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ADULT PATIENTS FAILING FIRST AND SECOND LINE THERAPIES – CHRONIC REFRACTORY ITP

This defines patients who fail to respond to first line treatment or require unacceptably high doses of corticosteroids to maintain a safe platelet count. The actual percentage of patients de?ned as having refractory ITP varies from 11% (Portielje et al, 2001) to 35% (George et al, 1994). A large number of drugs have been used as second line therapy for ITP with variable success. The therapy used will depend on the age of the patient, the severity of the presentation, the level of 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 original ?rst line therapies (corticosteroids, IVIg or splenectomy) should be reconsidered and implemented if possible (George et al, 1996), although the doses may have to be altered compared with those used in first line therapy. Additional supportive therapy may need to be considered to allow their chronic use. For example, 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 actual 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 ?brinolytic inhibitors may be used, particularly if there is only mucous membrane bleeding, and in severe bleeding, such as gastrointestinal haemorrhage, then platelets may be transfused. Although these are rapidly cleared from the circulation and have a severely shortened half-life they are often effective in stopping 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 are a wide variety of 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.

High dose corticosteroids. 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; Demiroglu & Dundar, 1997; Kuhne et al, 1997).

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 < 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 pre-treatment levels (Akoglu et al, 1991). von dem Borne et al, 1988) compared the effect of methylprednisolone with IVIg in 22 adult patients 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 that to intravenous methylprednisolone (von dem Borne et al, 1988). Again, the response to intravenous steroids was transient in all patients and maintenance with oral steroids was required to achieve an adequate platelet count.

High dose IVIg. High dose intravenous immunoglobulin at a dose of 1 g/kg per day for two consecutive days, often in combination with corticosteroids, will raise the platelet count rapidly in a proportion of patients (Bussel & Hilgartner, 1984; Imbach et al, 1985). Side effects, particularly headaches, may occur, but if successful can be given on an intermittent basis or substituted with intravenous anti-D (Blanchette et al, 1993). Godeau et al (1993) reported good responses, including sustained complete response (CR), in some patients with refractory ITP treated with IVIg (1–2 g/kg) repeated every 2–3 weeks. In general, however, the platelet response to IVIg is transient with rare durable remissions (Schiavotto et al, 1995). IVIg is usually reserved for patients with symptomatic ITP in whom a rapid increase in platelet count is required, prior to operative procedures likely to cause blood loss, or in pregnancy.

Intravenous anti-D. Intravenous anti-D has been shown to elevate the platelet count in 79–90% of adults (Scaradavou et al, 1997). The mechanism of action is believed to be mediated through the destruction of Rh (D) positive red cells which are preferentially removed by the reticuloendothelial system, particularly the spleen, thus sparing autoantibodycoated platelets through Fc receptor blockade (Bussel et al, 1991a).

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 Rh (D) positive patients who are not splenectomized, and 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. Around 50% of splenectomized patients will respond, but sustained responses are observed in less than 10% of patients (Berchtold & McMillan, 1989; Manoharan, 1991; George et al, 1996; Blanchette et al, 1998). Available drugs include vincristine 1 mg (occasionally 2 mg) intravenously (IV), or vinblastine 5–10 mg IV weekly for 4–6 weeks.

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 responsive patients 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 that was sustained for more than 2 months. Older females and those who have undergone splenectomy appeared to have the best response (Ahn et al, 1989). Danazol, when given for longer than a year, induced remissions lasting for years even after its discontinuation, but early relapses were frequent when it was administered for less than 6 months (Ahn et al, 1989). The mechanism of action of danazol is unknown but it is postulated to downregulate the number of Fc receptors on splenic macrophages (Schneider et al, 1997).

Immunosuppressive agents. Immunosuppression may be required in patients who fail to respond to alternative therapies. Treatment with azathioprine (2 mg/kg, usually up to a maximum of 150 mg/d) or cyclophosphamide as single agents may be considered and up to 25% of patients may have a sustained response.

Bouroncle & Doan (1969) used azathioprine in 17 patients and reported excellent responses in 23.5% and good responses in 41% after treatment for an average of 10 months (a good response was one in which the normal platelet count was sustained only with continued use of azathioprine). Another review of the use of azathioprine (Quiquandon et al, 1990) reported 53 patients with chronic ITP who were treated with azathioprine at 150 mg per day for a median of 18 months; 40 of the 53 patients had previously undergone splenectomy. Platelet responses were documented in 64% of patients and were complete in 45% of these.

Azathioprine is slow-acting, and should be continued for up to 6 months before being deemed a failure. When a platelet response occurs the dose should be reduced, while maintaining a safe platelet count (Blanchette et al, 1998).
Cyclosporin A has been shown to increase the platelet count when given either alone or with prednisolone but its side effects make it unlikely to be of widespread practical use. It may, however, sustain the patient over a dif?cult period. Emilia et al. (1996) reported eight patients treated over a 13–62 month period with cyclosporin A (three patients had autoimmune haemolytic anaemia (AIHA), four ITP and one Evans' syndrome). Responses were seen in all patients (six CR and two partial responses). Side effects were moderate but transient. In most cases cyclosporin A had to be continued in order to maintain an adequate platelet count (Emilia et al, 1996). In a recent study (Kappers- Klunne & van’t Veer, 2001), 20 patients with ITP all of whom were refractory to corticosteroids and half of whom had undergone splenectomy, were treated with cyclosporin A for at least 4 weeks. The dose was reduced by 50 mg ? d every 2 weeks in those showing responses. Five patients remained in complete remission for at least 2 years after discontinuing cyclosporin A, and a further six patients showed partial responses. Cyclosporin A was discontinued in six patients due to side effects.

Dapsone. In a series of 66 adults with chronic ITP and platelet counts < 50×10⁹/ l treated with dapsone at 75–100 mg orally, responses were observed in 33 of 66 patients (50%), 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).

Half of all patients with chronic ITP treated with dapsone will show some response within 3 weeks, but it appears to be less effective in severe cases of ITP. The response rate to dapsone is low in patients who have undergone splenectomy (Hernandez et al, 1995).