美罗华-TPO-ITP.ppt

,*,单击此处编辑母版标题样式,Rituximab,合,TPO,治疗,糖皮质激素无效的,成人,ITP,的临床观察,山东大学齐鲁医院,2011.02,血小板破坏,增加,血小板的生成,受损,B,细胞,Anti GP-abs,IL-2,TNF-,APC,活性,作用于,T,细胞,T,细胞,Th1,Tregs,细胞毒作用,TGF-1,其他,血小板破坏,增加,血小板的生成,受损,ITP,病理生理学,减少血小板破坏，促进血小板生成,是治疗,ITP,的策略,Rituximab,的,作用机制,清除,CD20+B,细胞克隆,1,、补体激活（,complement activation,）,2,、,ADCC,（,antibody-dependent cytotoxicity,）,3,、诱导凋亡（,apoptosis induction,）,4,、抗增殖效应（,antiproliferative effect,）,5,、,Fc,受体多态性（,Fc receptor polymorphism,）,增加,Treg,细胞数量，改善其功能,Platelet Production Is,Suboptimal,in ITP Patients,Autologous,111,In-platelet studies show platelet production normal in 2/3 patients,TPO levels normal in 75%of ITP patients(relative TPO deficiency),Autoantibodies inhibit both Mk growth and Mk apoptosis,Hou et al.Br J Haematol 1998;101:420-4,Rituximab,联合,TPO,治疗,糖皮质激素无效的,ITP,的临床观察,开放性、非随机化、,非安慰剂的、,多中心,开始日期,：,2009,年,6,月,至今,治疗方案,美罗华,：,375 mg/m,2,，每周给药一次，分别于第,1,天，,8,天，,15,天，,22,天应用（共,4,剂）。,特比澳,：,3000ug/Kg/d,，,ih,，,14,天,若,PC50,10,9,/L,，停用,TPO,。,临床资料,10,例均符合,ITP,诊断标准；且,PLT30,10,9,/L,；有明显出血表现。,男,3,例，女,7,例。中位年龄,36,岁（,33-61,岁）。,病程,5,240,月，既往激素治疗无效，或激素有效但疗效不能维持，,1,例切脾术后。,无活动性乙肝。,一般临床资料,病例,性别,年龄,病程,（月）,既往治疗,出血表现,1,M,47,12,泼尼松、,IVIG,、达那唑、长春新碱,鼻出血、牙龈出血、皮肤瘀斑,2,M,53,24,泼尼松、达那唑,皮肤出血点,3,F,55,180,泼尼松、达那唑,鼻出血、牙龈出血、皮肤瘀斑,4,F,44,96,泼尼松、脾切除术,牙龈出血、皮肤瘀斑,5,F,35,36,大剂量地塞米松、,IVIG,、长春新碱,鼻出血、口唇血疱、皮肤瘀斑,6,M,49,84,泼尼松、达那唑、长春新碱,皮肤瘀斑,7,F,33,12,大剂量甲基泼尼松龙、大剂量地塞米松、,IVIG,皮肤出血点,8,F,58,2,大剂量甲基泼尼松龙、,IVIG,、大剂量地塞米松,口腔血疱、皮肤瘀斑,9,F,49,6,泼尼松、,IVIG,、长春新碱,鼻出血、皮肤瘀斑,10,F,61,36,泼尼松、,IVIG,、达那唑，大剂量地塞米松,皮肤瘀斑,注：泼尼松治疗均指标准剂量（,1mg,kg,-1,）；大剂量地塞米松：,40mg,qd,4d,；,IVIG,：,400 mg,kg,-1,d,-1,4d,5d,。,美罗华联合特比澳,治疗,ITP,的疗效,.,病例,血小板计数（,10,9,L,-1,）,疗效,疗效持续时间,(,月,),治疗前,3,天,1,周,2,周,3,周,4,周,8,周,12,周,16,周,20,周,24,周,至今,月,1,26,22,53,203,54,flu,31,10,IVIg,51,65,59,51,13,：,91,R,11,2,3,43,42,63,77,81,100,85,55,61,77,13,：,100,R,12.5,3,27,28,51,108,123,56,76,75,65,66,59,13,：,55,R,13,4,13,106,461,861,731,230,390,320,330,379,333,13,：,324,CR,13,5,8,12,15,12,12,11,14,(,切脾）,126,95,97,90,13,：,148,CR,退出,11,6,21,59,96,90,95,106,112,132,128,120,130,19,：,110,CR,18,7,6,12,27,37,68,424,339,311,273,235,211,10,：,107,CR,9,8,2,7,12,6,9,13,11,2,：,11,NR,0,9,4,15,33,39,51,55,87,2:107,R,1,10,7,17,22,53,77,91,81,2,：,81,R,1.5,美罗华联合特比澳,治疗,ITP,的疗效,美罗华联合特比澳,治疗,ITP,的早期疗效,疗效评价,疗效评价,Rituximab+TPO,（,9,例可评估患者）,Rituximab,(,齐鲁医院等，,2010,）,Rituximab,文献报道,*,（文献数,/,病例数）,rhTPO,(,北京协和医院等，,2004),Dex+,Rituximab,（,Zaja,，,Blood,，,2010,）,总有效,88.9,(8/9),61.76%,(21/34),62.5,(19/313),85.3%,(70/82),63%,(31/49),CR,33.3%,(3/9),41.18%,(14/34),46.3%,(13/191),53%,(26/49),R,55.6%,(5/9),20.59%,(7/34),24%,(16/284),10%,(5/49),*Annals of Internal Medicine 2007,146:,25-33,疗效评价,疗效评价,Rituximab+TPO,（,9,例可评估患者）,Rituximab,(,齐鲁医院等，,2010,）,Rituximab,文献报道,*,（文献数,/,病例数）,rhTPO,(,北京协和医院等，,2004),Dex+,Rituximab,（,Zaja,，,Blood,，,2010,）,起效时间（范围，周）,1(0.5,3),3(1,8),5.5(2,18),(6/123),(,),(,),维持时间（范围，月）,11(1,18),(,),10.5(3,20),(16/252),(,),随诊时间（范围，月）,13(2,19),(,),9.5(2,25),(10/187),20(4,40),*Annals of Internal Medicine 2007,146:,25-33,免疫学检查结果与疗效的关系,GPIIb/IIIa,和,/,或,GPIb/IX,特异性自身抗体：,有效患者治疗后血小板自身抗体均转阴。,CD19,（,+,）,/CD20,（,+,）细胞数：,治疗后所有患者,B,细胞数均明显下降。,CD3,（,+,）、,CD4,（,+,）、,CD8,（,+,）细胞数：,治疗前后无明显变化。,不良反应,轻微，个别患者用药期间出现轻度发热、乏力、注射部位疼痛，,1,例患者用药,2,月后仍觉轻微乏力。,长期疗效随访,中位疗效持续时间,11,个月（范围,2-18,个月）。,7,例长期观察的有效者血小板数量均降低，但均无无复发。,1,例,R,患者于用药,12.5,月后,PC,达,100,10,9,/,L,美罗华联合特比澳治疗,ITP,的预后因素,性别、年龄、既往治疗、治疗前血小板计数、,B,细胞数量、血清免疫球蛋白水平等均与疗效无关,美罗华在治疗,ITP,中的地位：,2005,年,Annu.Rev.Med.,2005.56:425-42,美罗华作为脾切除术后失败的患者的治疗选择,美罗华在治疗,ITP,中的地位：,2008,年,British Journal of Haematology,2008,143,16-26,美罗华作为复发,/,激素依赖的患者的治疗选择，与脾切除术平行,Therapies for the treatment of ITP,Clinical situation Therapy option,First line(initial treatment for Corticosteroids:dexamethasone,IVIg,，,Newly diagnosed ITP)methylprednisolone,prednis(ol)one,Second line Azathioprine,Cyclosporin A,Cyclophosphamide,Danazol,Dapsone,Mycophenolate mofetil,Rituximab,Splenectomy,TPO receptor agonists,，,Vinca alkaloids,Treatment for patients Category A:treatment options with sufficient data,failing first-and second TPO receptor agonists,-line therapies Category B:treatment options with minimal data and,considered to have potential for consider-,able toxicity;Combination of first-and,second-line therapies;Combination,chemotherapy,Blood 2010;115(2):168-186,2009,年中华医学会血液学分会止血与血栓学组,ITP,治疗指南,小 结,特比澳已被,SFDA,批准用于,ITP,治疗。美罗华联合特比澳对糖皮质激素治疗无效的,ITP,有效，部分患者血小板起效快，可以长期维持，降低了致命性出血的风险。还需要观察更多量病例疗效。,小 结,其有效与否与年龄、性别、是否已行脾切除等临床和实验室指标均无相关。,治疗,ITP,安全性良好。,