NPC Archive Item: Update on new treatments for chronic idiopathic thrombocytopenic purpura

NOTE – This is an archive post from the NPC and has not been updated since first publication. Therefore, some hyperlinks may no longer be working.
On The Horizon Stop Press NPC Logo

6th April 2009

Romiplostim▼ has recently been licensed for idiopathic thrombocytopenic purpura (ITP), and a new study of oral eltrombopag (not currently licensed in Europe) showed increased blood platelet counts over a 6-week period in patients with relatively refractory chronic idiopathic thrombocytopenic purpura. Platelet counts generally returned to baseline within two weeks of discontinuing treatment. The future role of eltrombopag in ITP will be determined by the efficacy and safety results from longer term studies.

Local decision-makers are advised to engage with physicians to identify those specific patients who may be eligible for the new treatments for chronic ITP. Service planning should take into account that NICE guidance on romiplostim is anticipated in August 2009.

What is the background to this?
Idiopathic thrombocytopenic purpura (ITP) is characterised by increased platelet destruction and additionally, in some cases, inadequate platelet production. With ITP, platelet counts are below 150,000 per microlitre. Counts of 150,000 to 400,000 per microlitre are considered normal in adults. ITP that lasts longer than 6 months is defined as chronic.

ITP in adults is relatively benign and often does not require treatment. Signs and symptoms include  spontaneous bruising, mucosal bleeding and, in severe cases, gastrointestinal or intracranial bleeding. Treatment is usually required only when the platelet count is below 30,000 per microlitre unless procedures involving blood loss are planned.

Existing first-line treatments include corticosteroids and intravenous immunoglobulins. Further treatment options include splenectomy, other immunosuppressive agents and rituximab. All are associated with severe adverse effects that may outweigh the benefits.

New drugs are being developed including s.c. romiplostim, which has been licensed in Europe for certain adult patients with chronic ITP, and eltrombopag. The latter is an oral thrombopoietin receptor agonist that stimulates bone marrow megakaryocytes to produce blood platelets. The FDA has approved it for patients with chronic ITP, whose degree of thrombocytopenia and clinical condition increases the risk for bleeding, and who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The drug is yet to be licensed in Europe.

What does the eltrombopag study claim?
Eltrombopag administered for up to six weeks, in conjunction with standard care, was more effective than placebo in achieving platelet counts > 50,000 per microlitre at day-43 analysis. This primary endpoint was met in 59% of eltrombopag patients (n=73) and 16% (n=37) of the placebo group; odds ratio (OR) 9.61, 95% confidence interval (CI) 3.31 to 27.86, P<0.0001.  The wide confidence intervals may reflect the small number of patients in the study. Recruiting from a small patient pool such as this is difficult.

How does this relate to other studies?
The FDA approved eltrombopag on the basis of two 6-week studies, including the one discussed in this blog, and an open-label extension study. The short term studies had a six-week follow-up after discontinuation of eltrombopag and during this period there was an increased risk of haemorrhagic events in patients who had received the drug. Conference data from the recently completed RAISE 6-month study found that patients receiving eltrombopag were eight times more likely than those receiving placebo to achieve a platelet count of 50,000 to 400,00 per microlitre (OR=8.2, 95%CI 4.2 to 15.38, p<0.001). A long-term, open-label extension study (EXTEND) is on-going.

So what?
An increase in platelet counts is recognised as an acceptable measure of benefit for patients with chronic ITP. In this trial, short term platelet count response has been used as a surrogate marker for longer platelet count responses. The initial application for a US licence was for a short term indication e.g. for use around the time of a surgical procedure. Whilst the results demonstrate that that eltrombopag stimulates platelet count amongst a population with relatively refractory chronic ITP, the incidence of bleeding increased when the drug was stopped. Hence the FDA did not consider a short term indication appropriate.

The treatment of patients with chronic refractory ITP is difficult. About 40% of patients in this study were on concomitant medication and it is possible that may have influenced the results. If it is licensed in Europe the future role of eltrombopag (in this disease which can last for years or even life) will be determined by the efficacy and safety results from the longer term studies.

Study details
Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 2009; 373:641–8

Design: randomised, double-blind, placebo-controlled, phase III trial.

Patients: patients over 18 years of age with at least a 6-month history of ITP, and with a pre-treatment platelet count less than 30,000 per microlitre were included. They must have received at least one previous treatment for ITP and approximately 50% had received three or more previous therapies; corticosteroids being the most commonly prescribed. 39% of patients had undergone splenectomy. All patients received accepted standard of care and concomitant maintenance therapy was prescribed for 43% of participants (prednisone being most common).

Previous therapy with immunoglobulins, immunomodulators, rituximab and cyclophosphamide must have been completed two weeks or more before enrolment.

Intervention: eltrombopag 50mg once daily for up to six weeks (n=76).

The dose could be increased to 75mg after 3 weeks in patients whose platelet count was les than 50,000 per microlitre. Treatment was discontinued in patients who reached a platelet count > 200,000 per microlitre.

Comparison: placebo (n=38).

Outcomes: the primary endpoint was the proportion of responders, defined as patients who had an increase in platelet count to > 50,000 per microlitre at day 43. Patients who withdrew prematurely because of a platelet count > 200, 000 per microlitre were considered responders. Patients who discontinued treatment for any other reason were considered non-responders irrespective of their platelet count.

Secondary endpoints included platelet counts, incidence and severity of bleeding as measured using the WHO (5 grade) bleeding scale, safety and tolerability. Patients were assessed every week during the trial and for up to six weeks after discontinuation of study drug.

Results: the authors state that the results were by intention-to-treat analysis, but the patient numbers quoted decreased for reasons that are unclear. One patient in each group was declared not evaluable.

43/73 (59%) eltrombopag patients and 6/37 (16%) of placebo patients achieved platelet counts > 50,000 per microlitre; OR 9.61 (95%CI 3.31 to 27.86), P<0.0001. Of the 34 patients who increased their dose of eltrombopag to 75mg ten responded. Platelet counts generally returned to baseline values within two weeks of ending treatment.

Patients receiving eltrombopag had less bleeding during the study than those taking placebo, OR 0.49 (95%CI 0.26 to 0.89); P=0.021, but the numbers increased in the five weeks after discontinuation of active treatment.

Nausea and vomiting were recorded in 5% or more of the eltrombopag group and in none of those receiving placebo. Three patients taking eltrombopag and one receiving placebo developed cataracts. All had previously received corticosteroids. Raised transaminases twice the upper limits of normal were observed in six patients taking eltrombopag and in one receiving placebo.

Sponsorship: GlaxoSmithKline

Please comment on this blog in the NPC discussion rooms, or using our feedback form