LAUSR

The first-generation thrombopoietic agents, recombinant human thrombopoietin (rhTPO) and pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF), were developed following identification and cloning of human thrombopoietin (TPO) in 1994. Unfortunately, formation of cross-reactive antibodies to PEG-rHuMGDF capable of neutralising endogenous TPO in a minority of patients halted clinical development of these agents in the West. However, the clinical promise of these first-generation agents led to the development of secondgeneration thrombopoietic growth factors, the thrombopoietin receptor agonists (TPO-RAs). Ultimately, rhTPO did not have the same immunologic risks as PEG-rHuMGDF and completed clinical development in China, where it is used routinely in the management of chemotherapy-induced thrombocytopenia (achieved approval in 2005) and immune thrombocytopenia (ITP) after failure of other therapies (achieved approval in 2010). In this issue of the British Journal of Haematology, Mei and colleagues report the findings of a multicentre doubleblind, double-dummy randomised controlled trial of rhTPO versus eltrombopag in 96 Chinese adults with ITP. The study included patients who had received at least one prior treatment for ITP and who had a pre-treatment platelet count <30 9 10/l. Ninety-six patients were randomised 1:1 to receive eltrombopag 25 mg daily for two weeks or rhTPO 300 U/kg SC daily for two weeks. Both groups had a median baseline platelet count of 14 5 9 10/l. Seventy-five percent (36/48) of patients in the rhTPO group achieved the primary end-point, a platelet count ≥50 9 10/l at day 15, as compared with 44% (21/48) of those in the eltrombopag group. A higher proportion of those treated with rhTPO — 65% (31/ 48) — achieved a complete response, defined as a platelet count ≥100 9 10/l at day 15, vs just 25% (12/48) treated with eltrombopag. Accordingly, there were more non-responders in the eltrombopag group (26/48 vs 13/48). The one area where the eltrombopag group outperformed the rhTPO group was duration of response: upon discontinuation of treatment, there was a faster decline to baseline platelet counts in those on rhTPO (one week) compared to those treated with eltrombopag (four weeks). While on treatment, 11/48 (23%) of patients on eltrombopag reported any adverse event vs 5/48 (10%) of the rhTPO group; however, no patient in either arm developed any serious adverse events. Although the study suggests utility of rhTPO for rapid improvement in platelet count compared to eltrombopag, a significant limitation of the study, as Mei and colleagues acknowledge, is the choice of an eltrombopag dose of 25 mg daily. The study did not compare rhTPO with higher doses of eltrombopag. Early pharmacokinetic studies found increased plasma eltrombopag levels and decreased drug clearance in patients of East Asian descent leading to a lower recommended starting dose of 25 mg daily for East Asian patients compared to 50 mg daily for patients of other ethnicities. However, clinical studies investigating doses of eltrombopag 12 5 mg or 25 mg daily specifically in East Asian patients with ITP suggest higher doses are warranted, and patients in these studies often required dose increases to 50 mg and even 75 mg daily to achieve goal responses. In a study of 18 Korean patients with ITP, 54% (7/13) of responders required doses of eltrombopag higher than 25 mg daily to reach platelet counts >50 9 10/l. In a multicentre, double-blind, randomized, Correspondence: Eun-Ju Lee, Division of Hematology, New York Presbyterian Hospital, 1305 York Ave, 7th Floor, New York, NY 10065, USA. E-mail: [email protected] Hanny Al-Samkari, Division of Hematology, Massachusetts General Hospital, Suite 118, Room 112, Zero Emerson Place, Boston, MA 02114, USA. E-mail: [email protected] commentary