Promotional Advertisement written by Amgen, the sponsor of the study described and manufacturer of Nplate®
A summary of the Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia article previously published.3
Promotional Advertisement written by Amgen, the sponsor of the study described and manufacturer of Nplate®
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production.1 Many therapies are aimed at reducing platelet destruction.2 Treatments aimed at increasing platelet production, alone or in combination with existing therapies, provide an opportunity to improve outcomes in patients with ITP.2 The thrombopoietin mimetic Nplate® (romiplostim) is an Fc-peptide fusion protein that stimulates platelet production by binding the thrombopoietin receptor, thereby increasing the body’s natural production of platelets.3 Nplate® is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Nplate® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP. Nplate® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase their risk for bleeding. Nplate® should not be used in an attempt to normalize platelet counts.
A summary of the trial that compares Nplate® to medical standard of care (SOC) in patients with ITP published in the New England Journal of Medicine is presented. The design of the trial does not allow for the comparison of Nplate® to the individual treatments received in the SOC arm.
Thrombopoietin mimetics increase platelet count in patients with chronic ITP and reduce the risk of bleeding.2,4 Nplate®, a thrombopoietin mimetic, increases platelet production by binding to and activating the thrombopoietin receptor, a mechanism analogous to endogenous thrombopoietin.5 In patients who have had an insufficient response to corticosteroids or immunoglobulins, Nplate® may offer the potential for effective maintenance treatment in patients who wish to avoid or defer splenectomy or in whom splenectomy is contraindicated.5,7 Continuous weekly treatment with Nplate® increases platelet counts in many patients who have chronic ITP with an acceptable safety profile.4
Important Safety Information
- In Nplate® clinical trials of patients with myelodysplastic syndromes (MDS) and severe thrombocytopenia, progression from MDS to acute myelogenous leukemia (AML) has been observed. Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
- Additional serious adverse reactions associated with Nplate® are Thrombotic/Thromboembolic Complications, Bone Marrow Reticulin For-mation and Risk for Bone Marrow Fibrosis, Worsened Thrombocytopenia after Cessation of Nplate®, and Lack or Loss of Response to Nplate®.
- In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction.
Two 6-month, Phase 3 Pivotal Trials2,5
The results from the SOC study should be viewed in context with the prior pivotal, prospective, multicenter, randomized, placebo-controlled, international, double-blind phase 3 studies that evaluated Nplate® and placebo, one in splenectomized and one in nonsplenectomized patients. The primary end point was durable platelet response (weekly platelet responses of ≥ 50 × 109/L during 6 or more weeks of the last 8 weeks of treatment; no rescue therapy at any time during study). The secondary end point was overall platelet response (durable plus transient* rates of platelet response).
In nonsplenectomized patients:
- Durable platelet response was 61% (25/41) of patients on Nplate® versus 5% (1/21) of the control group (P < 0.0001).
- Overall platelet response was 88% (36/41) of patients on Nplate® versus 14% (3/21) of the control group (P < 0.0001).
In splenectomized patients:
- Durable platelet response was 38% (16/42) of patients on Nplate® versus 0% (0/21) of the control group (P = 0.0013).2
- Overall platelet response was 79% (33/42) of patients on Nplate® versus 0% (0/21) of the control group (P < 0.0001).
In the pivotal trials for Nplate®, prior ITP treatments in the Nplate® and control groups included corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine. Patients receiving corticosteroids, azathioprine or danazol at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the studies.
The recommended starting dose for Nplate® is 1 µg/kg. See the Nplate® prescribing information for complete dosing instructions, including guidelines for dose adjustments. In the pivotal trials, the median dose of Nplate® was 2 µg/kg (25th–75th percentile: 1–3 µg/kg) in the study of nonsplenectomized patients and 3 µg/kg (25th–75th percentile: 2–7 µg/kg) in the study of splenectomized patients.
- This was a multicenter, randomized, controlled, 52-week, open-label study designed to assess the efficacy and safety of Nplate® or SOC in adult patients with ITP.
- Patients were randomized, in a 2:1 ratio, to receive Nplate® (n=157) or SOC (n=77).
*Four or more weekly platelet responses without a durable platelet response from week 2 to 25.
- The clinical diagnosis of ITP was based on a platelet count < 150 × 109/L without any other clearly associated cause.
- Patients must not have undergone splenectomy.
- Patients with a history of ≥ 1 type of therapy for ITP and a pretreatment platelet count of < 50 × 109/L.
- A bone marrow–biopsy specimen was required to confirm the diagnosis of ITP in patients > 60 years of age.
- Key exclusion criteria were previous splenectomy, active cancer or stem cell disorder, history of cancer, previous exposure to a thrombopoietin mimetic, pregnancy, and lactation.
- At the time of enrollment, patients could have been receiving any therapy for ITP, except experimental treatments.
- Median duration of treatment for ITP at the time of study entry was approximately 2 years, but 36% of patients (85/234) entered the study after having ITP for a year or less (median duration in this subgroup, 0.25 years).
- Treatment groups did not differ significantly with respect to any baseline characteristics.
- Median age across the 2 groups was 57 years (with 36% of patients > 65 years of age and 18% > 75 years).
1-Year Randomized, Controlled, Open-Label Trial to Evaluate Nplate® or Medical SOC in Nonsplenectomized Adult Patients Diagnosed with ITP3
Primary and Secondary End Points3
- There were 2 coprimary end points:
— Incidence of treatment failure was defined as a platelet count of ≤ 20 × 109/L for 4 consecutive weeks at the highest recommended dose, a major bleeding event, or requirement for a change in therapy (including splenectomy) because of an adverse event (AE) or bleeding symptom.
— Incidence of splenectomy.
— A patient who had received any study treatment and had then discontinued the study was counted as having had both treatment failure and splenectomy.
- Secondary efficacy end points included:
— Time to splenectomy
— Platelet count
— Platelet response (platelet count > 50 × 109/L at any scheduled visit, excluding counts obtained after discontinuation of the randomized treatment or within 8 weeks after receipt of rescue medications)
- Safety end points: bleeding events, blood-product transfusions, and laboratory results
Study Results3: Platelet Count Over 1 Year
The mean platelet count was higher in the romiplostim group than in the SOC group throughout the treatment period.
- Platelet response from week 2 through the end of the 1-year treatment period ranged from 71% (108/152 patients) to 92% (127/138 patients) in the romiplostim group and 26% (16/62 patients) to 51% (26/51 patients) in the SOC group.
- Median platelet count was 108 × 109/L to 176 × 109/L in the romiplostim group and 35 × 109/L to 52 × 109/L in the SOC group.
- The mean (± standard error) weekly dose was 3.9 ± 2.1 µg/kg.
Patients in the Nplate® Group Were 2.3 Times as Likely to Have a Platelet Response as Those in the SOC Group (95% confidence interval, 2.0-2.6; P < 0.001)
Treatment Failure and Splenectomy
The incidence of treatment failure was significantly lower among patients receiving romiplostim (18/157 [11%]) than among those receiving SOC (23/77 [30%], P < 0.001).
The time to treatment failure was significantly longer in the Nplate® group than in the SOC group (P = 0.02).
Incidence of splenectomy was significantly lower among patients receiving romiplostim (14/157 [9%]) than among those receiving SOC (28/77 [36%], P < 0.001). Time to splenectomy was also significantly longer in the romiplostim group than in the SOC group (P < 0.001).
Throughout the study, all patients could receive additional therapies for ITP (including short-term rescue therapies, such as intravenous immune globulin, but excluding other thrombopoietin mimetics and investigational products) if they were deemed medically necessary by the investigator.
- Headache and fatigue were the most common AEs reported during treatment.
- SAEs occurred in 23% of patients (35/154) receiving Nplate® and in 37% of patients (28/75) receiving SOC.
- Treatment-related SAEs occurred in 5% of patients (7/154) receiving Nplate® and 8% of patients (6/75) receiving SOC.
- Treatment-related SAEs reported in > 1 subject in the Nplate® group included pulmonary embolism (3 subjects) and deep vein thrombosis (2 subjects).3
- Thrombocytopenia was the most common SAE, occurring in 3% of patients (5/154) receiving Nplate® and in 12% of patients (9/75) receiving SOC.
- The Nplate® group had significantly lower adjusted incidences of overall bleeding events (P = 0.001) and bleeding events of grade 3 or higher (P = 0.02) as compared with the SOC group.
- There were no significant differences between the treatment groups regarding less severe bleeding (P = 0.17).
- A total of 41 blood transfusions were administered to 12/154 patients (8%) receiving Nplate®, and 76 blood transfusions were administered to 13/75 patients (17%) receiving SOC.
- There were 3 deaths, not considered to be related to treatment, which occurred during the treatment period: 1 in the Nplate® group and 2 in the SOC group.
Nplate® is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Nplate® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP. Nplate® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. Nplate® should not be used in an attempt to normalize platelet counts.
Important Safety Information
Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia
- In Nplate® clinical trials of patients with myelodysplastic syndromes (MDS) and severe thrombocytopenia, progression from MDS to acute myelogenous leukemia (AML) has been observed.
- Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
- Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate® use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate®. Nplate® should be used with caution in patients with ITP and chronic liver disease.
- To minimize the risk for thrombotic/thrombo-embolic complications, do not use Nplate® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 × 109/L.
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis
- Nplate® administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Nplate®.
- In a clinical study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate® therapy. Clinical studies are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias.
- If new or worsening morphological abnormalities or cytopenia(s) occur, consider a bone marrow biopsy to include staining for fibrosis.
Worsened Thrombocytopenia after Cessation of Nplate®
- In clinical studies of patients with chronic ITP who had Nplate® discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia resolved within 14 days.
- Following discontinuation of Nplate®, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines.
Lack or Loss of Response to Nplate®
- Hyporesponsiveness or failure to maintain a platelet response with Nplate® should prompt a search for causative factors, including neutralizing antibodies to Nplate®.
- To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate® and thrombopoietin (TPO).
- Discontinue Nplate® if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.
- Obtain CBCs, including platelet counts, weekly during the dose adjustment phase of Nplate® therapy and then monthly following establishment of a stable Nplate® dose.
- Obtain CBCs, including platelet counts, weekly for at least two weeks following discontinuation of Nplate®.
- In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate® and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity.
- Most common adverse reactions (≥ 5% higher patient incidence in Nplate® versus placebo) were arthralgia (26%, 20%), dizziness (17%, 0%), insomnia (16%, 7%), myalgia (14%, 2%), pain in extremity (13%, 5%) , abdominal pain (11%, 0%), shoulder pain (8%, 0%), dyspepsia (7%, 0%), and paresthesia (6%, 0%).
- Nugent D, McMillan R, Nichol JL, Slichter SJ. Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production. Br J Haematol 2009;146:585-96.
- 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.
- Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010;363:1889-99. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010;363:1889-99. http://www.nejm.org/doi/full/10.1056/NEJMoa1002625. Accessed July 31, 2012.
- Kuter DJ, Bussel JB, Newland A, et al. Long-term efficacy and safety of romiplostim treatment of adult patients with chronic immune thrombocytopenia (ITP): a final report from an open-label extension study. Blood. 2010;116: Abstract 68. [Presented at 52nd American Society of Hematology Annual Meeting and Exposition; Orlando, FL; December 4-7, 2010.]
- Nplate® (romiplostim) [prescribing information]. Thousand Oaks, CA: Amgen.
- Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009;113:2161-71. [Erratum, Blood 2009b;113:4822.]
- Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168-186