Evolution of treatment for adults with primary immune thrombocytopenia
Until 10 years ago, the sequence of treatments for adults with primary immune thrombocytopenia (ITP) was rarely discussed. Corticosteroids were the initial (first-line) treatment, typically with a prednisone regimen of 1 mg/kg/day. Initial treatment was considered to be appropriate for all adult patients with severe thrombocytopenia, often defined as a platelet count less than 30,000/μL, because it was assumed that ITP in adults was typically a chronic, persistent disorder, in contrast to young children in whom ITP is expected to spontaneously resolve in most patients . If corticosteroids did not induce a response, or if symptomatic thrombocytopenia recurred when they were tapered and discontinued, then splenectomy was considered to be the next appropriate (second-line) treatment . Splenectomy had a 60-year record of success for achieving durable remissions, defined by a normal platelet count with no requirement for additional treatment, in approximately two-thirds of patients [2, 3]. In fact, before the availability of corticosteroids in 1950, splenectomy had been the first-line treatment for ITP . Following failure of splenectomy, many different immunosuppressive agents and combination regimens were used (third-line), often with unsatisfactory results and substantial toxicities .
The change of management of adults with ITP during the past 10 years has been dramatic. For first-line treatment, alternative regimens of corticosteroids were proposed for initial treatment and were reported to have greater efficacy for achieving durable responses [5, 6]. For second-line treatment, rituximab began to be used as an alternative for splenectomy [7–9] Two thrombopoietin (TPO)-receptor agonists, romiplostim (Nplate®), and eltrombopag (Promacta®) have been studied in randomized clinical trials during the past 10 years in both splenectomized and nonsplenectomized adults with ITP, and have been documented to be effective for increasing platelet counts and decreasing need for other therapies [10–15]. Both agents were approved by the FDA in the United States and the EMEA in Europe for treatment of adults with ITP in 2008. In the United States, the approval was for “adults with insufficient response to corticosteroids, immunoglobulins, or splenectomy”; in Europe, the approval was more restrictive, for “splenectomized adults who are refractory to other treatments. May be considered second-line for non-splenectomized adults where surgery is contraindicated”. Although the most important clinical benefit of the TPO-receptor agonists was for patients who had failed to respond to splenectomy and rituximab (third-line treatment), it has also become an option (in the United States) as a second-line treatment, as an alternative to splenectomy and rituximab. A summary of the current common sequence of treatment options is presented in Table I.
|Indication for treatment||Treatment|
|First-line treatment||Corticosteroids: daily oral prednisone, or dexamethasone, 40 mg/d x 4 days|
|Platelet count <30,000/μL, or symptomatic bleeding||IVIg or anti-D: appropriate additional treatment for patients with overt bleeding|
|Second-line treatment (after failure of initial corticosteroid treatment)||Splenectomy|
|Platelet count <20,000/μL, or symptomatic bleeding||Rituximab|
|Third-line treatment (after failure of splenectomy and rituximab)||TPO-receptor agonists|
|Platelet count <20,000/μL, or symptomatic bleeding||Immunosuppressive agents: as adjunctive treatment if TPO-receptor agonists are insufficiently effective, or as alternative treatment if no response to TPO-receptor agonists|
First-line treatment for adults with ITP
The decision between the two current corticosteroid regimens for first-line treatment is not critical; both are effective in most patients; either may have an advantage for individual patients. Daily prednisone and pulses of high-dose dexamethasone are currently being compared in a randomized, double-blind, placebo-controlled clinical trial by the Transfusion Medicine/Hemostasis Clinical Trials Network of the National Heart, Lung, and Blood Institute (NCT00991939). A recent report described a comparison between pulses of high-dose dexamethasone with or without rituximab as first-line treatment . Dexamethasone plus rituximab had more frequent and more durable responses. However, rituximab is not mentioned as an appropriate first-line treatment by two recent systematic reviews and guidelines for management of ITP [17, 18].
Third-line treatment for adults with ITP
Similarly the decision for third-line treatment is also notcritical. TPO-receptor agonists appear to have the best record for benefit and may also have the least risk, although long-term clinical experience is still limited. Regimens of combined immunosuppressive agents may be beneficial if the response to TPO-receptor agonists is not sufficient to prevent symptoms or if an attempt to induce a remission is considered .
Second-line treatment for adults with ITP
Therefore this discussion focuses on the options for second-line treatment of adults with ITP. Because many adults will fail to achieve a durable remission with corticosteroids and may have severe and symptomatic thrombocytopenia, and because the long-term side effects of corticosteroids are unacceptable [20, 21], second-line treatment will be required in most patients. The distinctions between the three principal options are great. Table II describes the advantages and disadvantages, the benefits and risks for each of the three options: splenectomy, rituximab, and the TPO-receptor agonists. The first distinction is between treatments that can induce a remission, hopefully a durable complete remission, by modifying the disease process (splenectomy, rituximab) and treatments that provide symptomatic benefit by maintaining higher platelet counts as long as treatment is continued to prevent bleeding symptoms without modifying the disease process (TPO-receptor agonists). If disease-modifying treatment is selected, then the second distinction is between splenectomy and rituximab.
|Splenectomy||1. The first effective treatment for ITP, with over 60 years of experience||1. Surgical procedure has a 0.2% mortality and 10% frequency of complications|
|2. The most effective treatment for ITP, with 66% durable complete remissions and an additional 22% partial remissions||2. Rare occurrence of overwhelming pneumococcal sepsis years after splenectomy|
|3. Possible increased risk for arterial or venous thrombosis|
|Rituximab||1. Nonsurgical treatment||1. Reported follow-up durations are short; 10–20% of patients may relapse within 2 years.|
|2. Extensive experience since first reported use for ITP, 1999||2. Severe toxicities (anaphylactic, serum sickness, pulmonary, infectious) in 2–6% of patients|
|3. Initial platelet count response in 31–63% of patients; responses at 2 years with no additional treatment in 31%|
|TPO-receptor agonists||1. Nonsurgical treatment||1. Long-term, perhaps permanent, treatment is anticipated; platelet count is supported but clinical course of ITP is apparently not modified|
|2. Daily oral agent, or weekly subcutaneous injection with the potential for self-administration||2. Long-term risks have not been sufficiently documented. 3. Potential risks are marrow fibrosis and thrombosis; hepatic and ocular toxicities have been reported with eltrombopag|
|3. Platelet count response in approximately 80% of patients, including patients who have failed splenectomy and rituximab|
The potential benefits of splenectomy are clear. Splenectomy was the first effective treatment and is still the most effective treatment for ITP . The biologic rationale for the principal role of the spleen in the pathogenesis of ITP was documented 50 years ago in studies of infusions of ITP plasma into normal subjects to induce thrombocytopenia . Subjects who had had a splenectomy required six-fold more plasma to achieve the same degree of thrombocytopenia . In a systematic review of all 130 articles reporting 15 or more consecutive patients who had splenectomy for ITP across 58 years, splenectomy consistently achieved a complete remission (defined as a normal platelet count requiring no further treatment for the duration of observation, 1–153 months; median 29 months) in 66% of patients; a partial response occurred in an additional 22% of patients; recurrence of ITP was uncommon, documented by consistent rates of complete remissions across all case series regardless of the duration of follow-up . No presurgical parameter other than age predicted the response to splenectomy; younger patients responded better . A recent report suggested that 111In-labeled autologous platelet scanning can predict which patients will not respond to splenectomy , but a systematic review of all reports of 111In-labeled autologous platelet scanning concluded that the results did not provide sufficient evidence to support a decision to proceed with or withhold splenectomy . Surgical complications are less common with current practice of laparoscopic procedures, but are still significant. Surgery-related mortality in 29 reports of laparoscopic splenectomy for ITP was 0.2% (3 of 1301 patients); complications requiring additional treatments occurred in 9.6% of patients . The long-term risks of infection and thrombosis have been emphasized as an important reason to avoid splenectomy. Although overwhelming and fatal sepsis with Streptococcus pneumoniae and related microorganisms can occur, it is extremely rare and may be prevented by appropriate immunizations and immediate treatment with appropriate antibiotics kept at home. Beyond 1 year after splenectomy for ITP, the increased relative risk for severe infection among splenectomized patients compared to ITP patients without splenectomy was not significant, 1.4 (95% CI, 1.0–2.0) . An additional concern is the long-term risk for thrombosis . Although the relative risk for venous thrombosis among patients who had had a splenectomy for ITP compared with appendectomized patients in a population-based cohort study was 2.6, the difference was not significant (95% CI 0.9–7.1) .
Less data are available to document the frequency of durable remissions and the frequency of side effects of rituximab than are available for splenectomy. A systematic review reported that a complete platelet count response (platelet count more than 150,000/μL) was achieved in 44% (95% CI, 30–58%) of patients and an overall response (platelet count more than 50,000/μL) was achieved in 63% (95% CI, 53–73%) of patients . Median response duration was only 10.5 months . Other studies have reported response rates of 31%  and 33% . The data on risks from rituximab treatment of patients with ITP are not conclusive. The systematic review reported that 10 (3.7%) of 306 patients had severe or life-threatening toxicities and 9 (2.9%) died. A study of rituximab treatment of 36 children and adolescents with chronic ITP reported that two (6%) children developed serum sickness and one (3%) developed primary varicella infection . A study of 60 adults reported one patient (2%) who developed serum sickness; this was the only patient who was required to discontinue treatment . A rare but devastating side effect of rituximab is progressive multifocal leukoencephalopathy. One report described 57 patients who developed progressive multifocal leukoencephalopathy at a median time of 5.5 months after their last dose of rituximab; 90% died; one of the 57 patients had been treated for ITP .
The TPO-receptor agonists are very effective for achieving durable increased platelet counts but this requires continuous treatment [10–15]. Patients treated with TPO-receptor agonists compared to “standard of care” (without splenectomy) had more sustained platelet count responses, less bleeding and fewer transfusions, decreased requirement for other treatments including splenectomy, and improved quality-of-life . TPO-receptor agonists are promoted as safer treatments that can avoid the toxicities of splenectomy and rituximab. Data from the clinical trials of romiplostim and eltrombopag support the safety of these agents, but the duration of their broad community use is not long, and since TPO-receptor agonists are maintenance treatments which require continued, perhaps permanent, use, more experience will be required to provide confidence of safety.
Recommendations of guidelines for treatment of ITP
The choice among these three options for second-line treatment of adults with ITP has been addressed in two recent guidelines, an International Consensus guideline  and the updated American Society of Hematology (ASH) guideline (Table III) .
|Treatments||Strength of recommendation|
|Consensus report||ASH guideline|
|TPO receptor agonists||A||2C|
|TPO receptor agonists||A||1B|
In the Consensus guideline  splenectomy was given a recommendation grade of C (evidence Level IV), the lowest level of recommendation and evidence. However, the basis for this recommendation was unclear. The statement with this recommendation was a sentence recommending to “wait at least 6 months from diagnosis before performing splenectomy due to the chance of spontaneous remission”. However no articles in the evidence tables addressed the timing of splenectomy. The previous sentence stated that “splenectomy remains the treatment option with by far the highest likelihood of producing cure”, but this sentence was not followed by a recommendation grade. The citations listed for splenectomy would correspond to a recommendation Grade of B, not a Grade of C. The ASH guideline  gave a strong recommendation (Grade 1) for splenectomy as the treatment for patients who have failed initial corticosteroid therapy supported by an intermediate level of evidence (Level B).
The Consensus guideline  gave a recommendation grade of B for treatment with rituximab, without distinction between patients who have or have not had a splenectomy. The ASH guideline  gave a weak recommendation rituximab (Grade 2) supported by a weak level of evidence (Level C). Both guidelines cited the same systematic review . The weak recommendation for rituximab by the ASH guideline was based on the relatively poor durable response rate and the relatively high frequency of adverse effects.
The Consensus guideline  gave a recommendation Grade of A for treatment with TPO-receptor agonists for patients either before or after splenectomy, based on randomized clinical trials evaluating romiplostim and eltrombopag compared to placebo in patients receiving standard of care, with or without previous splenectomy (evidence Level I) [11–13]. The ASH guideline, citing the same randomized clinical trials [11–13], distinguished between patients who have not had a splenectomy and patients who relapse after a splenectomy or in whom a splenectomy is contraindicated. The ASH guideline gave a weak recommendation (Grade 2) supported by a weak level of evidence (Level C) for patients who have not had a splenectomy. The basis for the weak recommendation was infrequent sustained remissions when treatment with TPO-receptor agonists is discontinued and the lack of long-term follow-up for adverse events. For patients who relapse after a splenectomy or in whom a splenectomy is contraindicated, TPO-receptor agonists were given a strong recommendation (Grade 1) supported by an intermediate level of evidence (Level B).