The oral thrombopoeitin receptor agonist eltrombopag is an effective, convenient treatment for chronic immune thrombocytopenia (ITP) and should be considered for patients refractory to current therapy, who have significant side effects from corticosteroid therapy, or who are not candidates for splenectomy. That is the conclusion of a six-month randomized study now available online in Lancet (doi:10.1016/S0140-6736(10)60959-2)
Eltrombopag, a once-daily, oral non-peptide agonist, already has FDA approval for treatment of chronic ITP, as does romiplostim, a peptide analogue given weekly by injection. The study was done to investigate the possibility of improving platelet counts in patients with chronic ITP with daily intake of the oral agent.
Platelet counts increased in more than 60% of patients independent of splenectomy status, and the benefits included significant falls in bleeding complications, decreased use of concomitant treatments, a lower requirement for rescue treatment, and improvements in health-related quality of life in patients who responded.
“Most responding patients maintained the response throughout the treatment period without any major side effects,” lead author Gregory Cheng, MD, of the Department of Medicine & Therapeutics at Prince of Wales Hospital, Shatin, Hong Kong said. “Moreover, the subjects had reduced bleeding symptoms and had improved quality of life.”
Dr. Cheng noted that earlier studies had been for six-weeks only, and that this is the first randomized study in ITP patients that specifically addressed the issue of improvement in quality of life.
‘The Bar Has Been Raised’
Asked for his opinion for this article, Keith McCrae, MD, Professor of Molecular Medicine at the Cleveland Clinic, said, “The bar has been raised for either one of the thrombopoeitin agents with the level of evidence in this important, randomized study.” Most practicing oncologists are already aware of these drugs, but there has been some concern about potential marrow thrombosis issues with their use, Dr. McCrae explained. “This study is reassuring that this is not a major complication.”
The patients—all at least age 18—had had primary chronic ITP for at least six months, baseline platelet counts lower than 30,000 per μL, and a previous response to at least one therapy for chronic ITP. Patients received either 50 mg of eltrombopag or matching placebo once daily for six months.
The drug dose was modified according to platelet count during treatment. Patients were assessed for response to treatment (defined as a platelet count of 50,000 to 400,000 per μL) weekly during the first six weeks and at least once every four weeks thereafter, the researchers reported.
A total of 197 patients (135 on eltrombopag, 62 on placebo) were included in the intention-to-treat analysis. In the eltrombopag group, 106 patients (79%) responded to treatment at least once during the study compared with 17 patients (28%) in the placebo group.
The odds of a response during the six-month study were higher for the eltrombopag-treated patients, Dr. Cheng noted. More than half of the patients receiving eltrombopag reduced concomitant treatment compared with about one-third of patients receiving placebo, and only 24 (18%) receiving eltrombopag needed rescue treatment compared with 25 patients (40%) on placebo.
“The clinical response to eltrombopag occurs after one to two weeks of treatment, so this is an ideal agent for raising the platelet counts of ITP patients before scheduled elective surgery,” said Dr. Cheng. Currently, these patients are given a two- to five-day course of intravenous immunoglobulin as an inpatient therapyto raise platelet counts. “Now, we can simply start the patients on eltrombopag as an outpatient therapy one to two weeks before the scheduled surgery, which is more convenient,” he said.
Patients responded to eltrombopag throughout the six months of treatment, irrespective of splenectomy status. In a post-hoc analysis, the rate of durable response to eltrombopag was high in both non-splenectomized (66%) and splenectomized (51%) patients, said Dr Cheng, who noted that this is in contrast to the 40% durable response rate with the use of romiplostim.
Reduced Risk of Bleeding
“Another important clinical benefit of increased platelet count is a reduction in bleeding risk,” he said. Bleeding rates were reduced both when measured prospectively and when reported as an adverse event.
Eltrombopag was generally well tolerated, he said. Three patients (2%) receiving the drug had thromboembolic events compared with none of the placebo patients. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients and no placebo patients had increases in total bilirubin.
Aminotransferase and bilirubin should be monitored before initiation of and during eltrombopag treatment, and the treatment stopped, if necessary, Dr. Cheng said. Four patients (7%) taking placebo had serious bleeding events, compared with just one patient (less than 1%) treated with eltrombopag.
Because many patients did not have bone marrow testing performed before starting on eltrombopag, the study could not adequately address the risk of myelofibrosis, which is a potential side effect,” Dr. Cheng said. This limitation will be addressed in a new clinical trial. Longer follow-up data are required to address the drug's long-term safety, he added.
Post-hoc analyses showed a significant reduction in steroid-associated side-effects, including dyspepsia, peripheral edema, and hyperglycemia, with eltrombopag. Reductions in corticosteroid use presumably contributed to the improved health-related quality of life in patients receiving eltrombopag, he said.
In conclusion, Dr. Cheng said, “eltrombopag seems to be beneficial for patients who have refractory immune thrombocytopenia, who have not responded to splenectomy, or who have had temporary or negligible responses to treatments such as corticosteroids, immunoglobulins, or rituximab and continue to have bleeding symptoms.” Currently, these patients have few alternatives, he noted.
Long-term Treatment for Low Platelet Counts
In an editorial accompanying the study, Alan T. Nurden, MD, of Hopital Xavier Arnozan in Pessac Bersol, France, commented that the results confirmed the feasibility of increasing dangerously low platelet counts to more than 50,000 per μL on a long-term basis.
Similar results have been found in other eltrombopag trials and in long-term, open-label extension studies with romiplostim, he noted, adding that the overall safety profile of eltrombopag is encouraging, although clinicians should be cautious about using the drug for patients with risk factors for thrombosis.
Dr. Nurden noted that platelet counts returned to pretreatment concentrations for most patients taking eltrombopag after discontinuation of the drug, which has also been seen in romiplostim studies. Thrombopoietin mimetics appear to alleviate the symptoms of the disorder, but not provide a cure, he added.
Both drugs are being used to increase platelet counts in thrombocytopenia related to hepatitis C and viral infection, in chemotherapy, and in myelodysplastic syndromes (MDS).
“The prognosis of patients with thrombocytopenia after chemotherapy or in MDS is poor, and complications of the thrombocytopenia, such as bleeding and infections, are major concerns,” Dr. Nurden said.
“Thrombopoietin mimetics have achieved a long-term increase in platelet count in patients with lower-risk MDS despite a potential hazard of hematological neoplasia. There is now hope that new-generation thrombopoietin mimetics will reduce bleeding risk for a range of thrombocytopenic disorders in the long term, and reduce the fear of intracranial hemorrhage, a particularly important factor in chronic ITP.”
Dr. Cheng said that oncologists will be interested in whether eltrombopag will be safe and effective in patients with malignancies. Trials involving MDS and acute myeloid leukemia patients are now being conducted.”
Low Risk of Hepatic Dysfunction & Myelofibrosis
“Eltrombopag is a safe, efficacious, well-tolerated drug, and the risk of hepatic dysfunction and myelofibrosis seems to be low,” said Dr. McCrae, who is also Director of Benign Hematology at the Taussig Cancer Institute in Cleveland. “Clearly, patients with refractory immune systems that do not respond to splenectomy are good candidates for the drug.”
Where eltrombopag fits in to chronic ITP therapy before splenectomy is still unknown. No study has addressed its use before rituximab treatments or splenectomy. Some patients are not good candidates for eltrombopag, including those with concurrent illness or heart disease, he said.
“I have been prescribing eltrombopag and romiplostim for a while, and I am personally convinced that they are safe drugs,” Dr. McCrae said. In other studies, patients have taken these drugs for more than five years with no new side effects and no increase in myelofibrosis: “These drugs seem to be safe to use in the three- to five-year range.”
Eltrombopag is certainly more convenient for the patient than romiplostim is, but there is an issue of compliance, as with any oral medication, Dr. McCrae said. “With an injection of romiplostim, you clearly know the patient is getting the drug and can see the response.”
There is no evidence that one drug is better than the other in terms of efficacy, but they are not necessarily interchangeable,” he continued. “If a patient is refractory to standard therapy, does not have other options, and does not respond to one drug, then try the other one.”
By the time patients reach the point that they need to use these agents, ITP has probably become a chronic disease, he noted. A small percentage of patients will go into remission.
“Some patients on these drugs do come off of them and maintain a normal platelet count. There is some evidence that these drugs have some immunomodulatory effects that were not previously anticipated.” He said that when he talks to patients, he explains that the drugs should be considered to be long-term, if not life-long, therapy.
He emphasized the importance of regular monitoring for patients taking eltrombopag, including liver function tests and blood smears to check for the development of myelofibrosis. Also, once a patient discontinues the drug, monitor the patient's platelet count closely for two weeks afterward.
The best choice of treatment for chronic ITP rests with a discussion of the options with each individual patient. “For some patients, I feel strongly they should have a splenectomy. I don't want a young, healthy, athletic patient bound to drug therapy for the rest of his or her life. Other patients who refuse to have a splenectomy might be good candidates for eltrombopag.”
ITP's New Name
Chronic immune thrombocytopenia was until recently generally known as idiopathic thrombocytopenia purpura, but the change was made after the consensus recommendations of an International Working Group of experts convened at a two-day meeting called the Vecensa Consensus Conference to define standard terminology and definitions, including the different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. The resulting report was published in March 2009 (Blood 2009;113:2386-2393).