al.Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia[J].Blood,2013,121(11):1976-1981.
[31]Zaja F,Baccarani M,Mazza P,et al.Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia[J].Blood,2016,115(14):2755-2762.
[32]Choi PY,Roncolato F,Badoux X,et al.A novel triple therapy for ITP using high-dose dexamethasone,low-dose rituximab,and cyclosporine(TT4)[J].Blood,2015,126(4):500-503.
[33]Zhou H,Xu M,Qin P,et al.A multicenter randomized open-label study of rituximab plus rh TPO vs rituximab in corticosteroid-resistant or relapsed ITP[J].Blood,2015,125(10):1541-1547.
[34]刘新光,刘晓帆,孟月生,等.重组人血小板生成素联合小剂量利妥昔单抗治疗激素无效/复发成人ITP的多中心临床研究[J].临床血液学杂志,2015,28(5):778-781.Liu XG,Liu XF,Meng YS,et al.Combination therapy with recombinant human thrombopoietin and low-dose rituximab for corticosteroid-resistant/relapsed adult ITP:a multicenter clinical trial[J].J Clin Hematol,2015,28(5):778-781.
[35]Wang S,Yang R,Zou P,et al.A multicenter randomized controlled trial of recombinant human thrombopoietin treatment in patients with primary immune thrombocytopenia[J].Int JHematol,2012,96(2):222-228.
[36]Rao VK.ITP:hematology's Cosette from Les Misérables[J].Blood,2013,121(11):1928-1930.
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