Characterized by thrombocytopenia and bleeding manifestations, particularly mucocutaneous, idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder seen in both adults and children. Although the majority of ITP cases in children are considered acute and typically resolve within 6 months often without therapy, adult ITP is generally chronic and requires therapeutic interventions to raise platelet counts.1
ITP can be associated with other disorders, including malignancy and infections, and is referred to as secondary ITP. However, the etiology of primary ITP is still largely unclear.1,2 Production of antiplatelet autoantibodies leading to platelet destruction by macrophages, coupled with the inhibition of mega - karyocyte platelet production, leads to an overall decrease in platelet counts in patients with ITP. Several studies have also demonstrated that antibody production may be driven by T-cell and Bcell clones. Because of the risk of hemorrhagic complications associated with severe thrombocytopenia, the general goal in the treatment of patients severely affected with ITP is to maintain platelet counts at or above 30 x 109/L to 50 x 109/L.
Corticosteroids have long been the first-line treatment and are considered the standard of care for the initial management of ITP. Response rates to corticosteroids range from 50% to 75%; however, this response is often short-term, and only up to 30% of patients have a prolonged response.1,3 Intravenous immunoglobulin (IVIG) is often the next step in the treatment of ITP after failure of corticosteroid therapy or development of hemorrhagic complications. Although splenectomy remains the most effective and possibly curative option for chronic ITP, with two thirds of patients having a sustained response,4 the postsurgical period can be complicated with infections, and many questions still remain regarding optimal timing and patient selection.3 Refractory ITP is defined as persistent thrombocytopenia after initial treatment including splenectomy that requires further treatment to maintain a safe platelet count. For these patients, options available include rituximab, danazol, cyclophosphamide, immunosuppressive agents (eg, cyclo sporine, azathioprine), mycophenolate mofetil, and vinca alkaloids, all of which exhibit varying degrees of effectiveness and adverse event profiles.1,4
Despite several effective treatment strategies for patients with chronic or relapsed ITP, a need for more salvage treatment options has prompted additional research on the biology of thrombopoiesis. This research has led to the development of agents that work by stimulating the production of platelets, in contrast to traditional therapies, which aim at inhibiting the production of antiplatelet antibodies. Endogenous thrombopoietin (TPO) is synthesized in the liver, releases into the circulation, and binds to TPO receptors on stem cells, progenitor cells, and platelets. Activation of these receptors leads to downstream signaling pathways and, ultimately, to proliferation of megakaryocytes, thus increasing the release of platelets into the bloodstream. Most patients with ITP have low or normal levels of endogenous TPO,5 despite the compensatory reaction that normally occurs—increasing TPO levels in situations with low platelet counts.
Initial clinical trials using thrombopoietin analogs were halted due to immunogenicity reactions and antibody formation leading to secondary thrombocytopenia and bleeding.6 Secondgeneration thrombopoiesis-stimulating agents that developed out of this setback have provided two new commercially available agents, which have minimal immunogenicity and are not structurally similar to endogenous TPO. Romiplostim was the first thrombopoiesis-stimulating agent approved by the US Food and Drug Administration, followed closely by eltrombopag for the treatment of patients with chronic ITP who have insufficient response to corticosteroids, IVIG, or splenectomy. Eltrombopag is a small-molecule, nonpeptide TPO receptor–agonist that binds to the transmembrane domain of human TPO receptors, thus inducing proliferation and differentiation of cells in the megakaryocytic lineage.7
Eltrombopag in the treatment of ITP
The results of two multicenter, randomized, double-blind, placebo-controlled trials have served as the platform for approval of eltrombopag for use in refractory ITP. The initial trial was a phase 2 dose-ranging trial designed to assess whether eltrombopag could safely increase platelet counts. This study included 118 patients with at least a 6- month history of ITP, who were at least 18 years of age (median age, 50 years), had received at least one previous therapy (47% with prior splenectomy), and had a platelet count <30 x 109/L (48% had platelet count ≤15 x 109/L) at enrollment. Patients were enrolled in a 1:1:1:1 manner into the placebo, 30-mg, 50-mg, or 75-mg eltrombopag groups to be taken orally once per day for up to 6 weeks. Maintenance immunosuppressive therapy, mainly glucocorticoids, with stable doses was allowed, but othertreatments for ITP had to be discontinued at least 2 weeks before enrollment.
In the 109 patients evaluated for efficacy data, the primary end point (platelets ≥50 x 109/L on day 43) was achieved in 11%, 28%, 70%, and 81% in the placebo, 30-mg, 50-mg, and 75- mg groups, respectively. By day 15 of therapy, more than 80% of patients in the 50-mg and 75-mg groups had reached platelet counts ≥50 x 109/L. Platelet counts rose to ≥200 x 109/L in 28 patients (26%), at which time eltrombopag was discontinued. After cessation of therapy, platelet counts re turned to near baseline levels within 2 weeks. The incidence of bleeding also de creased as platelet counts increased, particularly in the patients receiving the 50-mg and 75- mg doses of eltrombopag.8
A phase 3 trial was conducted as a follow- up to assess the efficacy, safety, and tolerability of eltrombopag 50 mg orally once per day compared with placebo. Inclusion criteria were similar in the two studies. The 114 patients enrolled were randomized 2:1 to eltrombopag therapy for up to 6 weeks or placebo. Eltrombopag could be increased to 75 mg daily after 3 weeks if platelet counts had not reached 50 x 109/L.
The primary end point (platelets ≥50 x 109/L after 6 weeks of therapy) was reached by more patients in the eltromb opag arm than the placebo arm (59% vs 16%, P <.0001). Of the 34 patients who received a dose increase to 75 mg, 29% met the primary end point; however, none of these patients reached platelet counts ≥200 x 109/L. Prior history of splenectomy, concomitant drugs for ITP, or baseline platelet count ≤15 x 109/L did not have a significant effect on response rates to eltrombopag compared with placebo. As is the goal in the treatment of ITP, a significant reduction in bleeding symptoms was seen in the treatment group compared with the placebo group (39% vs 60%, P = .029). As seen in the phase 2 trial, platelet counts returned to baseline following discontinuation of eltrombopag, as did the risk for bleeding complications.9
Dosing, administration, and toxicity
Eltrombopag should be started at a dose of 50 mg orally once per day on an empty stomach (1 hour before or 2 hours after a meal) and should be separated by at least 4 hours from antacids, calcium-rich food, and supplements containing polyvalent cations (iron, calcium, magnesium, aluminum, selenium, and zinc).7 Patients of East-Asian decent (Chinese, Japanese, Korean, and Taiwanese) should be started at 25 mg orally daily because of pharmacokinetic data showing this population had a 70% increased exposure compared with non- Asian subjects. Moderate to severe hepatic impairment (as determined by Child-Pugh criteria) will require dose reduction of eltrombopag to 25 mg orally once per day. The lowest dose of eltrombopag should be used to maintain a platelet count >50 x 109/L. Dose adjustments and monitoring parameters can be found in Table 1.
Because eltrombopag is metabolized by cytochrome P450 (CYP) 1A2, CYP2C8, and several uridine diphosphate- glucuronosyltransferases, patients receiving concomitant therapy with moderate or strong inhibitors of these metabolizers and eltrombopag should be monitored closely for signs and symptoms of excessive eltrombopag exposure. In vitro studies also show that eltrombopag is an inhibitor of the organic anion transporting polypeptide 1B1 and can increase systemic exposure to drugs that use this transport system, such as atorvastatin, fluvastatin, pravastatin, rosuvastatin, methotrexate, nateflinide, repaglinide, and rifampin. Although no specific dose reductions have been given, caution should be used with administering these drugs concomitantly.7
The most common adverse effects associated with eltrombopag use were headache, nausea, vomiting, and diarrhea. Adverse events associated with the 50-mg dose of eltrombopag combined from the two randomized studies are summarized in Table 2. The incidence of grade 3/4 adverse events during treatment in both studies was similar for patients receiving eltrombopag and placebo, 11 (7%) versus five (7%).8,9 Reticulin fiber deposition, without cytopenias, was reported in the bone marrow biopsies of seven patients. This observation prompted the manufacturer to warn prescribers to monitor patients closely by examining peripheral blood smears and to discontinue therapy if the patient develops new or worsening morphologic abnormalities or cytopenias.7 Thrombotic complications have also been observed in patients receiving eltrombopag and are likely a result of excessive increases in platelet counts.
Distribution program
Promacta Cares is a restricted distribution program that was designed to promote risk-benefit decisions before eltrombopag is dispensed to patients as well as to require prescribers to report baseline and periodic safety information for each patient enrolled. Before distribution of eltrombopag, each prescriber must complete a one-time enrollment form, which can be found on the Promacta Cares website.10 In addition, a completed enrollment form and patient baseline form must be sent in for each patient before the patient can receive the medication. Twice yearly, a consultant from Promacta Cares will contact the prescriber to collect safety information, verify the patient is still receiving eltrombopag, and verify whether the patient should continue therapy. To help establish long-term data regarding safety and use, registered prescribers must report any adverse events to the program. In particular, the risk for hepatotoxicity, bone marrow reticulin formation and fibrosis, worsened thrombocytopenia upon cessation of therapy leading to serious hemorrhage, thromboembolic/ thrombotic complications, and increased risk or progression of hematologic malignancies are the focus of the registry program. In addition to proper counseling regarding the use and side effects of eltrombopag, a mandatory medication guide must be distributed to each patient and can be found on the Promacta Cares website.10
Conclusion
With up to 10% of ITP patients developing refractory disease, the need for agents to reduce mortality from bleeding complications in this population has encouraged many researchers to delve into new mechanisms in the pathogenesis of ITP. Second-generation thrombopoiesis-stimulating agents were developed to provide an additional mechanism of increasing platelets by stimulating the production of platelets in the bloodstream. Eltrombopag has shown substantial efficacy in maintaining platelets above 50 x 109/L in patients with chronic ITP in two randomized controlled trials. Its long-term efficacy has not been established, however, as the duration of these trials was only 6 weeks. Several ongoing studies are looking at long-term use of eltrombopag in patients with chronic ITP. Preliminary data from the Eltrombopag Extended Dosing Study (EXTEND) have shown that 73% of patients with baseline platelets <30 x 109/L achieved platelet counts ≥50 x 109/L during a median treatment duration of 151 days, and the adverse event profile was similar to that in previous studies.11 The study also seeks to determine whether tapering of concomitant medications for ITP will maintain platelet counts while on eltrombopag, thus allowing patients to receive less corticosteroid therapy. Based on these favorable results, the use of eltrombopag and romiplostim is currently being studied in other disease states causing thrombocytopenia, including myelodysplastic syndrome and chemotherapy-induced thrombocytopenia.12-14 Continued research in the use of thrombopoiesisstimulating agents may identify which patients are more likely to respond to these therapies as well as determine whether these agents should be used as frontline therapy.
References
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