Immune thrombocytopenia: No longer ‘idiopathic’
ABSTRACTImmune thrombocytopenia (ITP) is a common hematologic disorder. Its pathogenesis involves both accelerated platelet destruction and impaired platelet production. First-line agents are usually effective initially but do not provide long-term responses. Splenectomy remains an effective long-term therapy, as does rituximab (Rituxan) in a subset of patients. Thrombopoietic agents offer a new alternative, although their place in the overall management of ITP remains uncertain.
KEY POINTS
- ITP is defined as an isolated platelet count of less than 100 × 109/L (100,000/μL) and usually presents without symptoms.
- Patients without symptoms who have a platelet count above 30 × 109/L should generally not be treated unless they have an increased risk of bleeding.
- Recent studies suggest that viruses and other pathogens play an important role in secondary ITP.
- Initially, corticosteroids are usually given as prednisone (1–2 mg/kg/day, then tapered), though recent studies suggest that dexamethasone pulses (40 mg/day for 4 days) may provide more durable responses when used in this setting.
- Thrombopoietic agents are important new treatments, although their place in the overall therapy of ITP has not been established.
SECOND-LINE THERAPIES
Second-line therapies, as designated by the international working group, include azathioprine (Imuran), cyclosporine A, cyclophosphamide (Cytoxan), danazol (Danocrine), dapsone, mycophenolate mofetil (CellCept), rituximab (Rituxan), splenectomy, thrombopoietin receptor agonists, and vinca alkaloids.27 Only the most commonly used therapies will be briefly discussed below.
The evidence for efficacy of the cytotoxic agents, ie, cyclophosphamide, the vinca alkaloids, and azathioprine, comes from small, nonrandomized studies.31 Although these agents are useful in some patients, they may be associated with significant toxicities, and they are used less commonly than in the past.
Splenectomy has a high success rate
Splenectomy probably offers the best response of any treatment for ITP. About 80% of patients with ITP respond rapidly—often within 1 week. Of those, 15% relapse within the first year, and after 10 years, two-thirds remain in remission.32,33
Because there is no well-accepted predictor of a short- or long-term response to splenectomy, and because more medical options are currently available, the use of splenectomy has declined over the past 10 years. Nevertheless, splenectomy remains a useful option for therapy of ITP.
Whether and which second-line drugs should be tried before splenectomy is still controversial and should be determined on a case-by-case basis. Some patients are poor candidates for splenectomy because of comorbidities. If possible, splenectomy should be delayed until at least a year after diagnosis to allow an opportunity for spontaneous remission.
Splenectomy increases the risk of subsequent infection by encapsulated organisms, and patients should be immunized with pneumococcal, Haemophilus influenzae type B, and meningococcal vaccines, preferably at least 3 weeks before the spleen is removed.
Splenectomy is associated with pulmonary hypertension and thrombosis, primarily in patients who have had their spleens removed because of accelerated red cell destruction. Whether these risks are applicable to patients with ITP is unknown, but if so they are probably much lower than in patients with red cell disorders.
Rituximab
Rituximab, a humanized monoclonal antibody against the CD20 antigen on B lymphocytes, was developed for treating lymphoma. However, it has been found to have significant activity in a number of immunohematologic disorders. Although many studies of rituximab for ITP have been published,34–38 it has never been tested in a randomized controlled study. The response rate is generally around 50%, and it is effective in patients with or without a spleen.
In one study,39 44 (32%) of 137 patients with chronic ITP who were given rituximab achieved a complete remission that was sustained 1 year. After more than 5 years, 63% of this group (ie, approximately 20% of the original group) were still in remission.
Potential drawbacks of rituximab include its expense as well as the risk of first-infusion reactions, which may be severe or, rarely, fatal. Rituxan has also been associated with rare cases of progressive multifocal leukoencephalopathy, usually in patients heavily treated with other immunosuppressive agents; however, very rare cases of progressive multifocal leukoencephalopathy have been reported in patients with ITP who received rituximab.
Thrombopoietin receptor agonists increase platelet production
Thrombopoietin receptor agonists are approved for patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Rather than inhibit platelet destruction, as do all the other ITP therapies, they enhance platelet production.
Diseases involving bone marrow failure that also involve a low platelet count tend to be associated with very high levels of serum thrombopoietin, which is produced constitutively by the liver. In ITP, thrombopoeitin levels tend to be close to normal and not significantly elevated, most likely because of accelerated thrombopoietin clearance when bound to antibody-coated platelets.40 This provides a rationale for the use of thrombopoietic agents in the treatment of ITP.
Earlier-generation thrombopoietic drugs had significant amino acid homology with natural thrombopoietin, and some patients who were treated with these drugs developed antibodies against them that cross-reacted with endogenous thrombopoietin. In some cases, this led to severe, refractory thrombocytopenia. Because the newer thrombopoietic agents have no sequence homology to natural thrombopoietin, antibody production has not been a significant problem.
Two drugs in this class are currently available for treating ITP:
Romiplostim (Nplate) is a peptibody (comprising an IgG Fc region and four peptidometic regions that interact with the thrombopoietin receptor, c-mpl) that is given subcutaneously once a week.
Romiplostim performed well in several phase I clinical trials.41 In a 24-week phase III trial that compared romiplostim against placebo in patients with ITP that had been refractory to other primary treatments, 79% of splenectomized patients and 88% of nonsplenectomized patients had an overall response (defined as a platelet count > 50 × 109/L for 4 weeks during the study period), and 38% of splenectomized patients and 61% of nonsplenectomized patients had a durable response (platelet count > 50 × 109/L for 6 of the last 8 weeks of the study).42
In an ongoing long-term extension study of romiplostim that allows dose adjustments to maintain a platelet count between 50 and 200 × 109/L, romiplostim dosage and efficacy have remained stable over 5 years.42,43
Eltrombopag (Promacta) is a nonpeptide small-molecule c-mpl agonist that is taken orally once daily. A recent randomized, placebo-controlled study in patients with ITP refractory to other primary treatments found that eltrombopag was highly effective in raising platelet counts over the 6 months of the study.44 Like romiplostim, it was effective in both splenectomized and nonsplenectomized patients.
Although eltrombopag has not been studied for as long as romiplostim, data over 3 years indicate that increased platelet counts are maintained without the emergence of drug resistance or cumulative toxicity.45
Several other drugs in this class are currently in development.
Adverse effects of thrombopoietic agents
Thrombopoietic agents have several associated toxicities:
Rebound thrombocytopenia occurs in up to 10% of patients following treatment with either romiplostim or eltrombopag. Rebound thrombocytopenia is defined as a fall in the platelet count that occurs following discontinuation of a thrombopoietic agent that may result in more severe thrombocytopenia, transiently, than before the drug was initiated. Thus, the platelet count must be closely monitored after treatment with these drugs is discontinued.
Bone marrow fibrosis, which consists primarily of increased marrow reticulin content, occurs in less than 10% of treated patients, and all patients on therapy must be monitored for this potential complication by close examination of the peripheral blood film on a frequent basis. Appearance of abnormalities such as teardrop cells or nucleated red blood cells in the peripheral blood smear should prompt at least temporary discontinuation of the drug and consideration of bone marrow examination. There have been no cases of actual irreversible myelofibrosis in which thrombopoietic agents have been clearly implicated in causation. Interestingly, some reports suggest that increased reticulin is a common finding in marrow from ITP patients who have not been treated with thrombopoietic agents.46
Thrombosis must be considered a risk of treatment with thrombopoietic agents, which increase the platelet count in a disease that may already be thrombogenic. However, in the placebo-controlled studies, a significantly increased incidence of thrombosis was not observed in the treatment arms vs placebo. Moreover, even in treated patients who developed thrombosis, there was no clear association with the degree of elevation in the platelet count. Nevertheless, thrombopoietic agents should be used according to the manufacturer’s recommendations, to increase the platelet count to a range of 50 to 200 × 109/L, but not to exceed that.
Progression of hematologic malignancies. Thrombopoietin receptor agonists act not only on megakaryocytes but also on stem cells and other hematopoieic precursors. Although trials for treating patients with hematologic malignancies and bone marrow failure with thrombopoietic agents are ongoing, there is concern that they could worsen certain hematologic malignancies, though there are no controlled data to either support or refute this concern at present. At this time, these drugs are approved only for ITP and should not be used for other conditions.
Hepatotoxicity has been seen with eltrombopag, but it is usually reversible and may resolve with continued therapy. Nevertheless, close monitoring for this potential complication is indicated.
