Eltrombopag for Inherited Thrombocytopenias

Overview

Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by a reduced number of blood platelets and a consequent bleeding tendency that ranges from mild to life-threatening. Thrombocytopenia is caused by genetic mutations and therefore is present throughout life and can be transmitted to the progeny. Some patients with severely reduced platelet count present spontaneous bleeding, which represents a major clinical problem: in fact, bleeding diathesis exposes these subjects to the risk of severe hemorrhages, affects their quality of life and often requires hospitalization and/or transfusions. Conversely, other patients with ITs have absent or mild spontaneous bleeding tendency. However, even these patients are at risk of major bleeding on the occasion of surgery or other invasive procedures. Therefore, the potential for hemorrhages on the occasion of invasive procedures represent a clinical problem for all patients affected by ITs. Eltrombopag is a drug, available in tablets, which stimulates the production of platelets by the bone marrow. A previous study demonstrated that a short course of eltrombopag was effective in increasing platelet count in most patients with the MYH9-related disease (MYH9-RD), the most frequent form of IT. Eltrombopag was given for 3 to 6 weeks to 12 patients with MYH9-RD and platelet counts lower than 50 x10e9/L. Eleven patients responded to the drug and 8 of them obtained platelet counts higher than 100 x10e9/L or three times the baseline value. Remission of spontaneous bleeding was achieved by 8 of 10 patients and treatment was well tolerated in all the cases. Based on these findings, short-term eltrombopag courses have been successfully used for preparing for major surgery two patients with MYH9-RD and less than 20 x10e9 platelets/L. The present study has two main objectives. - To verify if eltrombopag is effective in transiently increasing platelet count over 100 x 10e9/L and abolishing bleeding tendency in patients with different forms of IT. To this end, eltrombopag will be given for 3-6 weeks to patients with different forms of IT. Eltrombopag will be administered at the dose of 50 mg/day for 3 weeks. After 3 weeks of treatment, the patients who will obtain a platelet count higher than 100 x10e9/L and complete remission of bleeding tendency will stop therapy. In the other cases, patients will be treated with eltrombopag at a higher dose (75 mg/day) for 3 additional weeks. This treatment schedule is called "Phase 1" of the study. If the study will achieve this goal, short-term eltrombopag could be potentially used in the future to prepare these patients for surgery or other invasive procedures \- To verify if eltrombopag can be used to stably reduce spontaneous bleeding tendency for long periods of time in patients with clinically significant spontaneous hemorrhages. To this end, patients with clinically significant spontaneous bleedings at baseline and who had their bleeding tendency reduced during the Phase 1 of the study without severe side effects, will be admitted to the "Phase 2" of the study. During the Phase 2, patients will be treated with eltrombopag for 16 weeks. In order to determine the lowest dose of eltrombopag that is able to reduce or abolish their bleeding tendency, patients will start treatment with eltrombopag 25 mg/day for 4 weeks. Then, every 4 weeks, patients will be re-evaluated and the dosage of eltrombopag will be adjusted according to bleeding tendency and platelet count. The dosages of eltrombopag that can be used in the Phase 2 range from 12.5 to 75 mg/day. Other objectives of the study are: * to evaluate safety and tolerability of Eltrombopag in patients affected with ITs. * to identify the dosages of Eltrombopag required for achieving the primary endpoints of Phases 1 and 2. * to study the effects of Phase 2 treatment on patients' health-related quality of life (HR-QoL); * to study the effects of treatment on some laboratory parameters related to platelet production and function. All patients will be undergo a follow-up visit 30 days after completion of treatment. Patients will be treated as outpatients. The evaluation of patients at enrollment and at each subsequent on-treatment and post-treatment visits includes: medical history; physical examination; evaluation of bleeding tendency according to WHO bleeding scale; CBC and differential; platelet count by phase-contrast microscopy; peripheral blood smear examination; plasma transaminases, bilirubin, and creatinine; urine analysis; ophthalmic assessment (only at some visits); measurement of serum thrombopoietin level; evaluation of HR-QoL (only at baseline and during Phase 2); evaluation of in vitro platelet aggregation in response to ADP, collagen and ristocetin whenever platelet count is over 100 x 10e9/L.