Immune Thrombocytopenic Purpura — The Changing Therapeutic Landscape
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《新英格兰医药杂志》
Immune thrombocytopenic purpura (ITP) in adults is usually a chronic disease in which a low platelet count often causes mucocutaneous bleeding. ITP is a diagnosis of exclusion. Pseudothrombocytopenia and such disorders as drug-induced thrombocytopenia, microangiopathic thrombocytopenia, bone marrow failure, and congenital thrombocytopenia must be ruled out. The disorder can be primary (idiopathic) or secondary. Secondary ITP is associated with systemic lupus erythematosus, chronic lymphocytic leukemia, lymphoma, HIV infection or full-blown AIDS, hepatitis C infection, and a variety of other disorders.
Multiple mechanisms cause the thrombocytopenia in ITP, so the disorder is likely to be heterogeneous.1 Over 50 years ago, Harrington first demonstrated that a factor in plasma from patients with ITP induced thrombocytopenia in normal subjects. Subsequent studies identified this factor as an antiplatelet autoantibody against glycoproteins in the platelet membrane. Additional mechanisms that lead to platelet destruction involve the activation of helper T cells and cytotoxic T cells. However, the initial inciting event in ITP is unknown.
The bone marrow in patients with ITP contains normal or increased numbers of megakaryocytes. Surprisingly, studies of platelet turnover have shown that platelet production is decreased or normal in most patients with the disorder. In vitro, antiplatelet autoantibodies can impair megakaryocyte production and maturation, and they probably contribute to decreased platelet production in vivo. In addition, plasma levels of thrombopoietin, the major factor that stimulates the growth and development of megakaryocytes, are not elevated in patients with ITP, as compared with the levels in patients with thrombocytopenia resulting from chemotherapy or bone marrow failure.
The decision to treat ITP is based on the platelet count, the degree of bleeding, and the patient's lifestyle. Many patients with ITP require no therapy and only careful monitoring. Since severe bleeding is uncommon with platelet counts that exceed 30,000 per cubic millimeter, treatments are usually initiated when platelet counts fall below this level. Most current treatments are aimed at interfering with antibody-mediated platelet destruction by inhibiting the function of macrophage Fc receptors, decreasing antiplatelet antibody production, or both (see diagram).2 Corticosteroids (typically prednisone) are the backbone of the initial treatment, and they are effective in 50 to 80% of cases. However, when the dose of corticosteroids is reduced or when the treatment is stopped, remission is sustained in only 10 to 30% of cases. Regimens that include dexamethasone may lead to higher rates of sustained remission. Other effective initial treatments include intravenous immune globulin and Rh0(D) immune globulin for patients who are Rh-positive. Sustained remission with these agents, however, is uncommon.
Approaches to the Treatment of ITP.
Several drugs used in the treatment of ITP impair the clearance of autoantibody-coated platelets by Fc receptors expressed on tissue macrophages. Splenectomy works partly by this mechanism but may also impair the interactions between T cells and B cells that are involved in the synthesis of antibody in some patients (1). Corticosteroids may also increase platelet production by impairing the ability of macrophages within the bone marrow to destroy platelets, and thrombopoietin and thrombopoietic agents stimulate megakaryocyte progenitors (2). Many nonspecific immunosuppressive agents, such as azathioprine and cyclosporine, act at the level of the T cell (3). A monoclonal antibody against CD154 that is under clinical investigation targets a costimulatory molecule needed for the optimization of T-cell–macrophage and T-cell–B-cell interactions involved in antibody production (4). Intravenous immune globulin may contain antiidiotypic antibodies that decrease autoantibody production. A monoclonal antibody that recognizes CD20 expressed on B cells causes their depletion (5). Plasmapheresis transiently removes autoantibody from the plasma (6). Platelet transfusions are used to treat severe bleeding in an emergency (7). Adapted from Cines and Blanchette.2
Splenectomy is the traditional second-line treatment for patients who do not have a response to corticosteroids or who do not have a sustained remission with low doses of corticosteroids. In these cases, splenectomy can be curative. Complete or partial remission occurs in more than two thirds of patients who undergo splenectomy, but the relapse rate is 15 to 25%. The risks associated with splenectomy are small, but patients who have undergone the surgery have a lifelong increased risk of bacterial sepsis.
An array of third-line therapies is available for patients who decline splenectomy and for those in whom surgery is not indicated or must be delayed. Rituximab, the monoclonal antibody against CD20+ B cells, has an overall response rate of 25 to 50%, and many durable responses have been observed with this agent, with relatively few side effects. Other agents that have induced responses when used as third-line treatment include Rh0(D) immune globulin, intravenous immune globulin, azathioprine, cyclophosphamide, danazol, vinca alkaloids, dapsone, combination chemotherapy, cyclosporine, and mycophenolate mofetil. The decision to choose one of these agents is usually based on the physician's preference and experience with each agent, because data from prospective, randomized trials are lacking.3 With the exception of Rh0(D) immune globulin, which is active only in patients with a spleen, these agents can be useful in patients in whom splenectomy fails and who therefore require medical therapy. The major difficulties with many of these third-line therapies are modest response rates and, frequently, a slow onset of action — an effect may not be evident for several months. In addition, bone marrow suppression and an increased risk of infection complicate treatment with many of the immunosuppressive agents.
In the past 10 years, a new class of drugs known as thrombopoietic agents has emerged. Spawned by the cloning of thrombopoietin, the ligand for the Mpl receptor expressed by megakaryocytes and platelets, these agents induce the growth and maturation of megakaryocytes and result in elevated platelet counts in healthy volunteers. On the basis of the observation that platelet production is impaired in ITP, small pilot studies evaluated the use of a pegylated, truncated form of human thrombopoietin (PEG-MGDF), with encouraging results. PEG-MGDF was immunogenic, however, and it induced the production of neutralizing antithrombopoietin antibodies, resulting in thrombocytopenia in some recipients. The agent was therefore withdrawn from further clinical investigation. Nonimmunogenic thrombopoietic peptides and small, nonpeptide molecules have subsequently been developed. One such agent, AMG 531, is composed of an immunoglobulin Fc domain fragment linked to two identical peptide chains that bind and activate the Mpl receptor. In this issue of the Journal (pages 1672–1681), Bussel et al. report on a phase 1–2 study of AMG 531, administered subcutaneously for 3 to 6 weeks in 41 adults with chronic ITP in whom one or more prior therapies had failed. Most of the patients had undergone splenectomy, and many required corticosteroid therapy. Increases in the platelet count to the targeted range (50,000 to 450,000 per cubic millimeter and at least twice the baseline count) occurred within 8 days in most patients with a response to AMG 531; the overall response rate was 68%. Although the long-term complications of this agent are not known, distinctive adverse events included mild-to-moderate headaches and transient decreases in the baseline platelet count after discontinuation of the drug.
Thrombopoietic agents represent a promising new therapeutic strategy for ITP that is refractory to second- and third-line therapies. These agents might also serve as an alternative for patients who cannot tolerate immunosuppressive therapy or who are not candidates for it. The place of these agents in the armamentarium of ITP therapy, however, remains to be determined. Their use will be guided by further clinical trials of longer duration and a better understanding of the relative contribution of platelet destruction and impaired platelet production in individual patients with ITP.
Source Information
Dr. Bromberg is an associate professor of medicine and pharmacology at Temple University School of Medicine, Philadelphia.
References
Cooper N, Bussel J. The pathogenesis of immune thrombocytopaenic purpura. Br J Haematol 2006;133:364-374.
Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002;346:995-1008.
Vesely SK, Perdue JJ, Rizvi MA, Terrell DR, George JN. Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review. Ann Intern Med 2004;140:112-120.(Michael E. Bromberg, M.D.)
Multiple mechanisms cause the thrombocytopenia in ITP, so the disorder is likely to be heterogeneous.1 Over 50 years ago, Harrington first demonstrated that a factor in plasma from patients with ITP induced thrombocytopenia in normal subjects. Subsequent studies identified this factor as an antiplatelet autoantibody against glycoproteins in the platelet membrane. Additional mechanisms that lead to platelet destruction involve the activation of helper T cells and cytotoxic T cells. However, the initial inciting event in ITP is unknown.
The bone marrow in patients with ITP contains normal or increased numbers of megakaryocytes. Surprisingly, studies of platelet turnover have shown that platelet production is decreased or normal in most patients with the disorder. In vitro, antiplatelet autoantibodies can impair megakaryocyte production and maturation, and they probably contribute to decreased platelet production in vivo. In addition, plasma levels of thrombopoietin, the major factor that stimulates the growth and development of megakaryocytes, are not elevated in patients with ITP, as compared with the levels in patients with thrombocytopenia resulting from chemotherapy or bone marrow failure.
The decision to treat ITP is based on the platelet count, the degree of bleeding, and the patient's lifestyle. Many patients with ITP require no therapy and only careful monitoring. Since severe bleeding is uncommon with platelet counts that exceed 30,000 per cubic millimeter, treatments are usually initiated when platelet counts fall below this level. Most current treatments are aimed at interfering with antibody-mediated platelet destruction by inhibiting the function of macrophage Fc receptors, decreasing antiplatelet antibody production, or both (see diagram).2 Corticosteroids (typically prednisone) are the backbone of the initial treatment, and they are effective in 50 to 80% of cases. However, when the dose of corticosteroids is reduced or when the treatment is stopped, remission is sustained in only 10 to 30% of cases. Regimens that include dexamethasone may lead to higher rates of sustained remission. Other effective initial treatments include intravenous immune globulin and Rh0(D) immune globulin for patients who are Rh-positive. Sustained remission with these agents, however, is uncommon.
Approaches to the Treatment of ITP.
Several drugs used in the treatment of ITP impair the clearance of autoantibody-coated platelets by Fc receptors expressed on tissue macrophages. Splenectomy works partly by this mechanism but may also impair the interactions between T cells and B cells that are involved in the synthesis of antibody in some patients (1). Corticosteroids may also increase platelet production by impairing the ability of macrophages within the bone marrow to destroy platelets, and thrombopoietin and thrombopoietic agents stimulate megakaryocyte progenitors (2). Many nonspecific immunosuppressive agents, such as azathioprine and cyclosporine, act at the level of the T cell (3). A monoclonal antibody against CD154 that is under clinical investigation targets a costimulatory molecule needed for the optimization of T-cell–macrophage and T-cell–B-cell interactions involved in antibody production (4). Intravenous immune globulin may contain antiidiotypic antibodies that decrease autoantibody production. A monoclonal antibody that recognizes CD20 expressed on B cells causes their depletion (5). Plasmapheresis transiently removes autoantibody from the plasma (6). Platelet transfusions are used to treat severe bleeding in an emergency (7). Adapted from Cines and Blanchette.2
Splenectomy is the traditional second-line treatment for patients who do not have a response to corticosteroids or who do not have a sustained remission with low doses of corticosteroids. In these cases, splenectomy can be curative. Complete or partial remission occurs in more than two thirds of patients who undergo splenectomy, but the relapse rate is 15 to 25%. The risks associated with splenectomy are small, but patients who have undergone the surgery have a lifelong increased risk of bacterial sepsis.
An array of third-line therapies is available for patients who decline splenectomy and for those in whom surgery is not indicated or must be delayed. Rituximab, the monoclonal antibody against CD20+ B cells, has an overall response rate of 25 to 50%, and many durable responses have been observed with this agent, with relatively few side effects. Other agents that have induced responses when used as third-line treatment include Rh0(D) immune globulin, intravenous immune globulin, azathioprine, cyclophosphamide, danazol, vinca alkaloids, dapsone, combination chemotherapy, cyclosporine, and mycophenolate mofetil. The decision to choose one of these agents is usually based on the physician's preference and experience with each agent, because data from prospective, randomized trials are lacking.3 With the exception of Rh0(D) immune globulin, which is active only in patients with a spleen, these agents can be useful in patients in whom splenectomy fails and who therefore require medical therapy. The major difficulties with many of these third-line therapies are modest response rates and, frequently, a slow onset of action — an effect may not be evident for several months. In addition, bone marrow suppression and an increased risk of infection complicate treatment with many of the immunosuppressive agents.
In the past 10 years, a new class of drugs known as thrombopoietic agents has emerged. Spawned by the cloning of thrombopoietin, the ligand for the Mpl receptor expressed by megakaryocytes and platelets, these agents induce the growth and maturation of megakaryocytes and result in elevated platelet counts in healthy volunteers. On the basis of the observation that platelet production is impaired in ITP, small pilot studies evaluated the use of a pegylated, truncated form of human thrombopoietin (PEG-MGDF), with encouraging results. PEG-MGDF was immunogenic, however, and it induced the production of neutralizing antithrombopoietin antibodies, resulting in thrombocytopenia in some recipients. The agent was therefore withdrawn from further clinical investigation. Nonimmunogenic thrombopoietic peptides and small, nonpeptide molecules have subsequently been developed. One such agent, AMG 531, is composed of an immunoglobulin Fc domain fragment linked to two identical peptide chains that bind and activate the Mpl receptor. In this issue of the Journal (pages 1672–1681), Bussel et al. report on a phase 1–2 study of AMG 531, administered subcutaneously for 3 to 6 weeks in 41 adults with chronic ITP in whom one or more prior therapies had failed. Most of the patients had undergone splenectomy, and many required corticosteroid therapy. Increases in the platelet count to the targeted range (50,000 to 450,000 per cubic millimeter and at least twice the baseline count) occurred within 8 days in most patients with a response to AMG 531; the overall response rate was 68%. Although the long-term complications of this agent are not known, distinctive adverse events included mild-to-moderate headaches and transient decreases in the baseline platelet count after discontinuation of the drug.
Thrombopoietic agents represent a promising new therapeutic strategy for ITP that is refractory to second- and third-line therapies. These agents might also serve as an alternative for patients who cannot tolerate immunosuppressive therapy or who are not candidates for it. The place of these agents in the armamentarium of ITP therapy, however, remains to be determined. Their use will be guided by further clinical trials of longer duration and a better understanding of the relative contribution of platelet destruction and impaired platelet production in individual patients with ITP.
Source Information
Dr. Bromberg is an associate professor of medicine and pharmacology at Temple University School of Medicine, Philadelphia.
References
Cooper N, Bussel J. The pathogenesis of immune thrombocytopaenic purpura. Br J Haematol 2006;133:364-374.
Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002;346:995-1008.
Vesely SK, Perdue JJ, Rizvi MA, Terrell DR, George JN. Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review. Ann Intern Med 2004;140:112-120.(Michael E. Bromberg, M.D.)