Immune thrombocytopenia in adults: An update
ABSTRACTImmune thrombocytopenia (ITP) in adults is a chronic disease resulting from increased platelet destruction and impaired platelet production. Splenectomy remains the most effective and durable treatment in cases that are refractory to first-line therapy, but its use has declined because of the availability of alternate medical therapy, the associated risk of infection, and concern for surgery-related complications. Rituximab (Rituxan) may be an effective alternative but carries the risk of immunosuppression.
KEY POINTS
- Secondary ITP can be drug-induced or be a manifestation of human immunodeficiency virus (HIV), hepatitis C virus (HCV), a lymphoproliferative disorder, or systemic lupus erythematosus.
- Nonautoimmune conditions should also be considered, including pseudothrombocytopenia (a laboratory artifact induced by EDTA), thrombotic thrombocytopenic purpura, thrombocytopenia in pregnancy, and myelodysplastic syndrome (common in the elderly).
- Treatment is indicated to keep the platelet count above 30 × 109/L or to control bleeding.
- Initial treatment usually begins with glucocorticoids, with the duration limited by side effects.
- Patients for whom glucocorticoids fail generally require splenectomy, rituximab, or thrombopoietin receptor agonists.
SECOND-LINE TREATMENTS
Splenectomy produces complete remission in most patients
Patients who relapse and have a platelet count of less than 20 × 109/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.37
Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.38,39
Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.40 Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.41
Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.42
Rituximab in addition to or possibly instead of splenectomy
Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.
In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues43 reported an overall platelet response (defined as platelet count > 50 × 109/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.
Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 109/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 109/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.44 Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.
Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.45 Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.
Thrombopoietic receptor agonists require continuous treatment
In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.46
This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.
Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,47 so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.
Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 109/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.48
A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 109/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.49
Kuter et al,50 in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.
Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.
Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.51 In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.52 Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 109/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).52
Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.53
THIRD-LINE TREATMENTS FOR REFRACTORY CASES
Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.28,42
Combination chemotherapy
Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.3 However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.54
Arnold and colleagues55 reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 109/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.
Hematopoietic stem cell transplantation
Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.56,57
THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE
Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).
Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.
Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.58 Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.59 However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.60
Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.
Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.
