Fifty years of idiopathic thrombocytopenic purpura (ITP): management ...

British Journal of Haematology, 2002, 118, 933–944

Review FIFTY YEARS OF IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP): MANAGEMENT OF REFRACTORY ITP IN ADULTS Autoimmune disorders, in which there is loss of tolerance to self antigens, affects 5% of the population representing 14 million individuals in the USA and 3 million in the UK (Editorial, 2001). To date, the treatment of these disorders in adults has been disappointing, in part because of a lack of understanding of the underlying pathophysiology in this diverse group of disorders. Some 50 years ago, Harrington et al (1951) elegantly demonstrated the presence of a factor in the globulin fraction in the peripheral blood of patients with idiopathic thrombocytopenic purpura (ITP) that caused the thrombocytopenia. We now know that this factor was anti-platelet antibody. However, despite major advances in our understanding of immunology and autoimmunity, these have not been translated into improved diagnostic or therapeutic strategies for diseases such as ITP. Although several different classes of drug and other forms of treatment have been used in chronic ITP, no therapeutic modality is truly evidence based (George et al, 1996). In our opinion, ITP represents an ideal model of organspecific autoimmune disease for study. It is sufficiently common to make its study feasible and has the advantage of being manifested by a reduced peripheral blood platelet count. As such, the efficacy of treatment can be objectively measured by using the full blood count. In this article, we look at how far we have moved on since Harrington’s seminal work and define the disorder, discuss the underlying immunological features, summarize the standard therapy and evaluate the treatments available for non-pregnant adults who are refractory to standard first-line therapy. We have also reviewed therapies under development that appear to offer a more targeted approach to treatment. Using ITP as a model of human autoimmune disease could logically lead to improvements in the management of more complex disorders such as multiple sclerosis, systemic lupus erythematosus (SLE) and type I diabetes mellitus. HOW HAS THE DIAGNOSIS AND MANAGEMENT OF ITP ADVANCED IN THE LAST 50 YEARS? Disease definition Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder in which platelets, opsonized with anti-platelet autoantibodies, are removed prematurely by

Correspondence: Dr D. Provan, Senior Lecturer in Haematology, St Bartholomew’s & The Royal London School of Medicine & Dentistry, London, El IBB, UK. E-mail: [email protected] 2002 Blackwell Science Ltd

the reticuloendothelial system (RES), leading to a reduced peripheral blood platelet count. Although bone marrow megakaryocytes are often increased, relative marrow failure may play a role in a proportion of patients (Ballem et al, 1987). The aetiology of ITP in adults is unknown and the clinical course is variable and unpredictable. The incidence of chronic adult ITP is around 5Æ8–6Æ6 new cases per 100,000 population per year in the USA (Bottiger & Westerholm, 1972; McMillan, 1997), and a similar incidence in the UK. The overall combined incidence of new cases of adult and childhood ITP is higher, and may reach 20 per 100,000 population per year. The pathogenesis (and treatment) of ITP has been reviewed by several authors (Berchtold & McMillan, 1989; Chong, 1995; Ikehara et al, 1995; Semple & Freedman, 1995; Karpatkin, 1997; Wang & Shen, 1997; Blanchette et al, 1998; Yang & Zhong, 2000; Lechner, 2001). ITP in childhood is generally termed acute as the illness is seasonal, typically follows a trivial viral infection or vaccination, and in most cases is transient, requires no treatment and spontaneously recovers. In the adult (chronic) form there is usually no obvious antecedent illness and most patients have chronic thrombocytopenia; spontaneous recovery is uncommon (George et al, 1996). In adults, the frequency of death from haemorrhage in patients failing to achieve an adequate platelet count is 5% (George et al, 1996), although the frequency may be influenced by age and duration of thrombocytopenia (Frederiksen & Schmidt, 1999). Clinical features The ITP phenotype is heterogeneous: some patients suffer major bleeding from the outset, while others have few problems apart from an increased bruising tendency. This may partly be explained by the acquired platelet dysfunction which is seen in some patients with ITP, which in turn may be related to the target antigen involved in the autoimmune process (this is discussed later in Autoantibody characteristics). Autoantibodies reacting with glycoprotein (GP) IIb ⁄ IIIa affect platelet aggregation and anti-GPIb ⁄ IX autoantibodies impair platelet adhesion to the subendothelial matrix, causing unexpectedly severe bleeding for the level of the platelet count (Wang & Shen, 1997). In general, however, in contrast with thrombocytopenia due to marrow infiltration (e.g. leukaemias, lymphomas or other malignancies) or aplasia, patients with ITP are able to tolerate remarkably low platelet counts and maintain an adequate quality of life (Karpatkin, 1985). The degree of bleeding is largely dependent on the platelet count and patients with

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platelet counts below 10 · 109 ⁄ l (and usually below 5 · 109 ⁄ l) are at greatest risk of bleeding, including intracranial bleeding. Diagnosis Basic investigations comprise: clinical history and physical examination, full blood count, blood film examination, and bone marrow aspiration; the latter is controversial, and in childhood ITP marrow examination is not carried out unless there are atypical features (Eden & Lilleyman, 1992; Lilleyman, 1999; Medeiros & Buchanan, 2000). In adults with ITP, the American Society of Hematology panel consensus view was that marrow examination should be performed in patients over the age of 60 years. Myelodysplasia, which may present with thrombocytopenia in this age group, requires exclusion and bone marrow examination is appropriate. Other tests such as the autoimmune screen aim to exclude other autoimmune diseases which may be associated with thrombocytopenia, e.g., SLE or lupus anticoagulant ⁄ antiphospholipid syndrome. In a small proportion of cases, there may be a familial cause and this should be elicited from the history. Despite the availability of a variety of immunological assays (e.g. anti-platelet antibodies, direct platelet immunofluorescence test, monoclonal antibody immobilization of platelet antigens and others) the diagnosis remains clinical and one of exclusion. THE ORIGIN OF HUMAN AUTOANTIBODIES Autoantibodies arise in health as well as disease The generation of autoreactive T cells has been shown to be a feature of the normal immune system and is likely to be beneficial, and required for normal tissue repair (Schwartz & Cohen, 2000). However, a number of studies have shown strong evidence for dysregulation of the immune response in autoimmune disease (Refaeli et al, 1999; Straus et al, 1999; Wucherpfennig & Eisenbarth, 2001); there may be failure of the normal checkpoints such as clonal deletion, anergy, immune deviation and suppression which control autoreactive T cells in health (Stockinger, 1999). Autoimmune disease is multifactorial From studies of autoimmune disease, it is clear that ITP and other autoimmune disorders are multifactorial. It is likely that loss of tolerance to a self antigen alone is insufficient to generate the autoimmune disorder (Mackay, 2000); instead, patients probably require: (i) a specific set of genetic determinants [e.g. polymorphisms within major histocompatibility complex (MHC), cytotoxic T-lymphocyte antigen 4 (CTLA4) or other genes]; (ii) dysregulation of the immune response (involving dendritic cells, T or B cells, or all three); (iii) an environmental trigger. Autoimmune disease arises only when all these determinants are present in an individual at one particular time. This is further reinforced by the observation that selfreactive lymphocytes are commonly found in normal individuals. For example, siblings of patients who have autoimmune disorders are more likely to have autoantibodies themselves, albeit at lower titres than their affected

siblings, without evidence of autoimmune disease per se, perhaps because they have not been exposed to the environmental trigger required to tip the balance toward autoimmune disease. Genetic contribution to autoimmune disease Genes clearly play a part in the development of autoimmune disease, but other interactions are of major importance. Evidence for this comes from the observations of identical twins, one of whom has autoimmune disease while the other does not, i.e. there is a lack of concordance. In pairs of monozygotic twins where one twin has autoimmune disease, the other twin is affected in less than 50% of cases (Ermann & Fathman, 2001). Genetic studies over the years have concentrated on determining the contribution of MHC genes to the development of autoimmune disease, and strong associations have been reported between particular MHC haplotypes and disease. The best example is ankylosing spondylitis, associated with human leucocyte antigen (HLA) B27, which has a relative risk of 87Æ4. HLA studies in ITP have shown an increased frequency of HLA-DRB1*0410 in Japanese adults with ITP (Nomura et al, 1998). Conversely, the possession of a disease haplotype does not predict disease and studies of rheumatoid arthritis (RA) have shown that RA can develop in patients lacking a typical diseaseassociated MHC haplotype (Feldmann, 2001). In other diseases such as insulin-dependent diabetes mellitus (IDDM), the MHC association is so strong that the MHC alleles can be used as markers of predisposition to IDDM. How do allelic variants within MHC genes predispose to diseases such as IDDM? Autoimmune responses involve T cells and it is not surprising that there are strong MHC associations (Gautam et al, 1994; Haines et al, 1996). MHC polymorphisms may be associated with variable ability of MHC molecules to present autoantigenic peptides to T cells (Ridgway & Fathman, 1998). From studies of humans with IDDM and non-obese diabetic (NOD) mice with spontaneous IDDM, it has been shown that there is substitution of the negatively charged amino acid aspartic acid with a neutrally charged amino acid (Morel et al, 1999) which may influence antigen presentation. Rheumatoid HLA-DR variants that are associated with an increased risk of disease or are associated with more severe phenotypes contain a shared epitope, in the form of a conserved amino acid sequence within the b chain of the MHC class II molecule. Environmental influence on the development of autoimmune disease Acute ITP in children is often preceded, and presumably triggered, by a viral illness or immunization, but which environmental triggers might be involved in adult ITP? Studies of patients with multiple sclerosis (MS) have shown that there are features of infectious disease (Steinman, 2001). In addition, previous studies involving patients with SLE have shown a high incidence of prior infection with Epstein–Barr virus (EBV). A single antigenic determinant on EBV has been shown to be shared with one particular SLE autoantigen (James & Harley, 1998).

2002 Blackwell Science Ltd, British Journal of Haematology 118: 933–944

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AUTOANTIBODY CHARACTERISTICS Anti-platelet antibodies and target antigens Many patients with ITP have elevated levels of plateletassociated immunoglobulin (Ig)G which may represent the anti-platelet antibody. However, platelet-associated IgG rises in other non-immunological causes of thrombocytopenia (George & Saucerman, 1988). The autoantibodies involved in ITP are generally IgG, but IgA and IgM autoantibodies have also been reported (Kiefel et al, 1996). Antigenic targets Using antigen-specific assays such as the monoclonal antibody-specific immobilization of platelet antigens (MAIPA), platelet-associated IgG and antigen capture assays, several platelet target antigens have been characterized. These include GPIIb ⁄ IIIa (aIIIbb3, the fibrinogen receptor) and GPIb ⁄ IX (the von Willebrand receptor) which appear to be the most frequently involved (Brighton et al, 1996; Macchi et al, 1996; Warner & Kelton, 1997; Warner et al, 1999). Less commonly GPIa ⁄ IIa, GPIV and GPV are involved. Recent reports suggest possibly 40% of autoantibodies are reactive to both GPIIb ⁄ IIIa and GPIb ⁄ IX (Stockelberg et al, 1995), possibly due to the serum in some patients with ITP containing two different IgG antibodies. In terms of disease chronicity, GP-specific autoantibodies may be important in the pathogenesis of chronic ITP (Hou et al, 1995); from available data, GPIIb ⁄ IIIa appear to play a major role in the development of chronic ITP in 30–40% of cases (McMillan et al, 1987; Kiefel et al, 1991). Opsonized platelets are removed prematurely by the reticuloendothelial system (RES) predominantly through an Fc-dependent mechanism (Garvey, 1998); Fc-independent effectors may also play a role. Recently, Nieswandt et al (2000) have looked at the pathogenic effects of IgG monoclonal antibodies (mAbs) of different IgG subclasses against murine GPIIb ⁄ IIIa, Iba, Ib ⁄ IX, V and CD31. Their data suggest that, at least in mice, the antigenic specificity of the anti-platelet antibodies determines the pathogenic effects rather than the IgG subclass. They also demonstrated that antibodies against GPIb ⁄ IX caused thrombocytopenia through an Fc-independent mechanism, while that from autoantibodies against GPIIb ⁄ IIIa involved the Fc system. Further work is clearly needed in order to determine the significance of all of these findings, which may translate into stratification of patients into those in whom Fc receptor blockade or inactivation is a useful option, and those in whom it is not. Natural history of ITP Before discussing treatment options, it is useful to examine the long-term outcome of adults with ITP. Despite many studies of various treatment options, there have been few reviews of the outcome of cohorts of adult patients with ITP to determine whether ITP results in an increase in morbidity or mortality compared with that of the general population. A recent natural history study by Portielje et al (2001) looked at the outcomes of 152 adults with ITP. They were able to show that 93% of patients ultimately achieved

platelet counts greater than 30 · 10 ⁄ l and did so within 2 years of diagnosis. They also showed that 85% of patients achieved platelet counts above 30 · 109 ⁄ l off treatment and had an overall long-term mortality similar to that of the general population. Some 9% of patients with severe thrombocytopenia (platelet counts < 30 · 109 ⁄ l) had refractory disease and had a mortality risk fourfold higher than the general population. Deaths in this group were due equally to infection and bleeding. Six per cent of their patients required maintenance therapy to achieve a sustained platelet count above 30 · 109 ⁄ l. From this single study, it would appear that in most adults with moderate ITP the disorder runs a benign course, while the severe refractory group have higher morbidity and mortality than the general population. Standard therapy As very few trials have been conducted in ITP, we do not know which constitutes the best treatment. In addition, the efficacy of the available therapies is unpredictable and often transient. With some treatments, the side-effects may be severe and this must be balanced with the likely benefits. In general, patients with platelet counts exceeding 30 · 109 ⁄ l require no treatment unless they are undergoing any procedure likely to induce blood loss, including surgery, dental extraction or delivery (Yang & Zhong, 2000). Standard therapy comprises oral corticosteroids, intravenous immunoglobulin (IVIg), and splenectomy. Prednisolone Around two thirds of patients will respond to prednisolone at the traditional dose of 1 mg ⁄ kg body weight ⁄ d tapering off over several weeks, but relapse is common when the dose is reduced. Both lower (0Æ5 mg ⁄ kg ⁄ d) and higher (2 mg ⁄ kg ⁄ d) doses appear equally effective (Mazzucconi et al, 1985; Blanchette et al, 1998). Around 20–30% can expect a longterm response (Berchtold & McMillan, 1989; Manoharan, 1991; George et al, 1996; Blanchette et al, 1998). Intravenous immunoglobulin (IVIg) Pooled normal human immunoglobulin is effective in elevating the platelet count in 75% of patients, of which 50% will achieve normal platelet counts. However, 3–4 weeks following IVIg treatment platelet counts drift back to pretreatment levels (George et al, 1996). The effects of IVIg are usually not sustained, although some long-term responses have been reported (Newland et al, 1983). The mechanism of action of IVIg in ITP remains largely unknown but involves Fc receptor blockade, anti-idiotype antibodies in IVIg which block autoantibody binding to circulating platelets and immune suppression (Godeau et al, 1993; Chong, 1995). IVIg is well tolerated with few major side-effects. Splenectomy Splenectomy is the only curative treatment modality in ITP and was used before steroid therapy was introduced in 1950 (Chong, 1995; George et al, 1996). Two thirds of


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patients with ITP who undergo splenectomy will achieve a normal platelet count which is often sustained with no additional therapy. Patients who do not have a complete response can still expect some improvement in counts (e.g. partial response) or transient increases in platelet count (George et al, 1996). Recent work using indium-labelled autologous platelets has shown that when platelet destruction is splenic then 96% of patients between the age of 5–30 years and 91% of those above the age of 30 years can expect to obtain a remission. However, where the platelet destruction was hepatic or diffuse (mixed splenic and hepatic), 92% of patients failed to normalize their platelet counts or had incomplete responses to splenectomy (Najean et al, 1997; Cavenagh et al, 1999). Indium scanning therefore appears to be a reliable predictor of response to splenectomy, although others have proposed the response to IVIg as a predictor of likelihood of success of splenectomy (Law et al, 1997). Chronic refractory ITP This defines those patients who fail to respond to standard treatment or require unacceptably high doses of corticosteroids to maintain a safe platelet count. A number of drugs have been used as second-line therapy for ITP and those used will depend on the age of the patient, the severity of the presentation, the platelet count, whether the disease is primary refractory or relapsed, and the length of time prior to relapse. When considering second-line therapy, the first-line therapies (corticosteroids, reticuloendothelial blockade with IVIg or splenectomy) should be considered and implemented if possible (George et al, 1996). The doses may have to be altered compared with those used in first-line therapy and additional supportive therapy may need to be considered to allow their chronic use, e.g. there is a small but significant risk of osteoporosis and avascular necrosis in patients on long-term corticosteroids, and they should be assessed for this and treated accordingly with bisphosphonates or hormonal replacement if indicated. The necessity for treatment should always be considered, weighing up the risks and side-effects of treatment, against the risks of no treatment. In some patients, symptomatic therapy such as fibrinolytic inhibitors may be used, particularly if there is only mucous membrane bleeding, and in severe bleeding, such as gastrointestinal haemorrhage, platelets may be transfused. Although these are rapidly cleared from the circulation and have a severely shortened half-life, they are often effective in preventing bleeding (Carr et al, 1986). Conventional second-line treatment approaches For the patient in whom further conventional treatment with standard-dose corticosteroids is inappropriate, there is a variety of potential therapeutic options (Collins & Newland, 1992). These include: (i) high-dose steroids; (ii) high-dose IVIg; (iii) intravenous anti-D; (iv) vinca alkaloids; (v) danazol; (vi) immunosuppressive agents, including azathioprine and cyclophosphamide; (vii) combination chemotherapy; and (viii) dapsone.

The wide variety of treatments available for second-line therapy reflects their relative lack of efficacy and treatment should be tailored to suit the individual. It also worth bearing in mind that for the patient who has relapsed following splenectomy, an accessory spleen may be present in up to 20% and this should be looked for using radioisotope imaging while considering further treatment. High-dose steroids As an alternative to prednisolone, Andersen (1994) reported favourable responses in refractory patients using an oral high-dose dexamethasone regimen, comprising 40 mg of dexamethasone daily for 4 d, repeated every 28 d for six cycles. Ten patients were treated in this small study with favourable responses in all patients (all had platelet counts exceeding 100 · 109 ⁄ l) sustained for at least 6 months. At this dose, side-effects are common and subsequent studies conducted by other groups have not met with such success (Caulier et al, 1995; Arruda & Annichino-Bizzacchi, 1996; Kuhne et al, 1997). Anecdotal success has also been reported using dexamethasone at a lower dose such as 20 mg ⁄ d for 4 consecutive days monthly. Methylprednisolone Parenteral steroids such as methylprednisolone have been used as second- and third-line treatments for patients with refractory ITP. One study reported the results of nine adult patients with platelets less than 50 · 109 ⁄ l, all of whom were treated initially with oral corticosteroids (prednisolone ⁄ prednisone at 1 mg ⁄ kg ⁄ d). Methylprednisolone was given at 30 mg ⁄ kg ⁄ d for 3 d, 20 mg ⁄ kg ⁄ d for 4 d then 5, 2 and 1 mg ⁄ kg ⁄ d each for 1 week. The platelet count became normal within 3–5 d in all patients, although, in seven of nine, the response lasted only a few weeks before dropping to pretreatment levels (Akoglu et al, 1991). von dem Borne et al (1988) compared the effect of methylprednisolone with IVIg in adult patients (22) with a control series (17 patients treated with standard oral corticosteroids). The methylprednisolone was found to be as effective as IVIg in terms of the frequency of response, with no reported side-effects. The major difference noted between the modalities was that the response to oral steroids was slower than to intravenous methylprednisolone. Again, the response to intravenous steroids was transient in all patients and maintenance with oral steroids was required to maintain an adequate platelet count. High-dose IVIg High-dose intravenous immunoglobulin at a dose of 1 g ⁄ kg ⁄ d for 2 d consecutively, often in combination with corticosteroids, will raise the platelet count rapidly in a proportion of patients but may be associated with significant side-effects, in particular headaches, but if successful can be given on an intermittent basis or substituted with intravenous anti-D (Blanchette et al, 1993). Anti-D Intravenous anti-D has been shown to elevate the platelet count in 79–90% of adults (Scaradavou et al, 1997). The


Review mechanism of action is believed to be mediated through destruction of rhesus (D)-positive red cells which are preferentially removed by the reticuloendothelial system, thus sparing autoantibody-coated platelets. In a single arm open-label study of anti-D in 261 nonsplenectomized and 11 splenectomized patients, 72% of patients showed an increase in platelet count of greater than 20 · 109 ⁄ l and in 46% of patients the platelet count rose by more than 50 · 109 ⁄ l. The improvement lasted for more than 3 weeks in 50% of patients who responded (Scaradavou et al, 1997). Anti-D treatment is suitable for Rhesus (D)-positive patients who are not splenectomized, but is not recommended for refractory patients following splenectomy. Vinca alkaloids This group of drugs may cause a transient increase in the platelet count lasting between 1 and 3 weeks in two-thirds of patients treated. Sustained responses have been observed in less than 10% of patients (Berchtold & McMillan, 1989; Manoharan, 1991; George et al, 1996; Blanchette et al, 1998). Overall, this treatment is seldom used, although it may be of value when other therapies have failed and there is a need to raise the platelet count quickly.

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been treated previously with steroids and had undergone splenectomy. The platelet count was less than 5 · 109 ⁄ l in all patients. A complete response was seen in six patients (durable in four); a partial response was observed in two (one durable) and two died of intracerebral haemorrhage. Dapsone In a series of 66 adults with chronic ITP treated with dapsone at 75–100 mg orally, responses were observed in 33%, with a median duration of treatment required to achieve a response of 21 d. Sustained responses were observed in 19 patients (Godeau et al, 1997). Dapsone’s mechanism of action is unknown but may be due to reticuloendothelial blockade through increased red cell destruction (Godeau et al, 1997; Radaelli et al, 1999).

Danazol Danazol, an attenuated androgen, appears to be especially effective in patients with overlap syndromes between ITP and lupus, and can often be used as a corticosteroid-sparing agent in patients responsive but who require longer term unacceptably high doses. Ahn et al (1989) reported the outcome of 22 patients, of which 15 had undergone splenectomy, treated with danazol at a dose of 200 mg 2–4 times daily for more than 2 months. Around 60% showed elevation of the platelet count above 50 · 109 ⁄ l sustained from more than 2 months. Older patients and those who have undergone splenectomy appeared to respond best. The mechanism of danazol is unknown but is postulated to downregulate the number of Fc receptors on splenic macrophages thereby prolonging platelet survival (Schneider et al, 1997).

Patients failing standard and second-line approaches Up to 25% of adults with ITP fail to respond to first- or second-line therapies and pose major problems. Some of these are real (e.g. active bleeding) but many are only potentially problematic with bleeding, a theoretical management problem. While there have been few trials examining the efficacy of first- and second-line treatments, the situation becomes even worse when one looks at the evidence for third-line therapies. In effect, these agents represent a prosaic group of agents, often with little in common apart from the fact that in some patients these drugs may elevate the platelet count. There are no quality trials for any of these therapies and there are no useful predictors of response, making it extremely difficult for the treating physician to know which to try first. Fortunately most adult patients with chronic refractory ITP are able to tolerate marked thrombocytopenia relatively well (Blanchette et al, 1998) and are able to have normal or near normal quality of life. For those who fail to respond to standard first- and second-line therapy and who require treatment, the options are limited and include: (i) no drug treatment; (ii) cyclosporin A; (iii) interferon-a; (iv) protein A columns; and (v) other miscellaneous treatments such as Campath-1H or rituximab (these two agents are discussed later).

Immunosuppressive agents and combination chemotherapy Immunosuppression may be required in patients who fail to respond to alternate therapies. Treatment with azathioprine or cyclophosphamide as single agents may be considered and up to 25% of patients may have a sustained response. However, because of second malignancies, including acute leukaemia, which are more common in patients treated with these medications, initial use of cytotoxic therapy, especially in those who are young, should be carefully considered. In those patients with severe, symptomatic chronic ITP refractory to multiple previous treatments, the use of cyclophosphamide, vincristine and prednisolone combined in regimens such as those used in the lymphomas have been shown to be effective. Figueroa et al (1993) reported their results in 10 patients with refractory ITP. Two patients had underlying malignant disease (Hodgkin’s disease and chronic lymphocytic leukaemia). All 10 had

No drug treatment option This mode of treatment is becoming more common, largely because we often use all therapeutic options to no avail and are not confident about trying out unfamiliar anecdotal agents in patients who are largely well. Many of the immunosuppressive agents in current use are associated with significant toxicities, especially when used in high dose. From studies of childhood ITP, we know that despite extensive bruising, providing patients have no major bleeding problems, they can tolerate very low platelet counts and still maintain a normal quality of life. Most haematologists will have patients with severe refractory ITP in whom virtually all known treatments have been tried, and who are currently on no treatment and enjoying life. This management option also has some definite advantages: it is cheap and non-toxic, and provided the patients are given a full explanation of why they are not to be offered


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any further therapy, they are usually compliant. We need to accept that with our current status of knowledge, there will be some patients for whom there is no effective therapy. Such patients should be kept under regular review and advised to report any untoward symptoms or signs promptly to the haematology day ward or medical staff. Cyclosporin A Cyclosporin A has been shown to increase the platelet count when given either alone or with prednisolone. Cyclosporine appears to be relatively safe, providing cyclosporin levels and renal function are monitored. No large studies involving the drug have been conducted but from available data it may sustain the patient over a difficult period. Interferon a (IFN-a) There are several case series that report on the use of IFN-a in refractory ITP and have shown that 25% of patients can achieve a platelet count of over 100 · 109 ⁄ l for between 1 week and 7 months after the IFN-a treatment (Proctor et al, 1989; George et al, 1996). However, IFN-a is probably of limited value in severe thrombocytopenia, and in some cases may actually worsen the thrombocytopenia and induce bleeding (Matthey et al, 1990). The mechanism of action is unknown but may be due to modulation of effector B lymphocytes involved in the autoimmune process. Because of side-effects, expense and route of administration most clinicians and patients are reluctant to use IFN-a (Vianelli et al, 1998). Protein A immunoadsorption column Snyder et al (1992) reported on the use of protein A columns in 72 patients with refractory ITP, 49 of whom had undergone splenectomy. All 72 patients were given six immunoadsorption treatments for 2–3 weeks. Twenty-nine of the 72 (40%) were continued on low-dose steroid (prednisone < 30 mg ⁄ d). Some 25% of patients had good responses (platelets exceeding 100 · 109 ⁄ l, while 21% had fair responses (platelets between 50 and 100 · 109 ⁄ l). Over half the patients (54%) had poor responses. The mechanism of action of the protein A columns may involve reducing platelet activation (Cahill et al, 1998). The use of protein A columns requires good venous access, is cumbersome and relatively expensive (Karpatkin, 1997), and for this reason does not offer a useful therapy for most refractory patients. Miscellaneous treatments For patients who fail to respond to these therapies, there are limited data on the use of ascorbic acid (Brox et al, 1988), chlorodeoxyadenosine (Figueroa & McMillan, 1993), colchicine, liposomal doxorubicin and plasma exchange (Blanchette et al, 1998; Buskard et al, 1998). More recently, peripheral blood stem cell transplantation (PBSCT) has been explored as a treatment modality in a variety of autoimmune disorders, for patients suffering from severe intractable disease, including rheumatoid disease, SLE, multiple sclerosis and autoimmune cytopenias (Lim et al, 1997; Skoda et al, 1997; Tyndall & Gratwohl, 1999). Data from the European Blood and Marrow Transplant Registry ⁄

European League Against Rheumatism have shown that 16 patients with autoimmune cytopenias, nine of whom had chronic severe refractory ITP, have undergone PBSCT. Complete responses were seen in two patients with ITP, with deaths occurring within 100 d post transplant in three of the 16 patients (two were due to haemorrhage and infectious complications, and one was due to progressive haemolysis) (Passweg et al, 2001). Larger trials are required in order to determine the feasibility of using PBSCT in this setting and randomized trials are currently being considered for the treatment of severe refractory ITP (Alan Tyndall, personal communication). Targeted versus untargeted therapies Until recently, treatments for ITP and other autoimmune diseases have been relatively unselective in their modes of action. In effect, we have been attempting to induce global immunosuppression in the hope that, as part of this process, the ITP-related component of the immune system will be suppressed, thereby reducing the quantity of autoantibody produced and hence improve the platelet count. What remains unclear is whether the B-cell population that is generating the anti-platelet autoantibody is the primary problem or whether events downstream, such as those involving antigen presentation or T-cell regulation are disturbed and simply driving the passive B cells, resulting in the autoantibody phenotype. Recently, more selective therapies including Campath-1H and anti-CD20 have been evaluated in autoimmune disease. Although not entirely specific, these agents are able to target and remove B cells and theoretically should reduce the quantity of autoantibody produced. Other therapies which may be of benefit include mycophenolate mofetil (Dhawan & Mieli-Vergani, 2000; Richardson et al, 2000) and anti-CD40 ligand. Campath-1H Campath-1H is a humanized IgG monoclonal antibody which targets the CD52 antigen, present on mature human lymphocytes and monocytes (Gilleece & Dexter, 1993; Hale, 1995). To date, it has been used for the treatment of malignant B-cell disorders, especially B-cell chronic lymphocytic leukaemia (B-CLL), where it has been shown to be effective in clearing lymphocytes from both blood and bone marrow. In addition, Campath-1H has been shown to have clinical benefit in patients with poor prognosis B-CLL who have been heavily pretreated. Campath-1H has been used in a variety of autoimmune diseases, including rheumatoid arthritis (Isaacs et al, 1992), vasculitis (Mathieson et al, 1990) and Wegener’s granuloma (Lockwood, 1998). There is ongoing interest in the use of Campath-1H for the treatment of autoimmune haematological disease that is refractory to first- and second-line therapies. A recent study of the use of Campath-1H in autoimmune neutropenia, autoimmune haemolytic anaemia, pure red cell aplasia, immune thrombocytopenia and combined haemolytic anaemia and ITP (Evans’ syndrome) has shown responses in 15 out of 21 patients treated; in six patients the response was sustained (Willis et al, 2001).


Review First day reactions were common, including fever, rigors and chills. Overall, deaths were seen in seven patients from a variety of causes, including cerebral haemorrhage (two patients), Guillain–Barre´ syndrome, thrombotic thrombocytopenic purpura, recurrence of bronchial carcinoma, intractable intravascular haemolysis and systemic venous thrombosis, and non-Hodgkin’s lymphoma (NHL) transformation. Infection might be expected to accompany the use of Campath-1H as it induces profound lymphopenia. In studies of patients with CLL treated with Campath-1H, there was an increased incidence of opportunistic infection, especially reactivation of cytomegalovirus infection. However, this was felt to reflect immunosuppression induced by previous chemotherapy regimens rather than Campath-1H (Osterborg et al, 1997). In the study by Willis et al (2001), one patient suffered a mild viral illness but overall there was no increased incidence of infection. Campath-1H would appear to be an effective agent in severe refractory autoimmune disease; it was well tolerated but because it can precipitate bleeding during administration it should not be given in the presence of active bleeding (or active infection). For patients with ITP, Campath-1H might be worth considering if one is faced with a patient who is deemed to be at serious risk of bleeding and has failed all other therapies. Anti-CD20 monoclonal antibody therapy The genetically engineered chimaeric human ⁄ mouse antiCD20 monoclonal antibody, rituximab, has been developed primarily as a treatment for B-cell lymphoproliferative disease (NHL). The antibody is an IgG j immunoglobulin, comprising murine light and heavy chain variable region sequences, and human constant region sequences (Reff et al, 1994). The antigen binding domain binds to the CD20 antigen on B cells while the Fc domain mediates B-cell lysis, through recruitment of immune effector cells. Because of its specificity for B cells, rituximab has been viewed as a potential treatment for autoimmune disease, the rationale being the reduction or elimination of autoantibody-producing B cells with concomitant improvement of the autoimmune disease. A recent study by Stasi et al (2001) reports on the efficacy of rituximab used to treat 25 patients with chronic refractory ITP. Patients were treated if their platelet counts were below 20 · 109 ⁄ l irrespective of symptoms or at higher platelet counts if bleeding or bruising was problematic. All patients had received between two and five previous treatments; eight had failed splenectomy. Rituximab was administered in the same manner and dose as that used in NHL. After four courses, 40% of patients achieved a platelet count of at least 50 · 109 ⁄ l; five achieved complete response (CR) (platelets > 100 · 109 ⁄ l) and five had a partial response (PR) (platelets 50–100 · 109 ⁄ l). Responses were seen during treatment with rituximab, with a peak response up to 4 weeks following the end of treatment. Twenty-eight per cent had responses that lasted for more than 6 months. As one might expect with chimaeric proteins, adverse events were common; 18 patients experienced 27 adverse events during treatment, which included fever, chills,

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headache, dizziness, asthenia, nausea, vomiting, hypotension and sinus tachycardia. These events were commonly seen during the first infusion and were generally brief and mild. Three patients suffered a drop in haemoglobin concentration (to 10–11 g ⁄ dl) at 6–8 weeks after the infusions had stopped. No infections were reported during treatment, although bacterial infections were reported up to 1 year of treatment (generally minor). Stasi et al (2001) concluded that the use of rituximab resulted in responses similar to other second-line agents used in ITP, including vinca alkaloids, cyclophosphamide and azathioprine of around 40–50%, but sustained responses to these agents is usually seen in less than 20% of patients (George et al, 1996; McMillan, 1997), i.e. lower than for rituximab. Rituximab would appear to be useful for some patients with chronic symptomatic refractory ITP in whom there is a definite need to elevate the platelet count to a safe level. Co-stimulatory blockade Therapies such as Campath-1H and anti-CD20 may not produce lasting remissions if the autoimmune B cells are driven by dysregulated T cells, and a novel agent, CTLA4-Ig, has been evaluated in psoriasis in an attempt to block T-cell co-stimulation, thereby inducing anergy in the T-cell compartment (Abrams et al, 1999). CTLA-4-Ig, a fusion protein between CTLA-4 and the Fc portion of human immunoglobulin, binds to B7Æ1 and B7Æ2 thus blocking T-cell co-stimulation. This small trial showed that, at least within this group of patients, CTLA-4-Ig was able to improve the disorder and was shown to be safe. CTLA4-Ig may have applications within other autoimmune disorders, including ITP. If a drug such as CTLA-4-Ig was shown to be effective in ITP, it would provide not only an additional targeted treatment modality, but would also provide useful evidence of T-cell dysfunction in this disease. Interestingly, the CTLA-4 gene has been mapped as a susceptibility gene in autoimmune thyroid disease (Warkentin, 1996) and IDDM in humans (Wucherpfennig & Eisenbarth, 2001). Finally, compounds that directly stimulate thrombopoiesis, such as thrombopoietin, are likely to become available in the near future. Initial data have shown favourable responses in immune-mediated thrombocytopenia (Rice et al, 2001). Other options: Helicobacter pylori eradication This bacterium is the main cause of gastritis and peptic ulcer disease (Marshall et al, 1985). It has also been implicated in the development of gastric adenocarcinoma and mucosa-associated lymphoid tumours (Forman et al, 1991), and some autoimmune disorders (de Luis et al, 1998; Zentilin et al, 1999). A previous study of H. pylori in ITP showed improvement in platelet counts after eradication of the bacterium in patients shown to be positive for H. pylori (Gasbarrini et al, 1998). More recently, Emilia et al (2001) looked for the presence of H. pylori in 30 patients with chronic refractory ITP. H. pylori was found in 13 of the 30 patients (43Æ3%). Standard triple therapy for H. pylori


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eradication resulted in a CR of ITP in four of 12 patients in whom the bacterium was eradicated, and PR in two of 12 (16Æ6%). The responses were maintained for a median of 8Æ33 months. In addition, there are other anecdotal reports of improvements in platelet counts in adults and children with ITP after eradication of H. pylori. Ideally a much larger study is required to confirm the findings of Emilia et al (2001), but from the available data, triple therapy appears to offer a non-immunosuppressive therapy for patients with refractory ITP. CONCLUSIONS AND FUTURE PROSPECTS So, have we advanced much in the 50 years since Harrington’s original paper? Yes and no. We certainly understand much more about the immune system and its role in the ITP process. We are beginning to understand how autoantibodies arise, their target antigens and even specific glycoprotein epitopes involved. However, we still have no tests to help diagnose ITP with certainty and we are forced to exclude other diseases before labelling the patient as having ITP. We cannot tell which patients will have a benign course or those who will require intensive therapy, although clinically this can sometimes be assumed, and

while we have many drugs at our disposal we are unsure which to use and in what circumstances. Are we trying to normalize the platelet count or simply alleviate the consequences of thrombocytopenia? Patients with moderate ITP require little therapy and may expect a normal life expectancy (Portielje et al, 2001). For those with more severe refractory ITP, there is an increase in morbidity and mortality due to either bleeding or infection. However, intensive measures are only warranted in patients with chronic ITP when the patient is in a lifethreatening situation. This is seldom the case with this condition and many patients can be maintained relatively free of problems with judicious juggling of conventional therapy, such as long-term low-dose corticosteroids. Unfortunately, it is rarely possible to wean the patients off such treatment, hence the continual exploration of further therapies. There has been recent debate concerning the reduction in life expectancy in patients with severe chronic ITP which appears to be higher in older individuals (Cohen et al, 2000; Djulbegovic & Cohen, 2001), and some would advocate medical intervention for such patients. Like others, we believe that answers to these questions will only come from long-term prospective study of patients with severe refractory ITP.

Fig 1. Management options in adults with severe refractory ITP. 2002 Blackwell Science Ltd, British Journal of Haematology 118: 933–944

Review The intensity of many of the newer treatments underlines the limitations of our understanding of the natural history of refractory ITP and further emphasizes the need to be certain of the diagnosis and to discuss with the patient the most appropriate treatment (Cahill & Newland, 1997). A more rational, consistent and effective approach will require a clearer understanding of the natural history of the disease and the development of targeted treatments in carefully designed randomized studies. In terms of the practical management of patients who fail to respond to standard and refractory disease therapies, we would suggest a plan similar to that outlined in Fig 1. There are few randomized controlled studies to help guide treatment (George et al, 1996) and we would anticipate that individual practitioners will develop their own treatment algorithms chosen from those available for refractory disease outlined in Table I. With our current state of knowledge, it is probably safe to keep a watching brief on those patients in whom bleeding is absent, intervening with therapy if bleeding occurs. As with childhood ITP, we are focusing our attention on the patient rather than the platelet count alone. For those who are bleeding or felt to be at high risk of bleeding, we would suggest reintroducing first- or second-line drugs, perhaps at higher doses, or consider using cyclosporin or rituximab. Agents that work rapidly in the bleeding patient include IVIg, and intravenous methylprednisolone with or without cyclophosphamide. Table I. Suggested therapies for ITP. Standard treatment

Refractory disease

Experimental therapies

Oral corticosteroids, e.g. prednis(ol)one IVIg Splenectomy Oral dexamethasone i.v. methylprednisolone* Danazol High-dose IVIg* Anti-D Dapsone Azathioprine Vinca alkaloids* i.v. cyclophosphamide* Combination chemotherapy Cyclosporin A (IFN-a) Rituximab Campath-1H Mycophenolate mofetil Anti-CD40 ligand Protein A columns Stem cell transplantation

*Indicates those agents that are faster acting and may be of value when the patient is bleeding where rapid elevation of the platelet count is required. Terms such as first-line and second-line are confusing and unhelpful, and it may be better to adopt the terms standard, refractory and experimental treatments. We have placed in parentheses those treatments that we would not advocate in refractory adult ITP.

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We also consider it worthwhile checking serology and breath test for H. pylori, as eradication of the bacterium may result in elevation of the platelet count. In ITP, like many non-malignant disorders, many unanswered questions remain and in order to answer these, larger natural history studies need to be conducted, looking particularly at patients with severe refractory ITP. For example, do patients with severe ITP in whom bleeding is not a problem require less therapy than those in which bleeding has been, or currently is, present? Intuitively one would expect this to be the case, but the studies need to be carried out in order to confirm this. Most of our treatments are ad hoc and many are completely ineffective but they remain in current usage. Clearly some simple randomized drug trials are required in order to guide us in our management of patients with ITP. Randomized controlled trials in malignant diseases, such as those conducted under the auspices of the Medical Research Council and other trial groups, have led to significant improvements in the outlook for patients with haematological malignancies, but, for too long, patients with non-malignant diseases have been treated in a completely non-evidence-based fashion and we must redress the balance by adopting strategies such as those used in the treatment of leukaemias, lymphomas and other malignancies in order to determine the optimal treatment for those who actually require it. St Bartholomew’s & The Royal London School of Medicine & Dentistry, London, UK

Drew Provan Adrian Newland

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Keywords: idiopathic thrombocytopenic purpura, adults, pathophysiology, treatment, refractory disease.
