Efficacy and Safety of Eltrombopag in Elderly Patients with Chronic Immune Thrombocytopenia: Analysis of Five Clinical Trials,

Patients (pts) with immune thrombocytopenia (ITP) with platelet counts persistently <30,000/μL are at risk for severe and even fatal bleeding events; this risk increases with age. Risk for major non-fatal hemorrhage has been estimated at 3% per year for pts <40 years and 71% per year for pts >60. The 5-year risk of fatal hemorrhage has been estimated at 2% for pts <40 years and 48% for pts >60 (Cohen 2000). Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic ITP, stimulates bone marrow progenitor cells, promoting differentiation and proliferation of megakaryocytes and platelet production. No data have been reported on the safety and efficacy of eltrombopag specifically in elderly pts. Aim: To assess efficacy and safety of eltrombopag in pts ≥65 years. Methods: A retrospective analysis by age was completed for 446 adult chronic ITP pts receiving eltrombopag in 5 clinical trials: two 6-week and one 6-month placebo-controlled studies (TRA100773A/B, RAISE); an open-label study with pts treated intermittently in 3 cycles of up to 6 weeks (REPEAT); and an ongoing extension study (EXTEND) of 299 pts who completed a prior eltrombopag trial. Bleeding was assessed prospectively using the WHO Bleeding Scale and using the NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Results: Pts receiving eltrombopag in each trial aged 18–49, 50–64, and ≥65 are shown in the Table. In the 6-week trials, response was defined as platelets ≥50,000/μL at day 43. In TRA100773A (eltrombopag 50 mg), response was achieved by 67% of pts aged 18–49 and 50–64, and 100% in pts ≥65. In TRA100773B, response was achieved by 50% of pts 18–49, 64% of pts 50–64, and 74% of pts ≥65. In RAISE, at any given visit, 40–53% of pts aged 18–49, 40–61% aged 50–64, and 42–75% ≥65 responded (platelets >50,000/μL and <400,000/μL). In REPEAT, response (platelets ≥50,000/μL and ≥2x baseline) in all 3 cycles was achieved by 67%, 72%, and 83% of pts who responded in Cycle 1, in the 18–49, 50–64, and ≥65 groups. In EXTEND, 84%, 94%, and 86% of pts aged 18–49, 50–64, and ≥65 had a response (platelets ≥50,000/μL); 15, 18, and 6 of these pts had platelets ≥50,000/μL at baseline. In EXTEND, 66%, 73%, and 78% of pts aged 18–49, 50–64, and ≥65 responded for >50% of assessments and 43%, 48%, and 53% for >75% of assessments. Across all 5 studies, pts aged 18–49 (n=220), 50–64 (n=148), and ≥65 (n=78) were treated with eltrombopag for a median (range) of 399 (5–1255), 484.5 (5–1302), and 244.5 (2–1267) days; median daily dose was 53 mg for pts 18–49 and 50 mg each for pts 50–64 and ≥65. The most common adverse events (AEs) (headache, nasopharyngitis, upper respiratory tract infection, and diarrhea) across all 5 studies were reported in similar proportions of pts across age groups. Fatigue, arthralgia, constipation, and cataracts were more common in elderly pts (11%, 10%, 5%, and 4% for pts 18–49 vs 19% each for pts ≥65). Thromboembolic events were reported in 4 (2%), 5 (3%), and 7 (9%) pts aged 18–49, 50–64, and ≥65. No age specific trend toward arterial vs venous events was observed. Proportions of liver enzymes elevation and bone marrow reticulin grade ≥2 were similar across age groups. Bleeding serious AEs (SAEs) were reported in 7% of pts aged 18–49 and 50–64, and 3% of pts ≥65. The most common bleeding SAEs were GI and CNS events, with no apparent difference in proportion of pts among age groups. Two pts experienced a fatal bleeding event (GI and CNS hemorrhages) 55 and 107 days after stopping eltrombopag; both were 18–49 and never responded to eltrombopag. Conclusion: No significant difference in the safety or efficacy profile of eltrombopag was observed for elderly versus younger pts, although elderly pts seemed to exhibit slightly more robust responses and slightly more nonhemorrhagic AEs (including thrombosis), which are not unexpected in an elderly population.

Olney:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pabinger:GlaxoSmithKline: Research Funding, Speakers Bureau. Mayer:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.