Efficacy and Safety Of Eltrombopag In Korean Adult Patients With Refractory Chronic Immune Thrombocytopenia

Eltrombopag is a synthetic non-peptide thrombopoietin receptor agonist (TPO-RA), which shows an excellent treatment outcome in immune thrombocytopenia (ITP) patients. For East Asians, starting dose of eltrombopag is generally recommended as a 25 mg/day and maximal dose is restricted as a 50 mg/day because of higher plasma eltrombopag AUC values. Furthermore, sensitivity to TPO-RA may increase or decrease over time. Here, we attempted to analyze the effective eltrombopag doses to achieve and maintain safe platelet counts in Korean ITP patients.

A total of twelve adult chronic ITP patients were enrolled, which showed insufficient response to previous ITP treatments (platelet counts less than or equal to 30,000/uL). All patients were allowed to take concomitant low dose prednisolone or danazol. Ten patients started eltromobopag at a dose of 25 mg/day and two patients started 25 mg every other day (EOD) because of previously detected hepatic problem. The doses increased every two weeks to achieve a target platelet count (equal to or more than 50,000/uL). For patients achieving platelet count within the range of 50,000 to 200,000/uL, firstly, we reduced concomitant ITP medications and then reduced eltrombopag doses to find the lowest effective dose of eltrombopag to maintain platelet counts more than 50,000/uL (maintenance dose).

Before starting eltrombopag treatment, patients received median 4 (ranges; 3-9) ITP treatments including 1 case of splenectomy (Table 1). Bone marrow (BM) examinations including reticulin / Masson-trichrome staining were performed and all patients confirmed not to have BM fibrosis before eltrombopag treatment. Follow-up BM examinations were performed at 1 and 2 year of eltrombopag medication. Of total 12 patients, 10 (83.3%) achieved platelet counts more than 100,000/uL, 1 (8.3%) achieved platelet between 50,000-100,000/uL and 1 (8.3%) failed to increase platelet counts. One failed patient was diagnosed as ITP 114 months ago and received eight ITP treatments before starting eltrombopag. Eleven (91.7%) patients who achieved the target platelet counts (equal to or more than 50,000/uL) could quit or reduce the dose of concomitant ITP medications and median time to achieve the target platelet counts was 21 days (6-151 days). Most common initially required dose to achieve the target platelet counts was 25 mg/day (63.6%). Others were 25 mg EOD (9.1%), 50 mg/day (18.2%) and 75 mg/day (9.1%). After achieving the target platelet counts, most common adjusted maintenance dose was 25 mg/day (63.6%). Others were 25 mg twice a week (27.3%) and 50 mg/day (9.1%). There was no more than gr. 2 bleeding episode during eltrombopag treatment. One patient who required 75 mg/day to achieve the target platelet was diagnosed as ITP 91 months ago and received nine ITP treatments before starting eltrombopag. In 11 responded patients, 9 discontinued eltrombopag medication. Among them, 6 (66.7%) were relapsed and median relapse-free survival (RFS) was 11 days (6-574 days). In an aspect of adverse events, seven (58.3%) showed hepatobiliary laboratory abnormalities (HBLA, two gr. 3), however, all HBLA resolved after reduction or short-term discontinuation of eltrombopag. Eight patients underwent follow-up BM assessment. In 2 year BM, one patient revealed gr. 1 BM fibrosis during eltrombopag medication, however, there was no significant hematologic abnormality or lactate dehydrogenase (LDH) elevation in peripheral blood and no definitive abnormal immature cell clusters in his BM specimen.

Eltrombopag was generally well tolerated and showed an excellent treatment outcome in refractory chronic ITP patients in Korea. Low doses eltrombopag (25 mg/day or 25 mg twice a week) were effective to maintain safe platelet counts in most Korean patients. However, some of the patients needed longer time and higher doses (50 or 75 mg/day) to initially achieve and to maintain the target platelet counts, especially in heavily pre-treated patients with longer time from diagnosis to starting eltrombopag treatment.

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No relevant conflicts of interest to declare.