Eltrombopag for the treatment of inherited thrombocytopenias: a phase II clinical trial

Abstract

Patients with inherited thrombocytopenias often require platelet transfusions to raise their platelet count before surgery or other invasive procedures; moreover, subjects with clinically significant spontaneous bleeding may benefit from an enduring improvement of thrombocytopenia. The hypothesis that thrombopoietin-mimetics can increase platelet count in inherited thrombocytopenias is appealing, but evidence is scarce. We conducted a prospective, phase II clinical trial to investigate the efficacy of the oral thrombopoietin-mimetic eltrombopag in different forms of inherited thrombocytopenia. We enrolled 24 patients affected by MYH9-related disease, ANKRD26-related thrombocytopenia, X-linked thrombocytopenia/ Wiskott-Aldrich syndrome, monoallelic Bernard-Soulier syndrome, or ITGB3-related thrombocytopenia. The average pre-treatment platelet count was 40.4 ×10⁹/L. Patients received a 3- to 6-week course of eltrombopag in a dose-escalated manner. Of 23 patients evaluable for response, 11 (47.8%) achieved a major response (platelet count >100 ×10⁹/L), ten (43.5%) had a minor response (platelet count at least twice the baseline value), and two patients (8.7%) did not respond. The average increase of platelet count compared to baseline was 64.5 ×10⁹/L (P<0.001). Four patients with clinically significant spontaneous bleeding entered a program of long-term eltrombopag administration (16 additional weeks): all of them obtained remission of mucosal hemorrhages, with the remission persisting throughout the treatment period. Treatment was globally well tolerated: five patients reported mild adverse events and one patient a moderate adverse event. In conclusion, eltrombopag was safe and effective in increasing platelet count and reducing bleeding symptoms in different forms of inherited thrombocytopenia. Despite these encouraging results, caution is recommended when using thrombopoietinmimetics in inherited thrombocytopenias predisposing to leukemia. ClinicalTrials.gov identifier: NCT02422394.

Figure 1

Mean increase in platelet count in the responders in part 1 of the study. Patients are categorized according to the diagnosis of the specific form of inherited thrombocytopenia. mBSS: monoallelic Bernard-Soulier syndrome; MYH9-RD: MYH9-related disease; . ANKRD26-RT: ANKRD26-related thrombocytopenia. XLT/WAS: X-linked thrombocytopenia/Wiskott-Aldrich syndrome. Mean values of platelet count at baseline and at the end of part 1 of the treatment along with their 95% confidence intervals (95%CI) are reported in the gray box.

Figure 2

Effects of treatments in part 1 and part 2 of the study in the four individuals who received long-term eltrombopag therapy. The figure summarizes the effects of eltrombopag administration on bleeding symptoms according to the World Health Organization (WHO) bleeding scale and on platelet count. Patients 1/1 and 12/10 have MYH9-related disease, patient 17/13 has ITGB3-RT, and patient 22/16 has Wiskott-Aldrich syndrome (see Table 5).