Current Options for the Treatment of Idiopathic Thrombocytopenic Purpura

Current Options for the Treatment of Idiopathic Thrombocytopenic Purpura Donald M. Arnold and John G. Kelton Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelets and bleeding. Platelet autoantibodies result in accelerated platelet destruction by the reticuloendothelial cells in the spleen and liver, overwhelming the compensatory capability of the bone marrow to increase platelet production. The goal of treatment for patients with ITP is to raise the platelet count to high enough levels to prevent bleeding using the least toxic therapy, recognizing the generally benign nature of the illness. Corticosteroids, intravenous immune globulin, and splenectomy remain mainstays of treatment; however, newer therapies including rituximab and the thrombopoietin receptor agonists are remodeling conventional treatment algorithms. Immune suppressant medications and cytotoxic drugs continue to be used in patients with severe and chronic refractory ITP with some success; however, estimates of the effect of these and other treatments are limited by the lack of randomized trials using clinical end points. In this article, treatments for ITP are reviewed with a focus on their mechanism of action and the best available evidence from clinical studies. A move towards early aggressive therapy may alter the natural history of this self-perpetuating illness. Semin Hematol 44(suppl 5):S12-S23 © 2007 Elsevier Inc. All rights reserved.

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diopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelets and mucocutaneous bleeding that ranges in severity from mild to lifethreatening. ITP is a common condition with an estimated annual incidence of approximately 1 per 10,000 to 1 per 1,000 persons.1-5 True estimates would undoubtedly be higher if they included patients with less severe thrombocytopenia. ITP is a self-perpetuating illness caused by increased platelet destruction mediated by platelet-reactive autoantibodies, and impaired platelet production as a result of a relative deficiency in the platelet regulatory hormone thrombopoietin (TPO).

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. Financial support for the development of this article was provided by an independent grant from GlaxoSmithKline. Funding: D.M.A. is a New Investigator for the Canadian Institutes for Health Research. J.G.K. is a Canada Research Chair. STATEMENT OF CONFLICT OF INTEREST: Dr Kelton has received consulting fees from GlaxoSmithKline. Dr Arnold has received grant/research support from the Canadian Blood Services, and has received grant monies from Hoffman-LaRoche; he will discuss the unlabeled/unapproved use of rituximab for idiopathic thrombocytopenic purpura. Address correspondence to John G. Kelton, MD, McMaster University, 1200 Main St W, Room 2E1, Hamilton, Ontario, Canada L8N 3Z5. E-mail: [email protected]

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0037-1963/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2007.11.003

Diagnosis of ITP Clinical Features Females are affected more commonly than males (2–3:1) and patients typically present in early adulthood. Some patients will present with asymptomatic thrombocytopenia, while others will have bleeding symptoms. Mucocutaneous bleeding is the hallmark of ITP and manifests as purpura (petechiae, ecchymosis), epistaxis, menorrhagia, oral mucosal, gastrointestinal, or rarely, intracranial hemorrhage (ICH). ITP is rarely life-threatening; for example, in a pooled analysis of ITP patients with persistent low platelet counts (⬍30 ⫻ 109/L), the rate of fatal bleeding (usually due to intracranial hemorrhage) was estimated at 0.02 to 0.04 cases per patientyear, but was highest (⬃0.13 cases per patient-year) among patients over 60 years of age.6 ITP is a diagnosis of exclusion. Secondary ITP occurs in the setting of specific drugs such as quinine and vancomycin, lymphoproliferative disease, systemic lupus erythematosus, the antiphospholipid antibody syndrome, hepatitis C infection, and human immunodeficiency virus (HIV) (see the article by Howard Liebman in this issue). Treatment of underlying disease is often necessary before improvements in the platelet count can be anticipated. Eradication of occult Helicobacter pylori infection should be considered in patients with ITP although in our experience, like that of others in North

Current treatment options for ITP Table 1 Differential Diagnosis of ITP Immune Primary ITP Secondary Drug-induced (eg, quinine) Post-transfusion purpura HIV Hepatitis C Infectious mononucleosis (EBV virus) SLE Crohn’s disease Antiphospholipid antibody syndrome Chronic lymphocytic leukemia Lymphoma IgA deficiency Common variable immune deficiency Sarcoidosis Non-immune Hypersplenism Myelodysplasia Acute leukemia Drug-induced marrow suppression (valproic acid, alcohol) Hereditary thrombocytopenia (MYH-9 mutations) Microangiopathic hemolytic anemia Abbreviations: ITP, idiopathic thrombocytic purpura; HIV, human immunodeficiency virus; EBV, Epstein-Barr virus; SLE, systemic lupus erythematosus.

America, it is rarely successful. Non-immune thrombocytopenia including myelodysplastic syndrome, hypersplenism, or familial forms can be difficult to distinguish from ITP. The association with other immune conditions such as thyroiditis, hemolytic anemia (Evan’s syndrome), and monoclonal gammopathy of uncertain significance7 supports the diagnosis. Table 1 lists causes of immune and non-immune thrombocytopenia that are frequently confused with ITP. Physical examination should focus on typical bleeding sites, and on excluding underlying diseases that may cause secondary (immune or non-immune) thrombocytopenia. Dependent areas and skin underneath tight clothing should be examined for petechiae, and oral mucous membranes should be examined for purpura. The remainder of the physical examination should be normal; in particular, lymphadenopathy and/or splenomegaly should be absent and, if present, should prompt investigations for a recent viral infection such as Epstein-Barr virus or primary HIV, underlying lymphoproliferative disease, or hepatitis. Congenital defects such as skeletal, renal or neurological abnormalities suggest an inherited thrombocytopenic syndrome.

Laboratory Tests Isolated thrombocytopenia is typical of ITP. At presentation, thrombocytopenia may range from severe to mild8 and examination of the peripheral blood film is required to exclude pseudothrombocytopenia (EDTA-dependent platelet agglutinating antibodies), schistocytic anemia, or blood cell abnormalities suggestive of other disorders. The mean platelet vol-

S13 ume (MPV) is usually increased. About 15% to 25% of patients with otherwise typical ITP have detectable antinuclear antibodies or antiphospholipid antibodies, usually in low titers. These patients generally do not have a different clinical outcome than patients without such antibodies.9 Coagulation screen is normal. Thyroid function tests are useful to uncover occult thyroid dysfunction, especially prior to surgery (including splenectomy). A bone marrow examination is not routinely performed, but is warranted in patients over the age of 60 in whom myelodysplasia is more common. In ITP, bone marrow morphology shows normal or increased megakaryocytes.

Specific Diagnostic Tests for ITP Fifty years since the discovery of platelet autoantibodies, there is still no diagnostic test for ITP. Platelet-associated IgG (PAIgG) is not useful,10 and glycoprotein-specific assays for platelet autoantibodies, while able to detect autoantibodies in up to 66% of patients with ITP, lack sufficient sensitivity to be used as a stand-alone diagnostic test.10,11 Moreover, platelet autoantibodies are generally low titer on platelets and may be difficult to detect in plasma. The immature platelet fraction percent, defined as the proportion of young, reticulated (RNA-containing) platelets,12 TPO assays, and enzyme-linked immunospot assays to detect GPIIb-IIIa–producing B cells, are currently being evaluated.13 A platelet count response to intravenous immunoglobulin (IVIg) is diagnostic of immune thrombocytopenia (either primary or secondary ITP).

Treatment Early treatments for ITP were aimed at removing the principal site of autoantibody production and platelet destruction by splenectomy, or diminishing the phagocytic ability of the reticuloendothelial system (RES) with corticosteroids and IVIg. Treatments aimed at decreasing platelet autoantibody production include cytotoxic agents such as vinca alkaloids and the monoclonal anti-CD20 antibody rituximab. Immunosuppressive drugs such as azathioprine and cyclosporine also decrease autoantibody production by reducing B and T cell number and function. TPO receptor agonists can overcome platelet underproduction in ITP, and have been shown to be effective in early clinical trials. The mechanism of action of various ITP treatments is depicted in Fig 1. Advances in our understanding of the pathophysiology of ITP should enable better treatments with fewer side effects.

Challenges Facing Clinicians in Deciding Upon ITP Treatments Clinicians charged with making treatment decisions for patients with ITP face various challenges. First, treatment recommendations derive largely from uncontrolled cohort studies, and expert opinion; second, criteria to define platelet count outcomes are not standardized across studies making their results difficult to compare; and third, important clinical outcomes such as bleeding and quality of life are rarely reported in clinical studies. In recent years and with the development of new treatments, randomized controlled trials

D.M. Arnold and J.G. Kelton

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Figure 1 Pathogenic processes in ITP that are targets of treatment. (1) T cells expressing surface CD 154 lose tolerance to platelet antigens (eg, GPIIb-IIIa and GPIb-IX), which are then presented to B cells in lymphoid tissues (primarily the spleen). Cyclosporine inhibits T cells, and azathioprine and mycophenolate mofetil inhibit lymphocyte proliferation; cytotoxic agents interfere at this stage; and antiCD154 monoclonal antibody disrupts the CD154 –CD40 interaction. (2) Autoreactive CD20⫹ B cells are stimulated to differentiate and produce platelet reactive antibodies. Rituximab, an anti-CD20 monoclonal antibody, targets and destroys B cells; and corticosteroids decrease autoantibody synthesis. (3) Platelet autoantibodies bind to specific platelet glycoproteins (typically GPIIb-IIIa or GPIbIX) through the Fab terminus. (4) IgG-sensitized platelets undergo FcR-mediated phagocytosis by reticuloendothelial (RE) cells. Splenectomy removes the primary site of platelet clearance; IVIg and anti-D block RE cells and prevent platelet clearance; corticosteroids decrease phagocytosis; and vinca alkaloids are toxic to macrophages. (5) Platelet reactive autoantibodies target and destroy megakaryocytes resulting in decreased thrombopoiesis. (6) Thrombopoietin (TPO) is constitutively produced in the liver and kidney, and upon stimulation in the bone marrow. In ITP, TPO levels are low for the degree of thrombocytopenia, thus platelet production is suboptimal. The administration of TPO receptor agonists can overcome platelet underproduction.

are being performed more frequently, tools to measure bleeding14 and quality of life15 are being developed, and there is a push to standardize outcome criteria.16 In the following section, we outline the treatment for ITP with a focus on chronic therapy. We present treatment recommendations based on evidence, and where such evidence is lacking, strategies that we use, based on our experience.

Goals of Treatment Key guiding principles of treatment for ITP are listed in Table 2. The prognosis for patients with ITP is generally good and many studies report greater morbidity from the treatment than from the illness itself.6,17,18 Mortality from ITP is esti-

mated at 4% overall,19 attributable almost exclusively to those patients with severe refractory thrombocytopenia.18 These observations argue for the selection of high-risk patients for treatment and for the need to consider patient preference. Drugs that interfere with platelet function including nonsteroidal anti-inflammatory agents and alcohol should be avoided. In general, the least toxic treatment should be administered to achieve hemostasis and a stable, but not necessarily normal, platelet count. Treatment for adults is generally recommended when platelets are less than 20 to 30 ⫻ 109/L, or below 50 ⫻ 109/L in the presence of bleeding.20,21 We use a “staircase” approach for ITP therapy where treatments build on each other (often cumulatively) and proceed in a stepwise fashion starting from the least toxic (Fig 2). In brief, following a period of observation, corticosteroid-based treatment with or without IVIg or anti-D is the initial treatment for most patients. Failing that, splenectomy offers the greatest chance of cure and is generally offered next for adults with persistent ITP; however, in the future, rituximab and/or TPO receptor agonists may allow splenectomy to be avoided in some patients. Most patients with refractory ITP post-splenectomy can achieve a stable remission, although this may take several years and multiple therapies including danazol, immunosuppressants, and cytotoxic chemotherapy.22 The efficacy and safety of various treatments for ITP are summarized in Table 3.

Observation Up to 80% of children with ITP will recover spontaneously after 4 to 8 weeks23 and serious bleeding is rare. In adults, spontaneous remissions are unusual— occurring in about 10% of patients—yet many will never bleed, especially if thrombocytopenia is not severe.21 Thus for the majority of children, and for asymptomatic adults with stable platelet counts, an initial period of observation and platelet monitoring is warranted.

Corticosteroids Corticosteroids improve ITP by reducing both phagocytic activity and synthesis of pathogenic autoantibodies. The optimal dose of corticosteroids continues to be evaluated in clinical studies.

Table 2 Principles to Guide Treatment Decisions for Patients With ITP Bleeding is rare, and platelet function is preserved in ITP; thus many patients do not need treatment despite moderate or even severe thrombocytopenia. Treatment should be individualized and decisions should be shared between patient and physician. Goals of treatment are to prevent bleeding and to achieve a safe, but not necessarily normal, platelet count. With newer treatments, splenectomy may potentially be delayed or avoided. Drugs that interfere with platelet function, particularly aspirin, nonsteroidal anti-inflammatory agents, and alcohol should be avoided.

Current treatment options for ITP

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Figure 2 Staircase approach to treatment of ITP. The goal of treatment is the achievement of a stable, hemostatic platelet count. Treatments should proceed in a step-wise fashion, starting from the least toxic and building on each other, like a staircase.

Standard-Dose Prednisone The standard initial dose of prednisone is 1 to 2 mg per kg for 2 to 6 weeks with tapering over several weeks following a platelet count response. In general, 60% to 70% of adults with acute ITP will achieve an initial response,24,25 with even higher response rates in children. Many investigators have reported 6-month remission rates in adults (platelet count ⬎100 ⫻ 109/L) of 20% to 25% following corticosteroids,17,26-28 while others have reported remission rates as high as 47% at 6 months29 and 52% at 3 months.30 With

longer follow-up, the risk of relapse among adult patients with an initial complete remission is substantial. For example, in one study, only 29% of adult patients remained in remission after 4 years.31 Our own experience is consistent with less than 25% of adults achieving a prolonged remission following corticosteroids. Conversely, the rate of long-term remission or “cure” approaches 80% in children. Thus, while the majority of patients with acute ITP will respond initially to standard-dose prednisone, less than 20% of adults and close to 80% of children will achieve a durable remission. Low-Dose Prednisone Low-dose may be an alternative to standard-dose prednisone for initial treatment of ITP. A 3-week course of low-dose (0.25 mg/kg/d) was compared with standard-dose (1 mg/ kg/d) prednisone in a randomized trial of 160 children and 223 adults with newly diagnosed ITP.32 The proportion achieving a platelet count above 50 ⫻ 109/L at 6 months was no different between the low- and standard-dose groups (133/160 [83%] for children, and 132/223 [59%] for adults). Another prospective study showed no difference between high-dose (1.5 mg/kg) and low-dose (0.5 mg/kg per day) prednisone.33 Thus, low-dose prednisone may be as effec-

Table 3 Drug Treatment for Patients With Refractory ITP

Drug

Efficacy (% of patients achieving a platelet count response)

Usual Dose

Prednisone

1 mg/kg, tapered over 4 to 6 weeks

70% to 80% of patients achieve an initial response; 20% achieve a durable response (adults) Up to 80% of patients achieve a response; durable responses are reported 80% to 90%

High-dose dexamethasone

40 mg per day ⴛ 4 days, for 1 to 6 cycles

IVIg

1 to 2 g/kg

Anti-D

50 to 75 ␮g/kg

Danazol

400–800 mg per day

80% to 90% (in Rh-positive patients) Up to 70%, while on treatment

Azathioprine

1 to 2 mg/kg per day

⬃ 25%

Mycophenolate mofetil

1 to 2 g per day

Up to 40%

Cyclosporine

3 to 5 mg/kg

Up to 50%

Cyclophosphamide

1 to 2 mg/kg per day

Up to 40%

Vinca alkaloids

1 mg/m2 (max 2 mg)

Dapsone

1 to 2 mg/kg per day

Temporary increases in platelet count in 50% of patients Up to 60% in some reports

Abbreviation: DIC, disseminated intravascular coagulation.

Complications Mood alterations, anxiety, insomnia, hypertension, hyperglycemia, infection, osteopenia Mood alterations, anxiety, insomnia, hypertension, hyperglycemia, infection Headache, fever, nausea, vomiting. Rare: aseptic meningitis, renal failure, thrombotic events Anemia. Rare: DIC, renal failure Virilizing effects, fluid retention, nausea, amenorrhea, hepatitis. Rare: thrombocytopenia Macrocytosis, leukopenia, hepatotoxicity. Rare: skin cancer Headache, gastritis, diarrhea, leukopenia (although less than azathioprine) Nephrotoxicity, hypertension, headache Teratogenesis, hepatic toxicity. Rare: leukoemogenesis, hemorrhagic cystitis, pulmonary fibrosis, cardiac damage Neuropathy, neutropenia, alopecia Hemolysis, rash

S16 tive as the standard dose for initial treatment of ITP, but long-term remission rates for both remain unsatisfactory. High-Dose Corticosteroids These include pulse methylprednisolone and pulse dexamethasone. For patients with acute ITP, high-dose pulse methylprednisolone may result in a more rapid rise in the platelet count compared with conventional doses. In a study of 57 adults, high-dose methylprednisolone (30 mg/kg per day intravenous) followed by a rapid taper and a switch to oral prednisone was associated with better short-term response rates than standard-dose prednisone (1 mg/kg per day) (80.1% v 52.7%; P ⬍.05); however, this effect was lost by 2 months.34 Similarly, other investigators have found that pulse oral methylprednisolone followed by a 6-week taper was effective at raising the platelet count quickly but did not improve longterm remission rates compared with conventional doses.35 In children with acute ITP, high-dose methylprednisolone (eg, 30 mg/kg per day intravenously for 3 days; or 30 to 50 mg/kg per day orally for 7 days) was also effective at rapidly increasing the platelet count.36 In a recent single-arm study, a single course of high-dose dexamethasone (40 mg per day for 4 days) resulted in the achievement of a platelet count above 50 ⫻ 109/L in 106 (84.8%) of 125 adults with acute ITP, and of those, 50% have a response that lasted 2 to 5 years.37 Repeated cycles of highdose dexamethasone may result in even higher rates of durable remissions, although this effect may simply be a function of time on treatment. In a recent pilot study, 6 monthly courses of high-dose dexamethasone (40 mg per day for 4 days) resulted in a platelet count above 50 ⫻ 109/L by 6 months in 31 of 37 (83.8%) newly diagnosed patients, including 24 (64.9%) for whom responses were maintained for over 2 years (range, 6 to 77 months).38 Compliance with this protocol was poor and side effects included hypertension, cataracts and bronchial pneumonia. In a follow-up study by the same investigators, four cycles of dexamethasone (instead of six), given every 2 weeks (instead of every month) was better tolerated but less effective: 76 of 95 (80%) adults and children achieved a platelet count above 50 ⫻ 109/L after 60 days, and 64 (67.4%) maintained a response after a median of 8 months (range, 4 to 24). High-dose corticosteroids have also been tested in patients with chronic ITP. In one study, 6 monthly cycles of high-dose dexamethasone (40 mg per day for 4 days) resulted in the achievement of a platelet count above 100 ⫻ 109/L for at least 6 months after the last cycle in 10 out of 10 adult patients treated.39 Conversely, other investigators using the same regimen reported that 13 of 32 patients (40.6%) had transient responses only.40 In another study, none of the nine patients with chronic ITP responded to high-dose dexamethasone, and five could not tolerate the treatment.41 In children with chronic ITP, few long-lasting remissions have been reported following high-dose dexamethasone42 but in one study, three of seven children achieved a platelet count above 50 ⫻ 109/L after 6 months, including one for whom the response was maintained to 1 year.43

D.M. Arnold and J.G. Kelton In conclusion, corticosteroids remain the cornerstone of treatment for patients with newly diagnosed ITP and should be tried in chronic patients who require treatment. While effective, low-dose prednisone is generally not recommended as initial treatment since long-term responses may be compromised, but based on our experience, low-dose (10 to 20 mg) prednisone every second or third day may be useful to maintain remission for some chronic patients. High-dose corticosteroids, especially high-dose dexamethasone, are associated with initial and durable platelet count responses that are as good as those reported with standard-dose prednisone for patients with acute ITP. Repeated cycles may be more effective but are limited by significant toxicities. Reported success with pulse dexamethasone in chronic ITP is conflicting, yet long-lasting durable responses are generally not expected.

IVIg and Anti-Rhesus Antibody (anti-D) IVIg and anti-D are commonly used for both acute and chronic ITP. Combining the results of the clinical data can be complex because of differences in patient population, dosage, and dosing schedules. Nonetheless, in this section we will summarize both treatments together because they have similar mechanisms of action and efficacy. Like many aspects of ITP treatment, the successful implementation of IVIg was serendipitous. In 1981, Imbach and co-investigators used high doses of IVIg administered over 5 days as a treatment for ITP in childhood.44 These observations were quickly extended to adults.45 The following year, Salama et al demonstrated that anti-D given to Rh-positive individuals was similarly effective.46 All subsequent advances focusing on dosing have followed these initial pivotal studies. The mechanism of action of high-dose IVIg and anti-D remains debated, but reticuloendothelial (RE) blockade is the principal explanation for the response to treatment in these patients. This evidence comes from several sources. For one, our group demonstrated that it was possible to alter the rate of clearance of IgG-sensitized red cells (an in vivo measure of RE function) by modifying the plasma concentration of monomeric IgG.47 Individuals with low plasma IgG had a more rapid clearance of IgG-sensitized red cells than normal. Elevation in the concentration of IgG in the plasma progressively impaired RE function until it was dramatically impaired, at concentrations of plasma IgG seen following high-dose IVIg. The competitive model of RE clearance would also explain why anti-D in an Rh-positive individual is effective in ITP. Although the plasma concentration of IgG is not altered by the administration of anti-D, IgG-sensitized red cells compete for RE Fc receptors (FcR). This effect would also explain why anti-D is ineffective in Rh-negative individuals, while other anti-Rhesus antibodies (such as anti-c) are effective in Rh negative (but c-positive) individuals. Other mechanisms of action have been proposed to explain efficacy of IVIg and anti-D. These include anti-idiotypic antibodies19; pro- or anti-inflammatory cytokines48; and upregulation or downregulation of various FcRs or the formation of soluble immune complexes.49 In a mouse model of

Current treatment options for ITP ITP, the inhibitory IgG receptor, Fc␥RIIB, was required for IVIg to cause an elevation in platelet count,50 and the transfer of IVIg-primed dendritic cells has been shown to recapitulate the effect of IVIg.51 The efficacy of IVIg and anti-D has been best studied in children, but there is debate even in this setting because of study differences in patient populations, doses, and delivery regimens. For acute childhood ITP, the most feared complication of thrombocytopenia is ICH, and thus treatment regimens focus on the prevention of ICH. However, ICH in acute childhood ITP is rare, typically 2 to 5 per 1,000 children, and it is not feasible to power a clinical trial based on this outcome. This has led investigators to use surrogate end points such the number of days below a designated “at-risk” platelet count such as 10 to 20 ⫻ 109/L, as the duration and severity of thrombocytopenia are important risk factors for ICH in children. Consequently, clinicians can question whether a 1- or 2-day shortening of this at-risk period is clinically relevant. Recognizing these caveats, a meta-analysis of randomized controlled trials in children that combined data from six studies (N ⫽ 401 children) showed that the platelet count rose more rapidly with IVIg compared with corticosteroids.52 Similar results have been observed in adults. A French study of 122 adults with ITP demonstrated that a higher proportion of patients receiving IVIg (0.7 g/kg per day for 3 days) show a platelet count rise to over 50 ⫻ 109/L within 5 days compared with patients receiving methylprednisolone (15 mg/kg per day for 3 days).53 But again, the clinical impact of this can be challenged. The efficacy of anti-D compared with IVIg has been studied primarily in children. Blanchette and colleagues demonstrated that more children had a platelet count greater than 10 ⫻ 109/L by day 3 of treatment using either of two IVIg treatments (0.8 g/kg for one day or 1.0 g/kg for two days) compared with anti-D or high-dose oral prednisone (4 mg/kg per day).54 However, this dosage regimen of anti-D was lower (25 ␮g/kg per day for 2 days) than doses used by other investigators. Higher doses of anti-D (75 ␮g/kg) have been associated with similar rises in platelet counts compared with IVIg.55 The review of prospective studies using IVIg and anti-D provides information on the frequency and duration of response, and on adverse effects. In the largest study evaluating IVIg (N ⫽ 97 children and adults) 80% to 90% of the patients showed a rise in platelet count to greater than 50 ⫻ 109/L by day 7, with most patients having a response within 2–3 days.56 Typically, the platelet count rose to an average of 150 ⫻ 109/L following 1 g/kg per day for 2 days. Platelets began to drift down after 2 weeks, but many patients had a response that lasted 4 weeks or more. A well-known observation using high-dose IVIg is tachyphylaxis. Often, patients who are repeatedly treated will have a progressive drop in the peak platelet rise and duration of the remission. The temporary withdrawal of the IVIg treatment typically allows the patient to respond once again in the future. Serious adverse events with IVIg are uncommon. In the largest prospective study56 in which pre-medications were

S17 not permitted, half of the patients developed headache and 10% had fever. Our own experience (often with anti-histamines and/or corticosteroid pre-treatment) has been that severe headache, fever, nausea, and vomiting occur in about 1 in 20 patients. Many patients treated with high-dose IVIg will have a modest but significant fall in hemoglobin and about 30% will have a nonspecifically positive direct antiglobulin test (DAT).57 Rare complications include aseptic meningitis and thrombotic events. The platelet rise and duration of response following treatment with anti-D has not been as well studied but is probably similar to IVIg.55,58,59 Some reports have suggested that anti-D is less effective in splenectomized patients, but others have not.59-61 Anti-D can cause hemolysis and occasionally renal failure in some patients, and repeated doses often lead to anemia.58 Fatalities from disseminated intravascular coagulation have also been described.62 The optimal dose of anti-D and IVIg is becoming clarified. Initially, lower doses of anti-D were used but 75 ␮g/kg has been shown to produce a more rapid rise in platelet count with a longer duration of response.63 Important studies and subsequent analysis by Bierling and Godeau have helped clarify dosing for IVIg. In a randomized study, patients with ITP were treated with 0.5 g/kg or 1 g/kg IVIg.64 The higher dose produced a more rapid and higher peak platelet count. In an earlier study, the use of 2 g/kg was shown to produce only a modest additional increase in the overall response rate compared to 1 g/kg.65 The authors suggested that an initial dose of 1 g/kg could be used in most patients and that a second dose of 1 g/kg could be reserved for those with particularly severe ITP.66 A number of investigators have questioned whether early treatment with high-dose IVIg or anti-D can lead to a longterm remission or a sustained response that is sufficient to allow splenectomy to be avoided. This hypothesis is intuitively interesting because ITP, like many autoimmune disorders, appears to be self-sustaining. While initial studies were suggestive,67,68 so far, this potential has not been confirmed.53,66,69

Splenectomy The spleen is an important site of antibody production and is the principal site of clearance of IgG-sensitized platelets. Prior to the introduction of glucocorticoids, splenectomy was the treatment of choice for patients with ITP. Today, it is generally reserved for adults who fail first-line treatments. Splenectomy is rarely performed in children under the age of 10 because of the risk of overwhelming post-splenectomy infection (OPSI) and the high chance of spontaneous remissions. Instead, many children are treated with intermittent maintenance therapy with IVIg, anti-D, or corticosteroids and splenectomy is reserved for resistant children only. Of all treatments, splenectomy is associated with the highest rate of durable platelet count responses with long-term follow-up. In the largest systematic review of the efficacy and safety of splenectomy for ITP, Kojouri et al reported that 66% of 2,623 adults achieved a normal platelet count and responses

S18 were durable for a median of 7.3 years.70 Response rates were even higher when children were included in the analysis, with 72% of 2,463 patients achieving a complete response. Relapses occurred in 15% of patients (range, 0% to 51%) after a median of 33 months. In the pooled analysis, only younger age was an independent predictor of response to splenectomy. Nevertheless, other investigators have shown that response to IVIg is a sensitive predictor of response to splenectomy in adults and children.71-74 Of complete responders, 90% will attain a normal platelet count by day 7; remissions are unlikely past 6 weeks. In a further 5% to 10% of patients, partial remission can be achieved. Approximately 30% of patients who relapse post-splenectomy have accessory spleens detected with sensitive radionuclide imaging, such as heat-damaged, technetium 99m– labeled red blood cells,75 or indium 111–labeled platelets; however, a durable platelet count response following accessory splenectomy is expected in less than 50% of patients.76 Our own experience is similar.71 Laparoscopic splenectomy is an increasingly popular surgical approach for the management of ITP.77 Platelet count responses and the frequency of missed accessory spleens causing recurrent disease are similar with laparoscopic compared with open splenectomy, but complications are fewer and length of hospital stay is shorter.78 Overall mortality is approximately 1% following laparotomy and 0.2% following laparoscopic splenectomy.70 The most frequent immediate complications are pleuropulmonary (pneumonia, subphrenic abscess, pleural effusion) occurring in 4% of patients, major bleeding in 1.5%, and thromboembolism in 1%. Postoperative thromboembolism is the most common cause of postoperative mortality; thus, for patients with delayed postoperative mobilization, prophylactic low-molecular-weight heparin should be considered when the platelet count is recovering. OPSI is a feared long-term complication of splenectomy; fortunately, it is rare. In a pooled analysis of 19,680 splenectomized patients from 78 studies, the incidence of post-splenectomy septicemia and/or meningitis (median follow-up, 6.9 years) was 3.2%, and overall infection-associated mortality was 1.4%.79 Among the 484-patient subgroup splenectomized because of ITP, these risks were 2.1% and 1.2%, respectively.79 All patients should be vaccinated with polyvalent pneumococcal vaccine, quadrivalent meningococcal polysaccharide vaccine, and Haemophilus influenzae type b vaccine, at least 2 weeks before splenectomy.80 In summary, splenectomy results in a durable response in 60% to 70% of patients. Complications of splenectomy are infrequent, especially with laparoscopic techniques and a skilled surgeon. We continue to offer splenectomy to patients who have failed corticosteroids and IVIg; however, with the introduction of a number of novel treatments, some clinicians recommend delaying splenectomy until later in the course of the illness.81

Rituximab Rituximab (Rituxan; Genentech, South San Francisco, CA) is a chimeric mouse/human monoclonal anti-CD20 antibody

D.M. Arnold and J.G. Kelton indicated for the treatment of non-Hodgkin’s lymphoma and rheumatoid arthritis. The Fab portion binds to CD20 on B lymphocytes, which results in FcR-mediated B-cell lysis by complement-dependent cytotoxic pathways82 and antibodydependent cell-mediated pathways.83,84 In ITP, rituximab depletes CD20⫹ B cells that are responsible for platelet autoantibody production, and rituximab-coated B cells may cause RE blockade.85 In a systematic review of adult ITP patients, half of whom had a splenectomy, rituximab was associated with a complete response (platelets ⬎150 ⫻ 109/L) in 43.6% of patients (95% confidence interval [CI], 29.5% to 57.7%), and an overall response (platelets ⬎50 ⫻ 109/L) in 62.5% (95% CI, 52.6% to 72.5%).86 In non-splenectomized adults who had ITP for a mean duration of 4.8 years, 24 of 60 patients (40%; 95% CI, 28% to 52%) achieved a platelet count of 50 ⫻ 109/L or greater 1 year after rituximab treatment.87 Cooper et al reported that 16 of 57 patients (28.1%) had a complete platelet count response that lasted more than 1 year following rituximab, and patients who had a longer duration of ITP (⬎15 years) were less likely to respond.48 After a prolonged follow-up of 31 patients with a good response to rituximab, 17 (54.8%) remained in remission after more than 2.5 years.88 These data suggest that using rituximab early in ITP may be more beneficial than waiting until late relapses occur. Corroborative evidence derives from a recent study that correlated rituximab-induced platelet count responses with normalization of T-cell abnormalities in ITP patients, suggesting that responses may be more likely at an early stage of the illness, when T-cell expansion is still dependent on B-cell costimulation.89 Furthermore, a subgroup analysis of a metaanalysis of IVIg versus corticosteroids as initial therapy for children showed that fewer patients in the IVIg group went on to develop chronic ITP.52 Rituximab may have a similar immune-modulating effect. Results with rituximab have been less encouraging in children. In a prospective single-arm study of 36 children with chronic ITP, 11 (30.6%) achieved a platelet count of 50 ⫻ 109/L or greater for 4 consecutive weeks 9 weeks after rituximab,90 and two children (6%) developed serum sickness. Rituximab is generally well tolerated; however, infusional side effects, including shakes and chills, blood pressure fluctuations, and respiratory complaints, occur in approximately 20% of patients with ITP. In patients with lymphoma, rituximab results in a modest increase in the frequency of bacterial infections, but this risk may be lower for patients with autoimmune disease. However, in 2006, the US Food and Drug Administration issued a safety alert following the reports of two patients who died of progressive multifocal leukoencephalopathy, a rare condition caused by reactivated JC virus.91 Concerns about safety have also been raised by Arnold et al in their review, which reported nine deaths among 306 patients treated (2.9%), even though attribution could not be confirmed in most cases.86 In summary, up to 60% of patients treated with rituximab may achieve a platelet count response, and of those, 20% will have long-lasting remissions; however, the long-term effects of rituximab in patients with autoimmune disease are uncer-

Current treatment options for ITP tain. We use rituximab for patients with relapsed or recurrent ITP following splenectomy; however, we are currently investigating its effects prior to splenectomy.

Treatment of Refractory Patients Post-Splenectomy Evidence to help guide treatment for patients with chronic refractory ITP post-splenectomy is limited and based on uncontrolled case series. Danazol is frequently effective92 and in a systematic review, rituximab, azathioprine, and cyclophosphamide had the most reported complete responses.93 For these challenging patients, the prevention of bleeding and the achievement of a stable, although not necessarily normal, platelet count is the goal. Other treatment options for refractory patients include low-dose or alternate-day corticosteroids, repeated doses of IVIg, immunosuppressant agents, vinca alkaloids, high-dose chemotherapy, and dapsone.94 Overall, single agents show less than a 30% success rate and combination treatment is often required.

Danazol Danazol is an attenuated androgen with mild virilizing effects that can be used to treat men and non-pregnant women with ITP. Its mechanism of action is hypothesized to decrease the number of FcRs and to slow the rate of clearance of IgGsensitized red blood cells. Usually, 400 to 800 mg is administered daily in divided doses, and a response occurs within 2 months. Up to 70% of patients achieve a platelet count response, which is often sustainable while on treatment.93 Danazol is generally well tolerated; the most frequent adverse effects are virilizing effects, fluid retention, nausea, amenorrhea, and reversible hepatitis.

S19 refractory ITP in one study97; however, combination therapy with other immunosuppressive agents may be more effective. The dose of mycophenolate is 1 to 2 g per day. Cyclosporine Cyclosporine is a calcineurin inhibitor that inhibits T-cell proliferation. Complete and partial responses have been described in up to 55% of patients with refractory ITP receiving cyclosporine at a dose of 5 mg/kg plus prednisone as maintenance therapy98; however, lower doses (2 to 3 mg/kg) are generally recommended. Long-term remissions are rare.99,100 In our experience, using cyclosporine as a single agent has been associated with modest success. Cyclophosphamide Cyclophosphamide is an alkylating agent that has been used for patients with refractory ITP at maintenance doses (1 to 2 mg/kg per day), and at high doses (1.0 to 1.5 g/m2 every 4 weeks intravenous) alone or in combination with high-dose chemotherapy. Cyclophosphamide has been evaluated in 5 studies (N ⫽ 102 treated patients) and up to 41% achieved a complete response.93 In one report, 14 patients were treated with high-dose cyclophosphamide and autologous peripheral blood stem cell support, of whom six achieved a complete remission (platelets ⬎100 ⫻ 109/L) sustained for 9 to 42 months.101 In general, our practice is to avoid cyclophosphamide because of the potential for leukemic transformation.

Vinca Alkaloids Vinca alkaloids (vincristine, vinblastine) can produce temporary increases in platelet counts in approximately half of patients.102,103 Side effects include neuropathy, neutropenia, and alopecia. The usual dose of vincristine is 1 mg/m2 (capped at 2 mg) intravenously, which can be repeated weekly for up to 3 or 4 doses. Typically, neuropathy is doselimiting.

Immunosuppressants Azathioprine Azathioprine, a precursor of 6-mercaptopurine, is an antimetabolite that inhibits lymphocyte proliferation. A systematic review identified 10 reports (N ⫽ 166 treated patients) of azathioprine in patients with ITP and found that up to 25% achieved a normal platelet count for the duration of followup.93 The dose of azathioprine is 1 to 2 mg/kg/d, and sometimes responses do not occur for 2 to 3 months. Recognized toxicities include leukopenia and hepatotoxicity, which are more frequent when the metabolism of azathioprine is impaired by drugs such as allopurinol, or by an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) caused by a homozygous mutation in the TPMT gene.95 It is not known if TPMT gene mutations should be investigated before initiation of treatment.

Combination Therapy

Mycophenolate Mofetil Mycophenolate mofetil is a prodrug of mycophenolic acid (MFA), a noncompetitive inhibitor of inosine 50-monophosphate dehydrogenase (IMPDH), which is a key enzyme involved in the purine biosynthesis pathway.96 It has been shown to be effective in seven of 18 (38.9%) patients with

In summary, treatment of patients with refractory ITP following splenectomy is challenging and while many drugs are available, no one treatment is widely accepted. Intensive treatment may be effective at the expense of increased toxicity, and thus should be reserved for patients with evidence of hemostatic impairment and persistently low platelet counts.

Combination therapy with different classes of drugs may be more effective than single-agent therapy, at the risk of increased toxicity. In a recent report, 35 adults and children with thrombocytopenia refractory to IVIg and high-dose corticosteroids, including 54% who had splenectomy, were administered a combination of IVIg 1 g/kg, IV methylprednisolone 30 mg/kg, vincristine 0.03 mg/kg, and/or intravenous anti-D 50 to 75 ␮g/kg, resulting in a minimal platelet count response in 71% of patients.92 Eighteen patients received maintenance therapy with danazol (10 to 15 mg/kg) and azathioprine (2 mg/kg) and of those, two thirds achieved a stable platelet count above 50 ⫻ 109/L. Maintenance therapy with a combination of immunosuppressant drugs has also been successful in some patients.104

D.M. Arnold and J.G. Kelton

S20 Our practice is to first try danazol and/or intermittent doses of IVIg (1 g/kg). We also use rituximab for such patients; however, funding for this expensive treatment has limited its availability for ITP patients in some countries (including Canada). Following that, we have found that combination immunosuppressive therapy with cyclosporine, azathioprine, and mycophenolate mofetil is frequently effective.

New Agents Currently Under Investigation Thrombopoietin Receptor Agonists TPO receptor agonists activate the human TPO receptor c-Mpl. Early (first-generation) TPO growth factors were discontinued because of development of antibodies that crossreacted with endogenous TPO, despite showing dose-dependent increases in platelet counts. As a result, research has continued and a second generation of TPO receptor agonists has now reached clinical investigation. These newer agents have no sequence homology to endogenous TPO, and thus do not form cross-reactive TPO antibodies. The rationale in ITP is that endogenous TPO levels are low to normal105 and platelet production is impaired.106 Early studies have shown a dose-dependent platelet response in many patients with refractory ITP.107 Clinical trials are still underway, but given the promising results thus far, these agents are bound to change practice (TPO agents are discussed in a separate paper by Adrian Newland published in this issue).

Other Potential Targets Under Investigation Anti-CD154 CD154 (CD40 ligand) on T cells is essential for T-cell priming, antigen presentation, and T-cell– dependent humoral immunity. In a phase I dose-escalating trial, 20 patients were treated with a humanized blocking monoclonal antibody to CD154.108 Of the five patients in the high-dose group, three showed a platelet count response; however, side effects were frequent. Agents That Interfere With FcR Signaling Monoclonal antibodies against Fc␥RIII and inhibitors of syk kinase that target the FcR signaling pathway are currently under investigation.3 Soluble Tumor Necrosis Factor-Alpha Receptor The soluble tumor necrosis factor-alpha receptor etanercept (Enbrel; Immunex, Thousand Oaks, CA), used for the treatment of rheumatoid and psoriatic arthritis, has been shown to have activity in the treatment of ITP. In one report, three patients with severe refractory ITP achieved a durable platelet count remission for 1.5 to 3 years.109

Emergency Treatment of a Bleeding Patient Any patient with ITP who has life-threatening bleeding should receive immediate platelet transfusion (5 to 10 U of

random donor platelet concentrates, or 1 to 2 U of single donor, apheresis platelet concentrates). IVIg (1 g/kg) should also be administered over 4 to 6 hours to block the RES, and additional platelet transfusions may be required.110 A continuous infusions of IVIg and platelets has also been used in this situation.111 Corticosteroids (high-dose) should be started simultaneously to achieve longer-term control of thrombocytopenia.

Preparation for Invasive Procedures High-dose IVIg usually is the treatment of choice for thrombocytopenic patients with ITP who require urgent surgery or an invasive procedure. Prophylactic platelet transfusion should be administered only for bleeding, because transfused platelets are expected to have a very short half-life. When the procedure can be planned several days in advance, less expensive and equally effective options include corticosteroids or anti-D.

Conclusions The etiology of ITP is complex. Effective treatments are aimed at different steps in the pathophysiologic process including the reduction of autoantibody production, interference with FcR uptake and signaling, suppression of B and T cells, and increase in TPO activity. While corticosteroids, IVIg, and splenectomy remain the most effective treatments for ITP, specific therapies such as rituximab and TPO receptor agonists can achieve platelet count responses in a proportion of heavily pretreated patients. Immune-modulating treatment, rituximab in particular, given early in the course of the illness may disrupt the self-sustaining nature of ITP and provide more durable remissions. The development of further specific therapies should allow for better treatments with fewer side effects, and should be tested in randomized trials using clinically important outcomes. Likely, combination treatments will continue to be required for challenging refractory patients.

Acknowledgments The development of this manuscript was supported by an unrestricted educational grant from GlaxoSmithKline. The authors thank Aurelio Santos for the illustrations in this article. Assistance in the development of this article was provided by Robert Coover and Brett Moskowitz, MA.

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