New drugs for familiar therapeutic targets: thrombopoietin receptor agonists and immune thrombocytopenic purpura

Various agents to treat immune thrombocytopenic purpura (ITP) have been developed on the principle that stimulating the thrombopoietin (TPO) receptor would increase platelet production. First-generation agents--recombinant human thrombopoietin (rHuTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF)--showed promise, but observations of antibody formation to PEG rHuMGDF led to the discontinuation of development of both agents. Second-generation agents--the TPO peptide mimetics, TPO non-peptide mimetics, and TPO agonist antibodies--have been developed to reduce or eliminate the problem of antigenicity. Clinical studies for some of these agents, such as AMG 531 (romiplosim, Nplate) and eltrombopag (Promacta), are demonstrating their relative safety and efficacy in increasing platelet counts in patients with ITP; AMG 531 and eltrombopag are in late-stage clinical development and are able to stimulate platelet production in patients with ITP. Some differences in safety profiles have been described and are undergoing further study. There are currently seven second-generation TPO receptor agonists that have been reported in the literature, representing the potential advantages--and continuing challenges--with this novel class of platelet-stimulating therapies for ITP and possibly thrombocytopenia in other disease states as well.     

免疫性血小板减少性紫癜分型施治的基础与临床研究进展

免疫性血小板减少性紫癜(ITP)的发病涉及血小板免疫性破坏增多和骨髓巨核细胞产生血小板过少两个方面。经典的ITP治疗只涉及抑制血小板免疫破坏的一个方面,即采用免疫抑制剂如糖皮质激素、免疫球蛋白和抗-D抗体(针对Rh系统D抗原的抗体),也有采用长春新碱或抗人CD20单克隆抗体清除B淋巴细胞,以及环孢菌素等免疫抑制剂等。对难治性病例还要进行脾脏切除手术。虽然免疫抑制治疗方案对大多数患者治疗有效,但30%以上的ITP患者会复发,且这类治疗不良反应较多,脾脏切除还会导致机体免疫力下降,容易出现感染等并发症。临床需要更加安全有效的治疗方法。重组人血小板生成素(TPO)由于自身抗体而继发严重的血小板,目前已退出ITP的治疗。最近,欧洲批准了2个血小板受体激活剂AMG 531和Eltrombopag,通过促进巨核细胞分化和血小板生成来治疗ITP。国内采用泛细胞保护剂为主的联合方案治疗难治/复发性ITP也取得了良好的效果。总之,根据ITP患者不同的发病机理进行个体化治疗是未来ITP基础与临床的研究方向。本文就ITP的发病机理和临床治疗作一综述,并对ITP分型施治的可能性进行了初步的探讨。     

免疫性血小板减少性紫癜分型施治的基础与临床研究进展

免疫性血小板减少性紫癜（ITP）的发病涉及血小板免疫性破坏增多和骨髓巨核细胞产生血小板过少两个方面。经典的ITP治疗只涉及抑制血小板免疫破坏的一个方面，即采用免疫抑制剂如糖皮质激素、免疫球蛋白和抗-D抗体（针对Rh系统D抗原的抗体），也有采用长春新碱或抗人CD20单克隆抗体清除B淋巴细胞，以及环孢菌素等免疫抑制剂等。对难治性病例还要进行脾脏切除手术。虽然免疫抑制治疗方案对大多数患者治疗有效，但30％以上的ITP患者会复发，且这类治疗不良反应较多，脾脏切除还会导致机体免疫力下降，容易出现感染等并发症。临床需要更加安全有效的治疗方法。重组人血小板生成素（TPO）由于自身抗体而继发严重的血小板，目前已退出ITP的治疗。最近。欧洲批准了2个血小板受体激活剂AMG531和Eltrombopag，通过促进巨核细胞分化和血小板生成来治疗ITP。国内采用泛细胞保护剂为主的联合方案治疗难治／复发性ITP也取得了良好的效果。总之，根据ITP患者不同的发病机理进行个体化治疗是未来ITP基础与临床的研究方向。本文就ITP的发病机理和临床治疗作一综述．并对ITP分型施治的可能性进行了初步的探讨。     

The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes

Thrombocytopenia can be seen in a variety of disease states, including immune mediated thrombocytopenic purpura (ITP) and myelodysplastic syndromes (MDS). The most concerning complication is the development of hemorrhagic complications that may contribute to patient morbidity and mortality. The ligand thrombopoeitin (TPO) and its interaction with its receptor (c-mpl) are important in platelet production. Thrombopoietic agonists can help in the management of thrombocytopenia related to these conditions. Amgen Megakaryopoiesis Protein 531 (AMG-531) (Romiplostim) is a recombinant TPO with a peptide fragment that shares no sequence homology with endogenous TPO, preventing the production of neutralizing antibodies. Recent studies have shown that it is effective in raising platelet counts, and is well tolerated in ITP and MDS patients. In this review, we discuss thrombopoiesis regulation by TPO; the chemistry, pharmacokinetics and pharmacodynamics of AMG-531 in animals and humans; the pathophysiological mechanisms leading to thrombocytopenia in ITP and MDS; and clinical trials demonstrating its efficacy in treating thrombocytopenia.     

Development of thrombopoietin receptor agonists for clinical use

Summary.  Thrombopoietin (TPO) is an essential hematopoietic cytokine for megakaryopoiesis. In 2002, we demonstrated that pegylated-recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increased platelet counts in patients with chronic immune thrombocytopenic purpura (ITP) in a Phase I/II clinical trial. After the cessation of clinical trials of PEG-rHuMGDF because of severe thrombocytopenia or pancytopenia due to the development of the neutralizing antibody cross-reacting with endogenous TPO, second generation non-immunogenic TPO receptor agonists have been developed. A small molecule eltrombopag and Romiplostim were approved for clinical use by FDA in 2008 to treat patients with chronic ITP who are refractory to the prior therapy. Although the efficacy of both TPO receptor agonists is convincing for the refractory ITP, further investigation is necessary to assess the potential long-term side effects and clinical applications of these therapies for other thrombocytopenic conditions.     

First-line therapies for immune thrombocytopenic purpura: re-evaluating the need to treat

Immune thrombocytopenic purpura (ITP) can be challenging to both diagnose and treat: despite the ability to detect anti-platelet antibodies, the diagnosis of ITP remains one of exclusion. Management of ITP is similarly difficult as many therapies pose potential risks that may be worse than the disease. It has been generally agreed that bleeding - not platelet count - should be the rationale for treatment. Despite the absence of prospective, controlled studies, there is consensus that bleeding risks are significantly greater in patients with platelet counts <20 x 10(9)-30 x 10(9)/L, and therefore treatment is indicated for these patients; for those with platelet counts that are higher, but still <50 x 10(9)/L, treatment is also indicated if accompanied by substantial mucous membrane bleeding. The standard initial treatment for ITP is oral corticosteroids to increase platelet counts. Intravenous immunoglobulin or anti-D immunoglobulin can also increase platelet counts and are particularly useful for stimulating rapid platelet increases before planned procedures. Splenectomy, which produces a long-lasting response in a majority of patients, is still commonly used for those who do not have long-term responses to steroid therapy and it should remain the gold standard therapy. However, splenectomy is an invasive procedure with some patients relapsing even after several years. Very rare cases of life-threatening or lethal infections may also occur at any time after splenectomy and thus physicians and patients are increasingly reluctant to advise or agree to this treatment approach. Other treatments have been evaluated to prevent or delay splenectomy, including high-dose dexamethasone, intermittent anti-D immunoglobulin infusions, and rituximab. There have been few randomized, placebo-controlled studies of these approaches, and they cannot currently be recommended as their efficacy and safety remain unclear. Thrombopoietin receptor agonists are currently under clinical investigation for the treatment of ITP and may represent an alternative treatment option in the future. The criteria for treating ITP and the benefits and risks of therapies are discussed here. Ongoing and future studies will help define the best strategies for increasing platelet counts and reducing the risk of bleeding in ITP patients.     

原发免疫性血小板减少症的规范化诊治

原发免疫性血小板减少症(primary immune thrombocytopenia, ITP)是一种获得性免疫介导的血小板减少性疾病,其发病机制为免疫失耐受导致的血小板破坏过多及巨核细胞产生血小板不足。临床表现主要为血小板减少性的出血及疲劳等症状。ITP的诊断无特异性指标,需排除其他的血小板减少性疾病。治疗目的为维持血小板在安全水平,预防出血,并提高患者生活质量。治疗指征为血小板≤30×10⁹/L和(或)有出血表现,对于老年患者、重体力劳动者、有高血压等出血风险较高的合并症患者以及需抗血小板、抗凝治疗患者等,可适当放宽治疗指征。一线治疗为糖皮质激素及静脉注射人免疫球蛋白;二线治疗包括促血小板生成药物、利妥昔单抗及脾切除等治疗;对于难治性ITP患者,可考虑维A酸等三线治疗。     

应用促血小板生成剂治疗儿童免疫性血小板减少症的研究进展

免疫性血小板减少症(ITP)是一种常见的获得性出血性疾病。传统观点认为,其发病机制为血小板相关抗体介导的血小板破坏增多,治疗靶点在于抑制抗体产生和阻断血小板在网状内皮系统破坏,但在部分ITP患者无效,逐渐演变成慢性/难治性ITP(C/RITP)。对于儿童C/RITP患者来说,一线治疗效果不佳,二线药物疗效不肯定且副作用明显,因而亟需一种安全有效的二线药物。近期发现,ITP发病机制中还存在血小板生成障碍,促血小板生成药物血小板生成素(TPO)和血小板生成素受体激动剂(TRA)逐步被研发和使用。国内rhTPO已通过成人C/RITPⅢ期临床试验,TRA代表药物Romiplostim和Eltrombopag也均已完成成人CITP治疗Ⅲ期临床试验,目前两项关于Romiplostim治疗儿童CITP的临床试验也证实了该类药物在儿科应用的有效性及安全性,且由于使用方便,更适宜在儿科应用。今后,促血小板生成药物的维持治疗将成为其主要的治疗方式之一。本文就促血小板生成剂的研发及其在儿科临床应用前景进行综述。     

One-year follow-up of plasma exchange therapy in 14 patients with idiopathic thrombocytopenic purpura

Fourteen patients with idiopathic thrombocytopenic purpura (ITP) have been followed for one year after plasma exchange therapy. Exchange was performed prior to splenectomy in eight of nine patients with acute ITP and following splenectomy in five patients with chronic ITP. None with chronic ITP showed a response in platelet count as a result of exchange therapy. Four of the nine with acute ITP had poor responses and required splenectomy because of persistent severe thrombocytopenia. Three of these have responded completely and are in remission. One patient with acute ITP had an equivocal response, with a most recent platelet count of 93,000/microliter. The remaining four patients with acute ITP had prompt and complete responses and now have platelet counts above 100,000/microliter without steroid treatment. Although the good responses were temporally associated with the use of plasma but not albumin, the data are not sufficient to conclude that a plasma factor must be infused to obtain a satisfactory result. The overall response after one year was about that expected for acute ITP patients treated with prednisone and early splenectomy. Exchange plasmapheresis may be of value in decreasing the number of patients who require splenectomy, but a randomized, prospective study is needed to adequately assess this possibility.     

Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand

OBJECTIVE: The objective of this study was to evaluate the tolerability, pharmacodynamics, and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand, after a single intravenous or subcutaneous injection in healthy subjects. METHODS: This was a first-in-human randomized, double-blind, placebo-controlled study with 48 subjects. Six subjects in each cohort were sequentially randomized in a 2:1 ratio to receive a single injection of AMG 531 or placebo. The dose ranges investigated were 0.3 to 10.0 microg/kg and 0.1 to 2.0 microg/kg via the intravenous and subcutaneous dosing routes, respectively. The pharmacodynamic response of AMG 531 was measured as the elevation in platelet counts. AMG 531 serum levels were determined by use of a validated enzyme-linked immunosorbent assay. RESULTS: Single intravenous or subcutaneous administration of AMG 531 induced a dose-dependent increase in platelet count in healthy subjects, with peak platelet count being achieved on days 12 to 16. The highest intravenous dose, 10.0 microg/kg, caused a nearly 6-fold increase in platelet count. The maximum increase for this cohort occurred on day 15, and the mean platelet count was 1380 x 10(9)/L (range, 923-1790 x 10(9)/L). Of 8 subjects receiving the 2.0-microg/kg subcutaneous dose, 6 had peak platelet levels that were double the baseline value. Platelet count was elevated to a similar extent after single intravenous or subcutaneous administration of AMG 531 at the same dose level (1.0 microg/kg), even though the subcutaneous serum levels were barely detectable. Platelet counts were close to the baseline value by day 28. After a single intravenous administration, the pharmacokinetics of AMG 531 was nonlinear in the 0.3- to 10.0-microg/kg dose range. Most AMG 531 serum levels fell below the assay's lower quantitation limit of 18 pg/mL after a single subcutaneous dose. There were no serious or life-threatening adverse events reported in this study. The most frequently reported events were mild to moderate headache and sore throat. CONCLUSION: AMG 531 was well tolerated in this study and was effective at raising platelet counts in healthy volunteers after single intravenous or subcutaneous administration.     

Autoimmune thrombocytopenia

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder in which platelets coated with mainly antibodies against platelet GPIIb/IIIa and GPIb/IX are destroyed in the spleen. Recent evidence suggests that platelets are also destroyed by cytotoxic T cells. The diagnosis is made by exclusion for other causes of thrombocytopenia. As routine blood counts are becoming more available, many mild cases of ITP (platelets >30 x 10(9) L(-1)) are being diagnosed and they usually do not require treatment. In patients with platelet counts persistently <30 x 10(9) L(-1), treatment with corticosteroids, and/or intravenous immunoglobulin (IVIG) or anti-D may be required. The primary goal of treatment is to maintain the platelet count at a safe level with minimal side effects. After 3-6 months, if spontaneous remission has not occurred and if the side effects are significant, splenectomy is recommended. This is the single most effective treatment of ITP. The refractory patients who fails splenectomy and subsequently first- and second-line therapies, is a management dilemma. Therapeutic options are limited, available treatments potentially toxic and the chances of sustained response low. Observation with no active treatment is a reasonable option. With the increased availability of the thrombopoietic agents in the future, there may be a good prospect of keeping the platelet counts of these refractory patients at a safe long-term level with one of these drugs.     

Management of patients with refractory immune thrombocytopenic purpura

In immune thrombocytopenic purpura (ITP), thrombocytopenia is a result of both increased platelet destruction and insufficient platelet production. In adults, the course is commonly chronic, but most patients never experience serious bleeding even with severe thrombocytopenia. In case series of consecutive adult patients identified at the time of diagnosis, the frequency of death from bleeding is low, < 1%. The goal of treatment is only to prevent bleeding, not to correct the platelet count to normal. All current treatments are designed to diminish the increased platelet destruction, either by immunosuppression or splenectomy. The frequency of death from complications of treatment is similar to the frequency of death from bleeding. Perhaps because of increasing recognition of both the infrequent occurrence of serious bleeding and the risks of immunosuppressive treatment and splenectomy, data from case series across the past 30 years suggest a trend toward less therapy and fewer splenectomies among patients with ITP. However treatment is necessary for patients with severe and symptomatic thrombocytopenia. Splenectomy remains the most effective treatment for ITP, with two-thirds of patients achieving durable complete remissions. Immunosuppressive agents, including rituximab and combinations of agents, may be less effective than splenectomy in achieving complete remissions and the remissions may also be less durable. New agents for patients with ITP are currently in development that enhance platelet production, rather than diminish platelet destruction. In preliminary reports, these agents have been effective in maintaining safe platelet counts in patients with chronic ITP that was refractory to splenectomy and other treatments.     

Management of immune thrombocytopenic purpura in adults

Primary immune thrombocytopenic purpura (ITP), also referred to as idiopathic thrombocytopenic purpura, is an organ-specific autoimmune disorder in which antibody-coated or immune complex-coated platelets are destroyed prematurely by the reticuloendothelial system, resulting in peripheral blood thrombocytopenia. The disease is heterogeneous with regard to its severity and clinical course and is unpredictable in its response to therapy. Although the basic underlying pathophysiology of ITP has been known for more than 50 years, current treatment guidelines are based on expert opinion rather than on evidence because of a lack of high-quality clinical trials and research. The only patients for whom treatment is clearly required are those with severe bleeding and/or extremely low platelet counts (< 10 x 10(9)/L). Treatment of patients with ITP refractory to corticosteroids and splenectomy requires careful evaluation of disease severity, patient characteristics related to risk of bleeding, and adverse effects associated with treatment. Clinical trials with numerous new agents are under way, which we hope will add more effective and targeted strategies to our therapeutic armamentarium. We describe a logical and structured approach to the clinical management of ITP in adults, based on a literature review and our personal experience.     

Plateletpheresis for postsplenectomy rebound thrombocytosis in a patient with chronic immune thrombocytopenic purpura on romiplostim

Immune thrombocytopenic purpura (ITP) is an autoimmune disease in which IgG‐coated platelets are removed from circulation by the spleen, and platelet production is impaired due to increased thrombopoietin (TPO) clearance. Romiplostim, a novel TPO‐mimetic agent, is approved for patients with ITP that are unresponsive to traditional treatments. However, there is little experience when using this drug before splenectomy. We describe herein the case of a young female with chronic ITP who was treated with romiplostim, underwent splenectomy shortly thereafter, and required plateletpheresis for postoperative rebound thrombocytosis with concomitant neurologic symptoms. J. Clin. Apheresis 28:321–324, 2013. © 2013 Wiley Periodicals, Inc.     

腹腔镜脾切除对难治性ITP治疗的应用价值

目的:探讨腹腔镜脾切除术(laparoscopicsplenectomy,LS)治疗难治性特发性血小板减少性紫癜(idiopathicthrombocytopenicpur- pura,ITP)的可行性和疗效。方法:回顾性分析2002年9月-2005年7月15例难治性ITP(血小板计数<50×109／L)行LS的临床资料。采用全麻仰卧位、三孔法进行手术。结果:1例中转传统开腹手术。14例完成LS,手术时间为56-172 min,平均107 min;术中出血量30-500ml,平均102 ml。3例术中发现副脾并切除。术后1周内血小板很快上升,胃肠蠕动恢复时间为12-24 h,平均住院时间5 d。发生并发症1例(腹壁静脉刺破出血)。随访均无复发。结论:LS治疗ITP安全可行,且临床疗效显著。     

Refractory idiopathic thrombocytopenic purpura

Chronic refractory idiopathic purpura(ITP) is defined as ITP with persistent thrombocytopenia despite conventional initial management with corticosteroids and splenectomy. The goal of treatment is not cure of the ITP, but only to achieve a safe platelet count, which is arbitrarily assumed to be greater than 30,000/mm3. The risk for major bleeding seems great only when the platelet count is less than 10,000/mm3. There is no accepted algorithm for management of patients with chronic refractory ITP. Recently, more targeted therapies including rituximab, anti-CD40 ligand and Campath-1H have been evaluated in refractory ITP.     

Management of adult idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) is defined as isolated thrombocytopenia without a clinically apparent cause. It is categorized as acute, chronic, and refractory. Its clinical presentation ranges from acute to insidious and the bleeding may vary from minimal to severe. The target platelet count with therapy is more than 30,000/microL in sedentary individuals. Since studies regarding therapies for ITP have been mostly uncontrolled case series, the treatment recommendations are largely derived from expert opinion. This review paper summarizes the data on available therapies for adult acute and chronic/refractory ITP. The therapies include splenectomy, steroids, intravenous immunoglobulin, anti-Rh(D), monoclonal antibodies, danazol, chemotherapy, plasma exchange, and others.     

Changing Paradigms in ITP Management: Newer Tools for an Old Disease

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia that may be accompanied clinically by bleeding and reduced health-related quality of life (HRQoL). While corticosteroids, splenectomy, and various immunosuppressants (used off-label) have served as historical mainstays of ITP treatment, their use is associated with adverse effects and morbidity. Over the last 15 years, the advent of the thrombopoietin receptor agonists has revolutionized the management of chronic ITP with high response rates, durable responses, and minimal adverse effects in most patients. With four agents now FDA-approved to manage chronic ITP, there is a renewed emphasis on improving HRQoL and minimizing the toxicities associated with traditional therapies. Promising agents with diverse mechanisms of action, ranging from those targeting Bruton's Tyrosine Kinase to the neonatal Fc receptor, are currently under investigation. This review highlights recent landmark clinical trials which have made significant impacts on ITP management and ongoing drug development. In critically analyzing studies of relevance, we illustrate the changing paradigms of ITP management and how the field is advancing beyond traditional therapies.     

腹腔镜脾切除术治疗特发性血小板减少性紫癜

目的：探讨腹腔镜脾切除术治疗难治性特发性血小板减少性紫癜（ITP）的手术安全性及临床疗效。方法：回顾性分析42例难治性ITP患者行腹腔镜脾切除的临床资料。结果：42例ITP腹腔镜手术成功率95.2%,2例中转开腹,平均手术时间105min,术中失血平均40mL。全组均于术后12～24h内恢复胃肠蠕动,术后6h下床活动,平均住院时间5d。术后1周内血小板很快上升,治疗有效率95.2%。发生并发症3例,其中1例膈下积液,2例皮下气肿。38例得到随访,4例失访,3例复发,总有效率88.1%。结论：腹腔镜脾切除术治疗ITP安全可行,临床疗效显著。