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Considerations for Treatment of Immune Thrombocytopenia

September 2012, Vol 5, No 6

SG is a 29-year-old female, recently married, who was referred to the hematology clinic due to a platelet count of 11 × 109/L. Additionally, she recently had 3 nosebleeds and heavy menstrual bleeding. She had dismissed them as another sign of stress from her hectic schedule, including her recent wedding, teaching full-time, and evening graduate school. A detailed and extensive review of her history and physical, serum chemistries, CBC, and peripheral smear does not reveal any potential underlying causes for her thrombocytopenia. She is negative for HCV and HIV, and her blood type is AB negative. Because her platelet count is <100 × 109/L without an identifiable cause, she is diagnosed with primary immune thrombocytopenia. What are considerations for appropriate first-line therapy?

Regardless of the stage of immune thrombocytopenia (ITP), previously referred to as idiopathic thrombocytopenic purpura, treatment decisions must take into account an individual’s preferences as well as comorbidities, bleeding, the urgency to increase the platelet count, and potential advantages and adverse effects of each treatment. The goal of therapy is to prevent major bleeding, and because most major bleeds are associated with platelet counts <20-30 × 109/L, treatment is generally instituted at a platelet level <30 × 109/L. In this patient with newly diagnosed (within 3 months of diagnosis) ITP requiring initial therapy, evidence-based practice guidelines suggest prednisone 1 mg/kg daily for 21 days with a subsequent taper.1 Other acceptable options include dexamethasone 40 mg PO daily for 4 days, or intravenous immunoglobulin (IVIg) 1 g/kg × 1; however, the longer course of corticosteroids is preferable due to longer response. Though anti-D Ig has demonstrated efficacy, SG would not be a candidate because she is Rh-negative. Anti-D therapy also carries a risk of severe hemolysis and should be used only in carefully selected patients.1

As SG did not have any contraindications to steroid therapy (eg, uncontrolled diabetes mellitus, active infection), she received a 21-day course of prednisone, which was quickly tapered over the subsequent week. One month after starting therapy, her platelet count increased to >100 × 109/L, with no further bleeding episodes for the next 2 months. At that time, her platelet count had dropped to 9 × 109/L. She received IVIg 1 g/kg × 1, which increased her platelet count to 35 × 109/L one week later. Does she need further therapy, and if so, what options does she have at this time?

Because of her young age, lack of recent bleeding episodes, and platelet count >30 × 109/L, SG does not receive further treatment, but again receives extensive counseling regarding monitoring for signs and symptoms of bleeding and use of bleeding precautions. Though IVIg rapidly increases the platelet count, response is not durable, typically lasting only 2 to 4 weeks.2 SG begins wearing a stylish medical alert bracelet, a present from her husband.

Four months later she reports mucosal bleeding (nosebleed and gum bleeding), and her platelet count has dropped to 7 × 109/L. She and her husband are very anxious and would like to know her options for treatment at this time.

The 2011 American Society of Hematology evidence-based guidelines recommend either a splenectomy for patients failing corticosteroid therapy (grade 1B) or a thrombopoietin receptor agonist (romiplostim or eltrombopag) if the patient has relapsed after splenectomy or has a contraindication to splenectomy and has failed ≥1 other therapy (1B). Other options include romiplostim or eltrombopag in a patient who has failed ≥1 other therapy and has not undergone splenectomy, or ri­­tuximab in a patient who has failed ≥1 other therapy such as corticosteroids, IVIg, or splenectomy, though the strength of these recommendations is lower (grade 2C).1

For several decades, splenectomy has been considered the gold standard for second-line treatment of ITP. The major advantage of a splenectomy is that approximately two-thirds of patients achieve a long-term response of at least 5 to 10 years.3 Laparoscopic splenectomy is associated with fewer complications than open splenectomy and is often the preferred approach in appropriate patients. The major risks associated with splenectomy include bleeding and infections. Additional com­plications include transfusion-related adverse events, thrombosis requiring anticoagulant therapy, adhesions/obstruction, hernia formation, and nerve palsies. To minimize risk of infection, all patients should receive recommended immunizations preoperatively (at least pneumococcal, meningococcal, and Haemophilus influenzae) as well as extensive counseling regarding the need for early detection and treatment for infections.4 Because patients may spontaneously go into remission, splenectomy may be deferred until 1 to 2 years after diagnosis, but there are no specific recommendations for optimal timing. This patient is young and without comorbidities, and she would likely tolerate a splenectomy.

Though splenectomy is not a contraindication, SG does not want to undergo surgery at this time, due to her busy work and school schedules. She and her husband have done much research on the Internet and have many questions about the potential benefits and risks associated with the thrombopoietin receptor agonists. She is 7 months postdiagnosis and is considered to have persistent ITP, as she has not had a spontaneous remission or a complete response to therapy. What are considerations before initiating romiplostim or eltrombopag therapy?

Both romiplostim and eltrombopag have demonstrated efficacy in both splenectomized and nonsplenectomized patients.5,6 In a prospective, randomized, open-label study of 234 patients with ITP without splenectomy, Kuter and colleagues assigned 157 patients to weekly romiplostim and 77 patients to standard of care for 52 weeks.6 The treatment in the standard-of-care arm was left to the investigator’s decision. The group receiving romiplostim exhibited a significantly lower incidence of treatment failure than those receiving standard of care (11% vs 30%, respectively; P <.001), and they were less likely to require a splenectomy (9% vs 36%, respectively; P <.001). The rate of platelet response (to a level >50 × 109/L) was 2.3 times that in the standard-of-care arm, and fewer patients required blood transfusions (8% vs 17%). At any given time between weeks 2 and 52, 71% to 92% of patients had an adequate platelet response. This study did allow short-term treatment with other therapies (most commonly glucocorticoids), which was required in 44% of the romiplostim group versus 79% of those receiving standard of care.

Despite the evidence that romiplostim is effective, there are important considerations before initiating therapy. Romiplostim is given as a subcutaneous injection and requires weekly platelet counts until dosage is stabilized. For some, this may be an inconvenience or burden that would rule out this therapy. Compliance is particularly important, because upon discontinuation of romiplostim, the platelet count will likely drop, in some cases to levels lower than when initiated. Cost is usually an additional factor, and depending on the insurance coverage and copays, the patient may be responsible for extraordinary out-of-pocket copays. There are excellent patient assistance programs to help qualified patients with expenses, and these should be fully investigated before ruling out this therapy based on cost alone.

For most people receiving romiplostim, the dose usually stabilizes after the first 12 weeks or so, and frequency of platelet counts may be extended to once every 4 weeks. In an open-label extension study, 63% of patients were stabilized on a dosage and were able to self-administer romiplostim at home.7 Although this would provide a convenient option for appropriate patients, self-administration of romiplostim is not approved by the US Food and Drug Administration at this time.8 From 2008 to 2011, romiplostim was available only through the restrictive Nplate NEXUS (REMS) Program, which required enrollment of the patient, prescriber, and pharmacy. Since termination of the program in 2011, however, any prescriber or institution can now order romiplostim, allowing for greater flexibility for patients to obtain treatment.9

In the short term, romiplostim is well tolerated, with primary side effects being headache, fatigue, arthralgia, insomnia, myalgia, and dyspepsia.8 A significant concern is formation of reticulin and development of fibrosis in the bone marrow; the long-term incidence and significance of this is unknown at this time.8 Other serious, yet rare, potential risks include development of thrombosis from elevated counts. For these reasons, romiplostim should be used only at the lowest dosage necessary to minimize bleeding by maintaining the platelet count >50,000 × 109; it is not the goal of romiplostim therapy to normalize the platelet count.8

Another concern for this patient is that romiplostim is not indicated during pregnancy and should be discontinued beforehand. Romiplostim crosses the placenta, though the effects on the fetus are unknown at this time.8 Current evidence-based guidelines suggest treatment with corticosteroids or IVIg during pregnancy and lactation.1 There are a multitude of additional considerations regarding ITP and pregnancy and delivery, and these should be discussed and planned for with experienced physicians.

In addition to romiplostim, several other second-line treatment options are available to treat ITP, including eltrombopag, rituximab, azathioprine, cyclosporine A, cyclophosphamide, mycophenolate mofetil, danazol, dapsone, vinblastine, and vincristine.1,2 Eltrombopag, an oral agent taken once daily, also demonstrates efficacy and toxicities similar to romiplostim, with the exception of an increased incidence of elevated liver function tests, requiring close monitoring.1,3 Rituximab, a CD20 monoclonal antibody typically administered once weekly for 4 weeks, also has demonstrated efficacy, with reports of long-term response. Concerns with rituximab include infusion reactions and increased infections.3 Many of the studies for the additional agents are small and nonrandomized, using many different inclusion, exclusion, and assessment criteria. Thus, the heterogeneity of the data makes it difficult to confidently predict outcomes with many of these treatment options.

Fortunately for patients with ITP, there are more options than ever for treatment. When deciding on a course of therapy, the pros and cons of each option should be discussed with the patient, and a realistic plan should be formulated. Treatment decisions may be heavily influenced by patient preferences, as well as lifestyle, socioeconomic, and other practical considerations, in addition to existing comorbidities. As we do not have a means to predict who will have the best responses with the least toxicity, the approach to ITP treatment remains individualized.3

SG and her husband elect to begin therapy with romiplostim. She works near the clinic, and brief weekly visits will not be a burden, particularly if she has her platelet count drawn the day before her injection, omitting the need to wait for results. Her insurance covers the costs with minimal copay. The couple are diligent about using effective contraception and do not plan to have children for a few years. They continue to hope she will achieve a remission and that the romiplostim will buy them this time to perhaps avoid splenectomy, to plan for splenectomy at a better time, or to await for additional treatment options.


  1. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011; 117(16):4190-4207
  2. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115 (2):168-186.
  3. Ghanima W, Godeau B, Cines DB, et al. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood. 2012;120(5):960-969.
  4. Stasi R, Newland A, Thornton P, et al. Should medical treatment options be exhausted before splenectomy is performed in adult ITP patients?: a debate. Ann Hematol. 2010;89(12):1185-1195.
  5. Imbach P, Crowther M. Thrombopoietin-receptor agonists for primary immune thrombocytopenia. N Engl J Med. 2011;365(8):734-741.
  6. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010;363(20):1889-1899.
  7. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113(10):2161-2171.
  8. Nplate [package insert]. Thousand Oaks, CA: Amgen Inc; December 2011.
  9. Amgen Inc. Important prescribing information: Nplate® (romiplostim) REMS Program (Nplate® NEXUS Program): elimination of prescriber, institution, and patient enrollment requirements to prescribe and receive Nplate; serious risks associated with Nplate [letter]. Published December 6, 2011. Accessed September 4, 2012.

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