Agent Boosts Plateletsin ITP and Thrombocytopenia-Associated HCV


NEW YORK, Nov. 28 -- Eltrombopag (Promacta), an investigative thrombopoietin-receptor agonist, has boosted platelets in both immune thrombocytopenic purpura and hepatitis C-related cirrhosis, according to early trials.Higher daily doses elevated platelet counts to at least 50,000 per mm3 within two weeks in more than 80% of patients with relapsed or refractory chronic immune (or idiopathic) thrombocytopenic purpura, reported James B. Bussel, M.D., of Weill Cornell Medical College here, and colleagues.
Action Points
Caution interested patients that the early results for this investigative agent reported in these studies need to be confirmed in larger, longer-term phase III studies.
Inform interested patients that there is no FDA-approved treatment for thrombocytopenia in HCV-infected patients, although several options are available for treating chronic immune thrombocytopenic purpura.
A significant increase in platelets was also seen in 74% to 95% of eltrombopag-treated HCV patients with cirrhosis-related thrombocytopenia, a major reason why patients cannot endure antiviral treatments, reported John G. McHutchison, M.D., of Duke in Durham, N.C., and colleagues.
Results of both trials were reported in the Nov. 29 issue of the New England Journal of Medicine. Robert S. Schwartz, M.D., an NEJM editor, cautioned in an accompanying editorial, "The results reported for thrombopoietin-receptor agonists are too preliminary for any definitive statement about applications in clinical practice."
However, for hematologists thwarted by failure of every treatment for patients with ITP, he said, "a new, safe way of treating the disease would be a considerable advance."
Dr. Bussel's group conducted a multicenter phase I trial comparing oral eltrombopag and placebo. Patients were randomized to once-daily placebo or 30, 50, or 75 mg of eltrombopag for six weeks or until platelet counts reached 200,000 per mm3.
The trial included 118 adults with chronic ITP and platelet counts below 30,000 per mm3 who had failed at least one standard treatment, typically glucocorticoids or IV immunoglobulins. Among them, 47% had undergone splenectomy and 32% were receiving concomitant medication for the disease.
The trial was stopped at the first interim analysis when the two highest dose groups met predefined stopping criteria for efficacy.
Most patients on the higher doses reached the primary endpoint, a platelet count of 50,000 or more per mm3 on day 43. This included 81% on the 75-mg dose and 70% on the 50-mg dose but only 28% on the 30-mg dose and 11% of controls (P0.001).
The same results were seen without the last-observation-carried-forward analysis (73%, 56%, 22%, and 10%, respectively, P=0.002 for 50 mg versus placebo and P=0.001 for 75 mg versus placebo).
Median platelet counts approached the normal 150,000 to 400,000 per mm3 range by day 15 in both of the higher dose eltrombopag groups but returned almost to baseline within two weeks of the last dose.
Platelet counts rose above 200,000 per mm3 during the study in 4% of placebo group patients compared with 14% of those on 30 mg, 37% on 50 mg, and 50% on 75 mg of eltrombopag.
Bleeding events decreased during treatment with the higher doses. Adverse events were similar in incidence and severity to those in the placebo group.
For HCV-related cirrhosis, Dr. McHutchison's multicenter phase II trial randomized 74 patients with platelet counts of 20,000 to less than 70,000 per mm3 (median 55,000) to the same three dosages or placebo once daily for four weeks.
Patients who reached a platelet count of 70,000 or 100,000 per mm3 by week four could start HCV treatment with peginterferon alfa-2a (Pegasys) or peginterferon alfa-2b (PegIntron), respectively, plus ribavirin. Eltrombopag or placebo continued during the 12-week regimen.
This trial was also discontinued early when a predetermined criterion was met.
Platelet counts rose to 100,000 per mm3 or more at week four -- the primary endpoint -- with eltrombopag in a dose-dependent manner (P0.001 overall and versus placebo for each dose group).
Among the patients who could receive antiviral treatment were 22% of those on placebo, 71% on 30 mg of eltrombopag, 74% on 50 mg of eltrombopag, and 91% on 75 mg of the agent.
During the antiviral treatment phase, platelet counts were consistently higher with eltrombopag than with placebo. Despite a drop in platelet counts in all three eltrombopag groups during antiviral treatment, "perhaps owing to the antiplatelet effect of peginterferon," levels remained above the 50,000 per mm3 threshold at which a reduction in the peginterferon dose is recommended.
The most common side effects of eltrombopag were headache, dry mouth, abdominal pain, and nausea, but they did not cause treatment discontinuation.
Both research groups said their findings require confirmation in phase III trials with longer duration.
Primary source: New England Journal of MedicineSource reference: McHutchison JG, et al "Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C"N Engl J Med 2007; 357: 2227-36. Additional source: New England Journal of MedicineSource reference: Bussel JB, et al "Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura"N Engl J Med 2007; 357: 2237-47. Additional source: New England Journal of MedicineSource reference: Schwartz RS, "Immune thrombocytopenic purpura -- from agony to agonist"N Engl J Med 2007; 357: 2299-2301.