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New Treatments for Chronic Idiopathic Thrombocytopenic Purpura. Part 1. Romiplostim

April 2010 Vol 3, No 2

Although thrombocytopenia is a common problem in patients with cancer, idiopathic thrombocytopenic purpura (ITP) is relatively rare and is difficult to treat when duration exceeds 6 months. ITP can be either acute (duration ≤6 months) or chronic, can occur in both adults and children, and can be primary or secondary to another disorder, including the malignancy.

Primary chronic ITP is an autoimmune condition occurring more frequently in adults, which results from antibody-mediated platelet destruction and is characterized by a depressed platelet count and mucocutaneous bleeding.1,2 Although the stimulus for these antiplatelet antibodies in primary chronic ITP remains largely unknown, the goals of therapy include maintaining a platelet count above 50,000/mm3 to avoid life-threatening hemorrhagic complications.

Corticosteroids are a mainstay of therapy and are generally used as first-line therapy. Response rates range from 50% to 75%, but continued remission ranges from only 5% to 30%.2 Other options available for the management of ITP include rituximab, intravenous immunoglobulin, danazol, cyclophosphamide, immunosuppressive agents (eg, azathioprine, cyclosporine), and splenectomy, which all elicit varying degrees of responsiveness and have significant adverse effects limiting quality of life. Whereas splenectomy is regarded as the single best treatment approach for refractory patients, 30% to 40% of patients have platelet counts <50,000 × 109/L after the procedure, necessitating new options for salvage treatment with the goal of maintaining hemostasis.2

Traditional therapies for ITP have aimed at inhibiting the production of antiplatelet antibodies; however, the majority of patients with chronic ITP also have impaired platelet production in the presence of normal thrombopoietin (TPO) levels.3 Therefore, secondgeneration thrombopoiesis-stimulating agents have focused on methods to stimulate the TPO receptor, with minimal im munogenicity and no structural similarities to endogenous TPO. Romiplostim is the first US Food and Drug Ad ministration (FDA)-approved thrombopoiesis-stimulating agent and is in dicated in patients who have had in adequate response to corticoste roids, immunoglobulins, or splenectomy.4 Romiplostim is a recombinant protein that binds to the TPO receptor, stimulating platelet production. It bears no structural resemblance to endogenous TPO, thus escaping im mune recognition.

Supporting evidence
Results of two prospective, multinational, double-blind, phase 3 studies were recently published in a single manuscript, and serve as the foundation for which the approval of romiplostim was granted.3 The trials were of similar design, and data were combined for analysis. Both trials compared the efficacy of romiplostim with placebo (randomized 2:1) in patients with ITP. One trial enrolled patients after splenectomy, and the other enrolled nonsplenectomized patients; otherwise the eligibility was identical and included a mean platelet count <30 × 109/L, no active malignancy or history of stem-cell disorder, normal organ function, and a hemoglobin level >9 g/dL. Continuation of concurrent therapies for ITP was permitted at a constant dose and schedule, and other "rescue" medications were allowed at any point of the study if needed. The starting dose of romiplostim was 1 µg/kg administered subcutaneously once weekly and was titrated to maintain a platelet count of 50 × 109/L to 200 × 109/L. Platelet response was defined as a platelet count of ≥50 × 109/L at a weekly study visit. The primary efficacy measure for the study was a durable response, defined as weekly platelet responses during 6 or more of the final 8 weeks of evaluation.

At the end of 24 weeks, more patients randomized to romiplostim than to placebo experienced a durable response to therapy (splenectomized patients, 38% vs 0%, P = .0013; nonsplenectomized patients, 61% vs 4.8%, P <.0001; all patients, 49% vs 2%, P value not stated; respectively). Also, significantly more patients in the placebo group required rescue medications for persistent thrombocytopenia (59.5% vs 21.7%, P <.0001). In splenectomized and nonsplenecto mized patients, the median dose of romiplostim during the study was 2 µg/kg (1 µg/kg-3 µg/kg) and 3 µg/kg (2 µg/kg-7 µg/kg), respectively. However, doses required to maintain platelet counts varied widely between patients in both studies.3

Dosage, administration, and toxicity

It is recommended that the lowest possible dose of romiplostim be employed to maintain a platelet count of 50 × 109/L; the agent should not be used to try to normalize a patient's platelet count.4 The initial dose of romiplostim is 1 µg/kg based on actual body weight, administered subcutaneously once weekly. Monitoring parameters and strategies for dose modification can be found in the Table.

Romiplostim is supplied as 250-µg or 500-µg single-use vials of powder for reconstitution. After it is adequately mixed with preservative-free sterile water, a clear, colorless solution containing 500 µg/mL romiplostim should result. Because the final volume for injection may be very small, only syringes with graduations to 0.01 mL should be used.4

The most common adverse events associated with romiplostim (occurring more frequently than placebo) were arthralgia (26% vs 20%), dizziness (17% vs 0%), insomnia (16% vs 7%), and myalgia (14% vs 2%).3,4 The most serious adverse event noted with romiplostim thus far is reticulin fiber deposition within the bone marrow. Of 271 patients, reticulin was observed on bone marrow biopsy in 10 patients. One patient treated for an extended period progressed to bone marrow fibrosis during therapy. The manufacturer advises that the peripheral blood smear should be closely scrutinized before starting romiplostim to establish a baseline level of cellular abnormality.4 Worsening thrombocytopenia after discontinuation of romiplostim has been documented, and in several cases, platelet counts have fallen below baseline levels. Thrombotic complications and carcinogenesis are also potentially serious complications associated with romiplostim. As with all new drugs, the true incidence of these severe adverse events cannot be precisely quantified until more experience is gained with the agent.

Restricted distribution program and medication guide
To assure the appropriate use and safety of romiplostim, the agent is available only via the Network of Experts Understanding and Supporting Nplate and Patients (NEXUS) Program. NEXUS is considered a risk evaluation and mitigation strategy and was a condition that the manufacturer agreed to for the drug to gain FDA approval.5Twice yearly, healthcare providers are contacted by a NEXUS specialist to verify the patient enrollment roster, collect safety information, and discuss whether it is appropriate for each enrolled patient to continue receiving romiplostim. Pre scribers who are enrolled must complete enrollment and baseline data forms for each new patient prescribed romiplostim. The appropriate forms can be found on the NEXUS website.6 Healthcare institutions must enroll separately.

The manufacturer of romiplostim, Amgen, has also incorporated a mandatory medication guide into the risk management program, which is to be distributed to patients along with proper counseling prior to each dose of romiplostim. The most updated medication guide can be downloaded from the NEXUS website.7 Serious adverse events resulting from romiplostim therapy should immediately be reported to Amgen (877-675-2831) or the FDA (800-FDA-1088).

Romiplostim is a novel, thrombopoiesis-stimulating agent that has demonstrated substantial efficacy in patients with refractory chronic ITP. Although the long-term safety of romiplostim has not been clearly established, this agent appears to be relatively welltolerated in the majority of patients, but serious complications do occur and careful monitoring is necessary. The NEXUS risk management program should be beneficial in facilitating consistent monitoring and establishing the romiplostim risk-benefit profile. Favorable results in patients with ITP have encouraged investigation of use of romiplostim in other forms of thrombocytopenia, including thrombocytopenia secondary to myelo dysplastic syndrome or chemotherapy.8 The safety of romiplostim must first be established in these groups of patients, however, before widespread use is advocated, and reimbursement for this novel agent will be limited to FDA approved indications.


  1. Cines DB, Blanchette V. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995-1008.
  2. Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood. 2005; 106:2244-2251.
  3. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395-403.
  4. Nplate (romiplostim) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2008.
  5. Thompson CA. FDA approves thrombopoiesis-stimulating agent. Am J Health Syst Pharm. 2008;65:1788.
  6. Enrollment. How do I enroll in the Nplate NEXUS program? Accessed October 11, 2008.
  7. Medication guide. Nplate (romiplostim). Accessed October 11, 2008.
  8. Levy B, Arnason JE, Bussel JB. The use of secondgeneration thrombopoietic agents for chemotherapy-induced thrombocytopenia. Curr Opin Oncol. 2008;20:690-696.


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