Romiplostim use in ITP

Chronic immune thrombocytopenia or idiopathic thrombocytopenic purpura is a syndrome characterized by accelerated platelet destruction. In addition, more recent evidence has demonstrated that some patients also have reduced platelet formation as well. The abnormal autoimmune response to platelets may result from a loss of immunologic tolerance for self-antigens. These autoantibodies may inhibit megakaryocyte growth and maturation in the marrow as well as promote rapid platelet destruction by the reticuloendothelial system. The current therapies for ITP are primarily immunosuppressive in nature and work by suppressing the autoantibody production or by reducing the systemic clearance of the opsonized platelet.

Treatment

Lisa Lohr

The first-line therapy for symptomatic patients or those at high risk of bleeding is corticosteroids (oral prednisone 1 mg/kg to 2 mg/kg daily). However, less than 20% of patients have a long-lasting response to steroids as a single agent. For patients not responding to steroids or who face significant bleeding, IV immunoglobulin at a usual dose of 1 gm/kg daily for one to two doses is the next treatment option. There is a high response rate of about 80%, but responses tend to last up to only three to four weeks. In addition, anti-D immunoglobulin is a treatment option for patients who are Rh positive patients, which reduces the clearance of the platelets through the reticuloendothelial system.

Surgical splenectomy is another treatment option in patients who do not receive a durable response to other therapies, or patients who face catastrophic bleeding complications. Another treatment option is rituximab (Rituxan, Genentech), which eliminates B cells, including those producing the antiplatelet antibodies. Initial response rates are about 60%, with usual durations of 10 months to 12 months. Other immunosuppressive therapies are possibilities; however, all of these therapies are directed toward reducing the accelerated platelet destruction.

Thrombopoietic agents

Initial research with first generation thrombopoietic agents, such as recombinant human thrombopoietic and megakaryocyte growth and differentiation factor, were disappointing partially because of the development of auto-thrombopoietin antibodies, which could lead to paradoxical thrombocytopenia caused by the cross reactivity with native thrombopoietin. Newer second-generation thrombopoietin analogs, romiplostim (NPlate, Amgen) and eltrombopag (Promacta/Revolade, GlaxoSmithKline), have been developed. These agents stimulate the thrombopoietin receptor and increase platelet production. Eltrombopag and romiplostim were recently approved for the treatment of patients with chronic refractory ITP.

Romiplostim

Romiplostim is a novel recombinant protein that stimulates platelet production by binding to and activating the thrombopoietin receptors. It does not have sequences similar to native thrombopoietin. In initial trials, romiplostim was found to cause a dose-depending increase in platelet count. The pharmacokinetics of this agent are difficult to quantify because of the nearly undetectable serum levels at clinically relevant doses. The platelet count can increase within several days after administration and reach the maximum effect from a single dose after about two weeks. It is administered at a starting dose of 1 mcg/kg (actual body weight) subcutaneously weekly. The dose can be increased in increments of 1 mcg/kg/dose weekly to achieve a platelet count of >50 K/L. The maximum dose of romiplostim is 10 mcg/kg/dose. The median dose in patients who have not had a splenectomy is about 3 mcg/kg/dose weekly. In those patients who have already had a splenectomy, the median dose is about 5 mcg to 6 mcg/kg/dose weekly.

Clinical trial

In a recently published pivotal trial, Kuter and associates studied romiplostim in patients with chronic ITP. The trial used a 2:1 (romiplostim:placebo) randomization schedule in 63 splenectomized and 62 non-splenectomized patients. The doses of the study drug started at 1 mcg/kg/dose subcutaneously weekly, and could be increased by 1 mcg/kg to 2 mcg/kg every one to two weeks (in a fairly complex dose adjustment schedule, depending on platelet count) to achieve a platelet count of 50 K/L to 200 K/L. The primary endpoint was the proportion of patients achieving a durable platelet response, defined as weekly platelet counts >50 K/L, during six of the last eight weeks of the six-month trial. A transient platelet response was defined as fewer than four weekly platelet counts of >50 K/L in four weeks during weeks two through 26 of the trial. The major outcome measures are described in the table.

In addition, the researchers found a lower use of rescue therapies for patients receiving romiplostim as well as a higher number of weekly platelet counts >50 K/L. The variables predictive of a durable response were weight <70 kg and splenectomy status. The weight variable may indicate a pharmacokinetic difference and the splenectomy status may indicate severity of ITP.

Romiplostim was generally well tolerated. The most frequent effect reported by study patients were headache, fatigue, epistaxis and arthralgia. These effects also were reported by patients receiving placebo, although in a somewhat lower frequency. Much less commonly observed were more serious effects of bone marrow reticulin formation (one patient receiving romiplostim) and arterial thromboembolic events (two patients receiving romiplostim and one patient receiving placebo). No patients developed antibodies to either romiplostim or thrombopoietin.

Distribution and Registration

Romiplostim can be distributed only within the NPlate NEXUS program (1-877-675-2831.) Physicians, pharmacists and patients must be enrolled and registered with the program prior to starting therapy. Instantaneous initiation of therapy is not possible.

Romiplostim is available in 250 mcg and 500 mcg single-use vials that must be reconstituted prior to use and then discarded. The drug acquisition cost may vary by institution, but will be around $1,000 to $2,000 per week of therapy.

Conclusion

Romiplostim is a novel thrombopoiesis stimulating agent, with few serious adverse effects. It offers a therapeutic alternative for patients with chronic ITP whose disease cannot be controlled with traditional therapies, such as corticosteroids, IV immunoglobulin, splenectomy, rituximab and others.

A larger question unaddressed in current research is whether romiplostim would be clinically or financially feasible in the treatment of chemotherapy- or radiation-induced thrombocytopenia, especially in patients with leukemia and those receiving hematopoietic stem cell transplantation.

Lisa Lohr, PharmD, BCPS, BCOP, is Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member.

For more information:

• Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of Romiplostim in patients with chronic immune thrombocytopenia: a double-blind randomised controlled trial. Lancet. 2008;371:395-403.
• Stasi R, Evangelista ML, Stipa E, et al. Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management. Thromb Haemost. 2008;99:4-13.
• Stasi R, Evangelista RM, Amadori S. Novel thrombopoietic agents: a review of their use in idiopathic thrombocytopenic purpura. Drugs. 2008;68:901-912.