The thrombopoietin-receptor agonist eltrombopag for the treatment of inherited thrombocytopenias

Inherited thrombocytopenias (ITs) are a group of rare disorders characterized by reduced platelet count and variable bleeding phenotype. IT patients often require platelet transfusions to raise platelet counts before surgery or invasive procedures. Moreover, some subjects have clinically significant spontaneous bleeding, which may benefit from a durable improvement of their thrombocytopenia. The hypothesis that thrombopoietin-mimetic drugs, which are currently approved for several forms of acquired thrombocytopenia, can increase platelet count in ITs is appealing, but evidence is scarce. In fact, only one prospective study enrolling patients affected with MYH9-related disease, MYH9-RD, has been conducted so far. In this trial, a short course of the oral thrombopoietin-receptor agonist eltrombopag was given to 12 patients, and 11 of them showed a significant increase in platelet count. From 2010, to all MYH9‐RD patients followed at our Institute who needed elective surgery and had a platelet count too low for a safe procedure, a short‐term eltrombopag cycle has been offered, and 11 consecutive surgical procedures (including major surgeries) were carried out after eltrombopag administration so far. Eltrombopag successfully and safely replaced platelet transfusions prior surgery in 10 out of 11 cases. We then conducted a novel prospective, phase II clinical trial to investigate the efficacy of eltrombopag in a wider group of ITs. We enrolled 24 patients affected with MYH9-RD, ANKRD26-related thrombocytopenia, (ANKRD26-RT), 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%) a minor response (platelet count at least twice as much as 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. Four patients with clinically significant spontaneous bleeding received a long-term eltrombopag administration (16 additional weeks): all of them obtained remission of mucosal hemorrhages, which persisted throughout the treatment period. The treatment was globally well tolerated: five patients reported mild adverse events and one a moderate adverse event. In our study, a variable extent of platelet response was observed, either among different forms of IT and among different patients suffering from the same disease. By exploiting a silk-based miniaturized 3D bone marrow tissue model, which recapitulates ex vivo platelet biogenesis of subjects with different ITs, we demonstrated that the ex vivo model can predict the in vivo clinical platelet response to eltrombopag in individual patients affected with MYH9-RD and ANKRD26-RT. In fact, the number of platelets recovered in the ex vivo model under standardized conditions - including exposure to eltrombopag - was significantly correlated with the increase in platelet count that we had observed in vivo in the same subjects after eltrombopag treatment. In conclusion, eltrombopag was safe and effective in increasing platelet count and reducing bleeding symptoms in different forms of IT. With regard to the less rare IT, i.e. MYH9-RD, short‐term eltrombopag should be considered as the first‐line treatment to prepare patients with severe thrombocytopenia for elective surgery. Despite these encouraging results, caution is recommended when using eltrombopag, particularly in patients with ITs predisposing to hematological malignancies. In a near future, tools that mimic the bone marrow ex vivo can be used to predict the individual response to this and others drugs stimulating platelet production, thus informing therapeutic choices in a personalized view.