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• patients planning to undergo medical or dental procedures likely to provoke or bring about blood loss, such as the extraction of a tooth • patients with lifestyles associated with an increased risk of bleeding, such as those participating in hazardous or dangerous activities such as full-on contact sports. Current treatments for patients with ITP Currently, four treatment options that focus on reducing platelet destruction are commonly used: corticosteroids, anti-D immunoglobulin, intravenous immunoglobulins (IVIGs), and splenectomy. Corticosteroids, typically prednisone, are considered the first line of therapy and are effective in 50-75% of patients. (8) Unfortunately, the long-term use of corticosteroids can be associated with various side effects, including hypertension, diabetes, osteoporosis, glaucoma, and in extreme cases, Cushing’s syndrome as well as an increased risk of infection associated with steroidinduced immunosuppression. Anti-D immunoglobulin is equally effective, but only in 70-75% of Rhesus+ patients in the non-splenectomised setting (4). IVIGs are recommended for patients unresponsive to corticosteroids, or those with severe bleeding (7). Possible side effects associated with immunoglobulins include fever, chills, headache, nausea, dyspnea, and chest pain. In rare cases, patients may develop acute kidney failure, aseptic meningitis, or haemolytic anaemia following the administration of immunoglobulins. Splenectomy is an option for patients with severe ITP refractory to corticosteroids but the trend now is for more conservative medical management of patients. Patients can have a lifelong increased risk of infection following splenectomy, and 40-50% of splenectomised patients later relapse (1). Rituximab is not currently approved for the treatment of ITP but has demonstrated efficacy. (9,10). Approximately 45-65% of patients have a response to rituximab (11) but treatment can be complicated due to unpredictable patterns of response. Some patients have an early increase in platelet counts (after the first or second infusion) which peak between weeks 6 and 10; others may have a late response where increases in platelet count are first achieved 6 to 8 weeks after treatment initiation and reached a peak count quickly.(12,13) New treatment options for patients with ITP New therapies developed to address sub-optimal platelet production include growth factors that stimulate platelet production (4). The first recombinant TPO—manufactured by adding the relevant DNA into the existing genome of bacteria so that proteins are created that stimulate the production of platelets—was similar to endogenous TPO produced naturally in the body. The recombinant TPOs proved to be immunogenic and the body’s immune system identified the recombinant TPO as ‘foreign’ leading to the production of autoantibodies and the destruction of endogenous TPO. The second recombinant TPO receptor agonist, romiplostim and the small molecule TPO receptor agonist, eltrombopag, currently in late phase clinical development have no structural similarity to endogenous TPO and do not stimulate an autoimmune response. Romiplostim Romiplostim is a thrombopoeisis-stimulating Fc-peptide fusion protein (peptibody) which binds to the TPO receptor on the surface of platelet-producing megakaryocytes (Figure 3). The binding of romiplostim activates cell signalling pathways which lead to activation of platelet production (4). Romiplostim is administered as a onceweekly, subcutaneous injection and the dose of romiplostim is individualised for each patient and their specific platelet level. The efficacy and safety of romiplostim (1μg/kg weekly) was investigated in two 24-week, parallel, placebo-controlled, double-blinded, phase III trials, one in splenectomised patients (romiplostim N= 42; placebo N = 21) and the other in non splenectomised patients (romiplostim N=41; placebo N= 21) (14). Patients could receive concurrent ITP therapy with corticosteroids, azathioprine, and danazol. The primary endpoint of both studies was durable platelet response defined as a weekly platelet count of ≥ 50 x 10 9 /L during at least 6 of the last 8 weeks of treatment, in the absence of rescue medication at any time during the study. Transient response was defined as 4 or more weekly platelet responses without a durable response from week 2-25. Platelet responses that occurred within 8 weeks of rescue treatment were not included in any measures of platelet outcome. Altogether 83% of the romiplostim-treated patients achieved an overall platelet response (either durable or transient) compared with 7% of patients receiving placebo (p
similar or worse compared with patients with diabetes or arthritis (19). Patients report that the bruising and bleeding resulting from ITP has a substantial negative effect on their quality of life, and fatigue (possibly due to the anaemia caused by bleeding) hinders their ability to perform their routine daily activities. (20). When presented with a patient with ITP, the nurse therefore has to help the patient adapt to the physical and psychosocial demands of the disease. The changes to body image associated with corticosteroid treatment, the implications of a potential splenectomy, rehabilitation, roles and responsibilities, and the risk of sepsis are examples of some of the fears and concerns that nurses should be assessing and addressing when informing patients about, and explaining, different treatment options to patients with ITP. Keeping up to date with the developing and future therapeutic options enables the nurse to educate and reassure the patient, thereby potentially alleviating fears of treatment failure or that eventual splenectomy is unavoidable. The long-term efficacy and safety of romiplostim are now being confirmed in an ongoing, open-label, extension study (15). The European Medicines Evaluation Agency is currently reviewing the Marketing Authorisation Application for romiplostim. Romiplostim was recently approved for the treatment of adults with chronic ITP in the US and Australia. Eltrombopag Eltrombopag is a small molecule TPO receptor agonist that is administered orally once-daily. It activates the TPO receptor by binding to the transmembrane region. Although eltrombopag binds to the receptor differently than endogenous TPO or romiplostim, the final pathways seem to be identical (4). The results from a 6-week treatment-period, placebo-controlled phase II trial where the primary end point was a platelet count of ≥50 x 10 9 /L on day 43 of treatment showed that 28%, 70%, and 81% of patients receiving, respectively, 30 mg, 50 mg or 75 mg of eltrombopag daily achieved this endpoint (versus 11% in the placebo group). (16) When considering the management of the patient, two important Mild to moderate headache was the most commonly reported issues during the treatment of ITP arise: firstly, the need for treatment adverse event followed by aspartate aminotransferase elevation, concordance and secondly, regular platelet count monitoring. A onceweekly subcutaneous therapy such as romiplostim may facilitate constipation, fatigue, and rash. Cataracts have been noted in both preclinical and clinical studies of eltrombopag, and elevated alanine concordance; it also combines treatment with frequent platelet transaminase in conjunction with raised bilirubin levels have been count monitoring and reinforces regular contact with medical staff observed in some patients treated with eltrombopag (17). Phase III which may be reassuring for the patient. This approach facilitates studies of eltrombopag are currently ongoing and the published data individually tailored and controlled dosing schedules and minimises are awaited soon. the risk of thrombosis that might occur if platelet counts increase (e.g. due to irregular drug intake). Discussion With the development of the TPO receptor agonists, the treatment In adults, ITP is a chronic disease often associated with a remitting options for patients with ITP have been widened. Current treatments – relapsing course. Many patients do not require treatment and the can have many side effects and the treatment of ITP may result decision to introduce therapeutic interventions will be based upon in increased morbidity from adverse effects and opportunistic the laboratory findings, clinical circumstances, and individual patient infections, which often surpass the problems actually caused by ITP risk factors. The development of the upcoming TPO receptor agonists (18). The phase III trials investigating romiplostim and the phase II provides patients with a new perspective to living with this chronic trials on eltrombopag show that TPO receptor agonists appear to be medical condition. well-tolerated and effective in patients with ITP (14, 16). As the TPO receptor agonists are not immunosuppressive agents, the problems Acknowledgements associated with immunosuppressive treatment can be avoided and This article was supported by Amgen Europe GmbH, Zug, Switzerland. the overall health of the patient better maintained. Author for Correspondence: 033 Bevan House, Birmingham City Both the symptoms of ITP and its treatment affect the quality of life University, Edgbaston , Birmingham, B15 3TN, UK E-mail: dion. of the patient; indeed the impact on quality of life is perceived as smyth@bcu.ac.uk 26 - newsletter fall 2008
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