The traditional goal of management is to provide a hemostatic platelet count (> 20–30 × 109 L−1 for most patients and clinical scenarios) while minimizing treatment-related toxicity. Therapy is generally not indicated for patients with platelet counts above this threshold.
Treatment should be tailored to the individual patient and clinical setting. Individuals with extensive bleeding symptoms, comorbidities or lifestyles that predispose to bleeding and those that require concomitant antithrombotic therapy or an invasive procedure may benefit from a higher platelet count. Conversely, a lower target platelet count may be acceptable in patients who bleed little and tolerate treatment poorly.
Corticosteroids, supplemented with either intravenous immune globulin G (IVIG) or anti-Rh(D) as needed, are used as upfront therapy to stop bleeding and raise the platelet count acutely in patients with newly diagnosed or newly relapsed disease. Dosing, time to response and selected toxicities of these agents are shown in Table 3. Most (80–90%) patients evince a partial or complete response to first-line therapy . A non-response should prompt reconsideration of the diagnosis and an investigation for alternative causes of thrombocytopenia.
Table 3. First-line treatment options for immune thrombocytopenia (ITP)
|Prednis(ol)one||0.5–2 mg kg−1 day−1 × 2–4 weeks followed by slow taper||Several days to several weeks||Mood swings, insomnia, anxiety, psychosis, weight gain, Cushingoid facies, hyperglycemia, decreased bone density, hypertension, skin changes, gastrointestinal distress and ulceration, avascular necrosis, increased susceptibility to infections, cataracts, adrenal insufficiency|
|Methylprednisolone||30 mg kg−1 day−1 × 7 days||2–7 days|
|Dexamethasone||40 mg day−1 for 4 days every 2–4 weeks for 1–4 cycles||Several days to several weeks|
|IVIG||0.4 g kg−1 day−1 × 5 days |
1 g kg−1 day−1 × 1–2 days
|1–4 days||Headache, aseptic meningitis, renal insufficiency, fever, chills, nausea, thromboembolism, anaphylactoid reactions in patients with IgA-deficiency|
|Anti-Rh(D)||50–75 μ kg−1||1–5 days||Hemolytic anemia, fever, chills. Rarely, intravascular hemolysis, DIC, and renal failure|
Several uncontrolled studies suggest that high-dose dexamethasone for one to four cycles as initial therapy increases response rates and prolongs remission without additional toxicity [49,50]. However, a recent randomized controlled trial of a single cycle of high-dose dexamethasone vs. standard-dose prednisolone did not corroborate these findings . Zaja and colleagues randomized patients to receive one cycle of high-dose dexamethasone, alone or in combination with rituximab, as initial therapy. Patients in the rituximab arm showed a higher response rate at 6 months (63% vs. 36%, P = 0.004), but this difference eroded over extended follow-up and grade 3 and 4 toxicities were more frequent in patients treated with combination therapy . In a recent pilot randomized controlled trial of non-splenectomized patients with newly diagnosed or newly relapsed ITP, the addition of rituximab to standard therapy did not improve outcomes at 6 months . Further controlled trials with long-term follow-up are needed to determine whether aggressive therapy at the onset of disease can ameliorate the natural history of ITP.
Anti-Rh(D) is indicated in Rh(D)-positive non-splenectomized patients. It is rarely associated with life-threatening intravascular hemolysis, disseminated intravascular coagulation (DIC) and acute renal failure, and should be avoided in patients with pre-existing hemolysis. Some experts recommend avoidance of anti-Rh(D) in all patients with a positive direct antiglobulin test not as a result of previous therapy .
Although a majority of patients respond to first-line therapy, most ultimately relapse after treatment is tapered and require a second-line approach to maintain a hemostatic platelet count . Standard second-line options include a splenectomy, rituximab and the TRAs, romiplostim and eltrombopag (Table 4).
Table 4. Second-line treatment options for immune thrombocytopenia (ITP)
|Splenectomy||N/A||Two-thirds of patients achieve long-term remission||0–24 days||Adverse effects of surgery and anesthesia, increased risk of infection, long-term vascular complications|
|Rituximab||375 mg m−2 weekly × 4 weeks (lower doses may be effective)||40% at 1 year; 20–25% at 5 years||1–8 weeks||Infusion reactions, reactivation of hepatitis B infection, rare cases of progressive multifocal leukoencephalopathy|
|Eltrombopag||12.5–75 mg PO daily||> 80%. Most responses are sustained for up to 3–5 years with continual administration||1–4 weeks||Increased bone marrow reticulin, rebound thrombocytopenia, thrombosis. Eltrombopag also associated with liver function test abnormalities|
|Romiplostim||1–10 μg kg−1 SC weekly|
A splenectomy offers the best chance for prolonged remission. Two-thirds of patients attain a durable long-term remission and another 10–20% attain a partial response that may permit a reduction in the use of concomitant ITP medications . Distant relapse five or more years after splenectomy has been reported in a minority of responders . Response rates are lower in older patients . Apart from age, there are no reliable predictors of a response in individual patients with the possible exception of 111In-labeled autologous platelet scanning, which is neither widely available nor well standardized . Open and laparoscopic splenectomy are equally effective and operative risk is low in experienced hands . The relative risk of post-splenectomy sepsis is 1.4 (95% CI: 1.0–2.0) in the first year after surgery and remains elevated throughout life . This risk is reduced by adhering to recommended vaccination protocols and initiating antibiotics at the first sign of a febrile illness . All patients with newly diagnosed ITP should be vaccinated in anticipation of the possible need for splenectomy in the future. Recent concerns about vascular complications after splenectomy including thrombosis, atherosclerosis and pulmonary hypertension require further study . The risks of splenectomy depend, in part, on the nature of the underlying disorder. A greater incidence of post-splenectomy infection and thrombosis has been observed in patients with congenital and acquired hemolytic anemia than in individuals with ITP .
Rituximab, an anti-CD20 monoclonal antibody, induces complete remissions at standard doses (375 mg m−2 weekly × 4 weeks) in 40% of patients at 1 year . Approximately half of such individuals enjoy sustained responses lasting five or more years . A small uncontrolled study of low-dose rituximab (100 mg weekly × 4 weeks) showed similar efficacy . An initial rise in platelet count often occurs within 1–2 weeks of the first infusion, suggesting an effect on platelet clearance, but more durable responses may not be observed for several weeks to months . Individuals that achieve a complete remission at 1 year and subsequently relapse often respond to retreatment. Partial responders, in contrast, often relapse within 1 year and generally do not achieve sustained responses with retreatment . Rituximab is contraindicated in patients with active hepatitis B infection owing to the risk of fulminant hepatitis. More than 50 cases of progressive multifocal leukoencephalopathy have been reported in HIV-negative patients treated with rituximab, one of whom had ITP . The contribution of rituximab to the acquisition of progressive multifocal leukoencephalopathy in these heavily pretreated patients is unclear.
The TRAs, romiplostim and eltrombopag, are approved by the US Food and Drug Administration for use in patients with primary ITP who require treatment after an initial course of corticosteroids. In some jurisdictions (e.g. European Union), approval is restricted to patients who have previously undergone a splenectomy or have a contraindication to surgery. Romiplostim is composed of an Fc fragment fused to four identical peptides that bind to the thrombopoietin receptor . It is delivered as a weekly subcutaneous injection. Current labeling requires administration in a physician’s office, although the feasibility of home injection has been demonstrated in selected patients . Eltrombopag, a small molecule that binds to the transmembrane domain of the thrombopoietin receptor at a distance from the thrombopoietin binding site , is formulated for daily oral administration. It must be taken several hours removed from meals and medicinal products containing polyvalent cations, which interfere with drug absorption. An initial 50% dose reduction is necessary in individuals of East Asian ancestry.
Both approved TRAs have demonstrated high response rates in randomized clinical trials, even among splenectomized and refractory patients. Sixty-three splenectomized and 62 non-splenectomized patients were randomized to receive romiplostim or placebo for 6 months. The primary endpoint, a platelet count of 50 × 109 L−1 or greater for at least 6 of the last 8 weeks of the study in the absence of rescue therapy, was achieved in 61% of non-splenectomized and 38% of splenectomized subjects receiving romiplostim and in only 1 of 42 placebo-treated patients . An open-label trial tested the utility of romiplostim as a means of delaying or avoiding a splenectomy. Non-splenectomized individuals (n = 234) were randomly allocated to receive romiplostim or standard of care for 12 months. The incidence of treatment failure (11% vs. 30%, P < 0.001) and splenectomy (9% vs. 36%, P < 0.001) were significantly lower in patients receiving romiplostim . Similar efficacy has been observed in trials of eltrombopag. In a 6-month phase III study, 197 subjects were randomized to eltrombopag or placebo. The primary endpoint, a platelet count between 50 and 400 × 109 L−1 at one or more time points during the study, was achieved in 79% and 28% of eltrombopag- and placebo-treated subjects, respectively (P < 0.0001) . Sustained responses of up to 5 years have been reported in open-label extension studies of both romiplostim and eltrombopag [73,74]. Patients treated during study with both drugs experienced less need for corticosteroids and other rescue medications, improved QOL and less overall bleeding as compared with placebo-treated subjects [71–76]. However, a recent meta-analysis failed to show a reduction in major (WHO grade III and IV) bleeding with these agents .
Romiplostim and eltrombopag are generally well tolerated . Increased bone marrow reticulin has been observed in < 5% of patients receiving treatment for at least 12 months. In most cases, reticulin deposition was not associated with a loss of response or a myelopthistic picture and was reversible with discontinuation of drug [79,80]. Although not our practice, some clinicians perform bone marrow biopsies on all patients before initiating treatment with a TRA to establish a baseline. Bone marrow examination should be performed if there is loss of response to treatment or new abnormalities appear in the peripheral blood cell counts or smear. It remains unclear whether TRAs increase the risk of thrombosis in patients with ITP . The incidence rate of thromboembolism across studies of eltrombopag and romiplostim was 4.6 and 5.2 events per 100 patient-years [82,83], respectively, figures in line with the reported incidence rate of thrombosis in the general ITP population . Both venous and arterial events were observed, most occurring at normal or subnormal platelet counts [82,83]. Almost all patients who developed thrombosis during a study had pre-existing thrombotic risk factors. Patients at highest risk (e.g. those with a history of venous thromboembolism or known atherosclerosis) were excluded from some TRA trials. We favor other second-line treatment options in such patients. Rebound thrombocytopenia to levels below those at the onset of treatment has been observed in approximately 10% of patients who discontinued either romiplostim or eltrombopag in clinical trials . Tapering of the dose, careful monitoring and/or preemptive introduction of concomitant therapy at the time of TRA cessation may prevent or alleviate this toxicity. Hepatobiliary laboratory abnormalities were detected in 13% of eltrombopag-treated patients in clinical studies, prompting a black box warning that calls for regular monitoring of liver function tests. In most patients, laboratory abnormalities are non-progressive or resolve without clinical sequelae . Eltrombopag stimulated cataract formation in rodents at doses five times the human clinical exposure, but has not been shown to promote cataract formation or progression in patients with ITP .
TRAs are expensive. Romiplostim costs approximately $4 per microgram and the average wholesale acquisition cost of a 30-day supply of eltrombopag 25 mg tablets is $1650 (USD) . The annualized cost for a 70-kg patient treated at a weekly dose of 5.9 μ kg−1 (the mean weekly dose in the romiplostim extension study ) is approximately $86 000. The yearly cost for a daily dose of eltrombopag 50 mg (the median dose in the 6-month phase III trial ) is about $40 000. Neither of these estimates includes the expenses of physician visits and laboratory monitoring associated with TRA use. Appraisals undertaken by the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom noted an absence of evidence for long-term cost-effectiveness of these drugs relative to appropriate comparators such as splenectomy and rituximab [86,87].
The optimal treatment for patients requiring second-line therapy is controversial. Some authorities favor splenectomy in the absence of a contraindication to surgery [2,61]; others do not express a preference among second-line options  or note a dearth of evidence necessary for prioritization of such options . Studies that directly compare the efficacy, safety, impact on QOL and cost-effectiveness of second-line options are needed to guide management of patients failing or relapsing after first-line therapy. Until comparative data become available, we remain unconvinced that there is a clear ‘winner’ among splenectomy, rituximab and the TRAs for all patients. Barring a contraindication, we discuss the pros and cons of each option (Table 5) with our patients within the context of the individual’s age, comorbidities, lifestyle, financial considerations, values and preferences. The goals of this conversation are to empower patients to actively participate in the decision-making process and to arrive at an individualized treatment plan with which they feel most comfortable. Because long-term remissions are most likely to occur in the first year after diagnosis [46,88], we generally recommend deferral of splenectomy until a chronic disease course has been established. Increasingly, patients in our practice and elsewhere are opting for medical therapy over splenectomy , although the use of TRAs prior to splenectomy remains off-label in some jurisdictions (e.g. European Union).
Table 5. Major pros and cons of second-line treatment options
|Splenectomy||Best chance for long-term remission |
Extensive long-term safety data available
|Need for surgery |
Increased risk of infection
Limited ability to predict whether an individual patient will respond
|Rituximab||Completion of treatment after 4 weeks |
|Least chance for long-term response |
Longer median time to response than other options
Low but non-negligible risk of serious infection
|High response rates |
|Need for ongoing treatment and monitoring in most patients |
Encouraging but limited long-term safety data
More costly than other options
Romiplostim requires weekly SC injection in a physician’s office
Eltrombopag must be taken 1–2 h removed from meals and 4 h removed from foods or supplements containing polyvalent cations