Recent years have seen a change in nomenclature and innovations in treatment for immune thrombocytopenia (ITP). What was once designated as immune thrombocytopenic purpura or idiopathic thrombocytopenic purpura has now, by consensus, been defined as immune thrombocytopenia, although the widely accepted abbreviation ITP remains.
The 2011 American Society of Haematology (ASH) practice guideline for ITP defined immune thrombocytopenia as: “an autoimmune disorder characterised by immunologic destruction of otherwise normal platelets most commonly occurring in response to an unknown stimulus. ITP may occur in isolation (primary) or in association with other disorders (secondary).”
Typically the disorder was thought to result from platelet destruction for which the bone marrow could not adequately compensate; however, it is now thought that many ITP patients also have decreased platelet production.
Diagnosis
ITP is a diagnosis of exclusion and is based on patient history, physical examination and blood counts. It is characterised by an isolated thrombocytopenia (a platelet count of less than 100 x 109/L)4 in the absence of other causes or disorders that might be associated with thrombocytopenia. Physical examination is usually normal aside from any manifestations of bleeding. Most patients present with bruising or mucosal bleeding; Table 1 shows the sub-classification of ITP.
Secondary ITP
Before proceeding to treatment, clinicians will exclude other causes of thrombocytopenia and will also look for causes of secondary ITP.
Treatment of the cause of secondary ITP, e.g. hepatitis C with ribavirin and interferon, is likely to provide resolution in the patient’s platelet count. Care should be taken when using drugs to treat secondary causes of ITP that can themselves reduce platelet count, e.g. interferon.
Drug-associated ITP
The US Food and Drug Adminstration reports 1444 drugs that can cause thrombocytopenia on their adverse events database. Recent work has collated this list along with clinical experience and laboratory testing and has confirmed a list of drugs associated with ITP (Table 3). This information will never be exhaustive; patients are individuals and react to treatments in an individual way, but it provides a quick reference when asked to review a patient’s medication history in the clinical setting.
Treatment options
Over recent years, new targeted treatments for ITP have been introduced to the market. In England and Wales, the National Institute for Health and Clinical Excellence (NICE) has issued guidance on two of these new agents but has agreed to the routine use of only one within the NHS. It is likely that this guidance will shape the treatment pathway in the UK for the foreseeable future.
To date the mainstays of treatment are similar worldwide; the international consensus document and the American Society of Haematology (ASH) guidelines, published in 20106 and 20112, give broadly similar advice. Both groups agree this is an area where practice needs further support from robust research. Existing treatment pathways remain broad and very dependent upon patient and clinician preference.
The first question will be: ‘Is treatment required?’ This will depend upon the degree of thrombocytopenia, suggested for platelet counts of less than 30 x 109/L, and the risk or presence of bleeding complications. Once the decision to treat has been made, international guidance is in agreement.
Initial treatment
Initial treatment remains high-dose steroids and immunoglobulin therapy. Anti-D is also suggested as first-line therapy in the ASH guidelines but is no longer licensed for this indication in the EU. Treatment response will be accepted as a platelet count greater than 30 x 109/L and a two-fold increase in platelet count from baseline (measured on two occasions, 7 days apart) and an absence of bleeding.
Corticosteroids
Corticosteroids are the standard initial intervention for patients with ITP. The major issues with corticosteroids are side-effect profile, patient tolerability and risk of complications. Most patients (70–80%) will respond initially to steroid therapy. Longer courses of steroids are associated with a longer duration of response and the ASH guideline recommends this course of action above a short course or cyclical administration of steroid, or intravenous immunoglobulin (IVIg). These guidelines suggest prednisolone 1mg/kg for 21 days, with tapering of the dose thereafter; this is based on a time to initial response of 4–14 days and a time to peak response of 7–28 days. The use of further measures if there is no response depends upon the patient’s clinical condition.
Intravenous immunoglobulin
Time to response with patients treated with IVIg can be very rapid, with some responding within the first 24 hours of therapy and a peak response occurring between 2 and 7 days. IVIg is administered by infusion at a dose of 0.4g/kg daily for 5 days, although current practice is tending towards administration at 1g/kg over a 1–2 day period. The ASH guidance also suggests that 2g/kg doses might be helpful in those patients who fail to respond to 1g/kg. The time over which IVIg is given should be based on the specific product advice and assessment of the patient’s overall condition, e.g. renal function, age, bleeding risk. When a rapid resolution of platelet count is required, IVIg and steroids can be used in combination.
Second-line treatment
There are a number of drugs used in clinical practice for patients who have failed to respond or are no longer responsive to initial measures; these include azathioprine, ciclosporin, mycophenolate, dapsone, danazol and vinca alkaloid therapy. These drugs are available to clinicians but they might perhaps favour those immunosuppressants such as ciclosporin that can be monitored by both serum drug levels and response. The treatment course is likely to change in the future because clinicians change practice as recent guidance is adopted. Future practice might routinely favour the use of rituximab and thrombopoietin (TPO) receptor agonists, which have previously been seen as third-line options, as well as offering patients the standard intervention of splenectomy. The use of rituximab (which is unlicensed in this setting), TPO receptor agonists or splenectomy will require detailed discussions with patients about outcomes, duration of treatment and risk factors.
Splenectomy
The role of splenectomy remains an issue of debate, with some clinicians advocating it as routine treatment and others avoiding its use. Patients themselves appear less accepting of a course of therapy that will have long-lasting effects on their immunity whether or not their health economy advocates lifelong antibiotic prophylaxis, the efficacy of which is unproven. The advent of new agents, which are themselves long-term therapies, as opposed to prior therapies, which have concentrated on producing a remission, may muddy the decision-making process for patients and will necessitate a detailed discussion of their pros and cons.
Splenectomy produces a response in platelet count in 80% of patients, and that response is maintained in 66% of those patients for at least 5 years. Response to splenectomy cannot be predicted easily and studies that have looked at ways of predicting outcome vary in their findings. Patients requiring splenectomy need appropriate pre-operative vaccination (follow up-to-date national guidance) and should be counselled to carry an alert card to inform physicians that they are asplenic. Patients who relapse after an initial response to splenectomy might have developed accessory splenic tissue and this should be excluded as a cause of the relapse before using other secondary treatments.
TPO receptor agonists: romiplostim and eltrombopag
These agents are considered maintenance therapies because on cessation most patients return to a low platelet count, with some individuals even dipping below their pre-treatment levels. TPO receptor agonists act by promoting platelet production through activation of the TPO receptor. Randomised controlled trials indicate that TPO receptor agonists are effective in both splenectomised and non-splenectomised patients for the treatment of chronic ITP, with response rates of greater than 79% for romiplostim and greater than 59% for eltrombopag. Romiplostim is administered by subcutaneous injection once weekly, in doses of 1µg/kg to 10µg/kg depending upon response, whereas eltrombopag is an oral agent given daily in doses ranging from 25 to 75mg.
Adverse effects are considered to be mild. Eltrombopag produces abnormal liver function tests in 13% of patients. Alanine aminotransferase increased to three-fold the normal upper limit in 3% of patients treated with eltrombopag, but, in the majority, was non-progressive or resolved. Both agents increase bone marrow reticulin in some patients, which could affect future bone marrow function. Further studies are required to determine whether routine monitoring of this adverse effect is needed. Bone marrow biopsies are sometimes incorporated into pre-treatment tests although no consensus on this has been reached. As more routine use of these agents is adopted, clinicians will gain a better understanding of their toxicity profiles as well as their utility.
Rituximab
Although not licensed for this indication, the use of rituximab, at both the standard treatment dose used in lymphoma (375mg/m2 weekly for 4 weeks) and at lower doses (100mg weekly for 4 weeks), is frequent in the treatment of patients with ITP. Pooled data show response rates of 62.5%; however, the duration of this response beyond 1 year may be as little as 30% (although patients who do not maintain a durable response might respond to retreatment). Rituximab is a useful treatment option in patients who have failed other lines of therapy and have a significant risk of bleeding. A recent systematic review found that 3.3% of treated ITP patients had a severe or life threatening complication on rituximab therapy. Progressive multifocal leukoencephalopathy has been reported in patients treated with rituximab, although the numbers of those with ITP were limited.
Conclusion
In England and Wales, the NICE guidance on romiplostim (positive) and eltrombopag (negative) has set in place a way forward for ITP treatment. In other areas of haematology, particularly in the treatment of myeloma, previous NICE guidance has driven therapeutic pathways and, as such, has led to some divergence in the treatment plans for patients in the UK from those of Europe and the USA. The authors of both the ASH guidelines and the international consensus report have called for further work in this area, which would provide further robust evidence on treatment pathways and could benefit patients and their health economies alike.
Author
Marie Brazil
Consultant Pharmacist Haematology Services
Wirral University Teaching Hospital, NHS Foundation Trust, UK
