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Frequently Asked Questions

What is the role of romiplostim for the treatment of ITP?

Background
Immune thrombocytopenic purpura (ITP) is a disorder characterized by low platelet counts (less than 50,000 cells/mm3) and subsequent risk of mucocutaneous bleeding.1 It occurs yearly in 100 people per million, half of whom are children.2 The acronym ITP is also referred to as idiopathic thrombocytopenic purpura because in many cases the pathophysiologic cause is unknown; however, it has been theorized that ITP is caused by antibodies against platelets and premature T-cell mediated platelet destruction. The disorder can be characterized by duration of low platelet counts; acute ITP is present for less than 6 months, and patients with chronic ITP maintain low platelets and increased bleeding risk for more than 6 months. No specific criteria for the diagnosis of ITP are recognized; diagnosis depends on the exclusion of other etiologies of thrombocytopenia.4

The practice guidelines for this condition were published by the American Society of Hematology in 1996 and the British Committee for Standards in Hematology in 2003. 3,4 Due to the lack of randomized and controlled studies in patients with ITP, both of these publications rely heavily on expert consensus for treatment rather than clinical evidence.4,5 Until recently, the available clinical data for treatment of ITP was limited to non-controlled case series in heterogeneous patient populations.

Not all patients require treatment; however, treatment should be provided in the setting of severe thrombocytopenia (platelets < 20 to 30 cells/mm3), or with less severe thrombocytopenia (<50 cells/mm3) and risk factors for bleeding including hypertension, peptic ulcer disease, or a vigorous lifestyle.4 Options for medical management include corticosteroids, intravenous immune globulin (IVIG), rituximab, and cyclophosphamide. Platelet transfusions are an option for emergent thrombocytopenia, but this approach may not raise platelet levels if the underlying pathology involves platelet destruction. The most definitive treatment for chronic ITP is splenectomy, however 30% to 40% of patients will not respond or will experience relapse after splenectomy.2 Despite the availability of multiple treatments, duration of remission with medical therapy remains low (5% to 30%).

Romiplostim is only available from the manufacturer through a limited access program called NEXUS, which sends the product directly to the physician for administration in the clinic setting.6 http://www.nplatenexus.com/

Romiplostim is the first medication to receive FDA approval for the treatment of ITP, which represents an advance in the therapies available for this condition. It is a protein that acts as an agonist at the thrombopoietin receptor to stimulate thrombopoiesis, the end result of which is the production of platelets. The dose is based on actual body weight (1 mcg/kg) and may be adjusted in increments of 1 mcg/kg to a maximum dose of 15 mcg/kg to achieve the therapeutic target of platelets >50 cells/mm3, which significantly reduces bleeding risk. Romiplostim is injected subcutaneously once weekly and has a median elimination half-life of 3.5 days. Elimination rate depends on the number of thrombopoietin receptors on circulating platelets and the extent of ongoing platelet destruction.

Literature review
The efficacy and safety of romiplostim in patients with chronic ITP was evaluated in 2 parallel, prospective, randomized, double-blind, placebo controlled trials by Kuter and colleagues.7 Patients were included if they had platelets <30 cells/mm3 and excluded in cases of active malignancy, history of stem cell disorders, evidence of renal or hepatic dysfunction, or anemia. Average baseline platelet count was 16 cells/mm3 (range 2 to 31 cells/mm3), and 79 (63%) of 125 patients had previously received ITP therapy with 39 (31%) currently taking ITP medications. After stratification based on prior splenectomy, patients were randomized to romiplostim or placebo subcutaneously once weekly for 24 weeks and were also allowed to receive treatment with corticosteroids, azathioprine, or danazol at stable doses. Romiplostim doses were titrated based on weekly platelet response to achieve goal platelet counts 50 to 200 cells/mm3. Patients were followed for 36 weeks or until platelets dropped to <50 cells/mm3. The primary efficacy outcome was durable platelet response. Secondary outcomes included transient platelet response, frequency of overall platelet response, number of weekly platelet responses, proportion of patients requiring rescue medications, frequency of durable platelet response with a stable romiplostim dose, and changes in concurrent ITP therapies. Data were analyzed according to a per protocol analysis.

The efficacy results of these studies are presented below.


Table 1. Efficacy outcomes for romiplostim compared to placebo.7   
a Durable platelet response defined as response during 6 or more weeks of the final 8 weeks of treatment. b Overall platelet response defined as durable plus transient (4 or more weekly responses during study weeks 2-25). c In both studies, 23 patients receiving romiplostim and 16 patients receiving placebo received concurrent ITP medications.

There were several notable findings of this study. First, patients achieving durable platelet response required lower median doses than those who did not achieve this response (3 mcg/kg/week compared to 5.3 mcg/kg/week). It should also be noted that platelet response was not maintained after discontinuation of therapy. Within 2 weeks of discontinuing romiplostim 37 (73%) of 51 patients who previously responded had platelets <50 cells/mm3, and 12 weeks following discontinuation only 7 patients who had received romiplostim maintained platelets >50 cells/mm3. Finally, multivariate analysis demonstrated that baseline weight <70 kg was associated with increased durable response (p=0.0106), greater number of weeks with platelet response (p=0.008), and less use of rescue drugs (p=0.0285).

Adverse effects were reported in 100% of romiplostim patients and 95% of placebo patients. The most commonly reported adverse events in both groups were headache, fatigue, epistaxis, and arthralgia. Adverse events reported more frequently in the romiplostim group compared to the placebo group included dizziness (17% vs. 0%), abdominal pain (11% vs. 0%), myalgia (14% vs. 2%), insomnia (16% vs. 7%), and pain in the extremities (13% vs. 5%). The authors stated that p-values for adverse effects were not reported because significance could not be assessed in such a small study population. Significant bleeding events (severe, life-threatening, or fatal) occurred in 6 (7%) of 84 patients receiving romiplostim compared with 5 (12%) of 41 in the placebo group. Two severe adverse events were reported in patients receiving romiplostim—bone marrow reticulin formation in 1 patient, and new-onset thromboembolism in 2 patients with previous history of vascular disease who had platelets above their baseline at the time of clot formation. No patients discontinued romiplostim due to adverse events.

The authors concluded that romiplostim was well-tolerated and resulted in platelet increases within 1 to 2 weeks that were sustained for 6 months. They stated that overall response in >80% of patients was similar or higher to response rates to other ITP medications (corticosteroids, IVIG, azathioprine, danazol, and splenectomy), which was significant in this study since most of the patients were refractory to conventional treatments. The authors speculated that the individual variation in response to romiplostim, varying dose requirements, and inability of all patients to achieve a durable response may be due to innate cycling of platelet counts, variations in antiplatelet antibodies, or variations in pharmacokinetics and dynamics (which may be influenced by patient weight). These possibilities remain an area of future study.

The available data about romiplostim raises new questions to be addressed in future publications and research studies, specifically the relationship between patient weight and response to romiplostim, reasons for individualized dosing requirements, and continued monitoring for adverse effects as more patients are exposed to this medication. Clinical trials are currently underway to assess the efficacy of romiplostim long-term (96 weeks), compared to other active treatments, and in other populations (myelodysplastic syndromes, pediatric patients with ITP). In addition, there are multiple other thrombopoietic growth factors in development including an oral agent (eltrombopag) currently in Phase III trials.2

Conclusion
In summary, romiplostim resulted in statistically and clinically increased platelet counts compared to placebo and decreased requirements for concomitant ITP therapies. This treatment is effective for managing thrombocytopenia, but the effects are transient and patients return to low platelet counts after discontinuation of treatment. In addition, romiplostim has demonstrated higher incidence of adverse effects compared to placebo, including some serious effects. The benefit of treatment with romiplostim for chronic ITP should be weighed against the risk for adverse effects, cost of long-term injectable therapy, and lack of outcome data. Based on currently published trials, the current role in therapy for romiplostim is short-term (up to 24 weeks) treatment for patients with ITP refractory to other medications. This role may expand pending results of on-going clinical trials.

References

  1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346(12):995-1008.
  2. Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109(11):4607-4616.
  3. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120(4):574–596.
  4. George JN, Woolf SH, Raskob GE et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996; 88(1):3–40.
  5. Godeau B, Provan D, Bussell J. Immune thrombocytopenic purpura in adults. Curr Opin Hematol. 2007;14(5):535-556.
  6. NPlate [package insert]. Thousand Oaks, CA: Amgen Inc; 2008.
  7. Kuter DJ, Bussel JB, Lyons RM et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomized controlled trial. Lancet. 2008;371(9610):395-403.
  8. Bussel JB, Kuter DJ, George JN et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. New Engl J Med. 2006;355(16):1672-1681.
  9. Panzer S. New therapeutic options for adult chronic immune thrombocytopenic purpura: a brief review. Vox Sanguinis. 2008;94(1):1-5.

By: Heather Ipema, PharmD