Efficacy of Eltrombopag to Improve Thrombocytopenia of MYH9-related Disease

An Exploratory Phase II Dose Escalation Study of Eltrombopag in MYH9 Related Disease

The term MYH9-related disease (MYH9RD) includes four genetic disorders: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome. All these disorders derive from mutation of a unique gene, named MYH9, and they have been recognized as different clinical presentations of a single illness that was named MYH9RD. All patients affected by MYH9RD present since birth with thrombocytopenia, which can result in a variable degree of bleeding diathesis; some of them subsequently develop additional clinical manifestations, such as renal damage, sensorineural hearing loss, and/or presenile cataracts. Eltrombopag is an oral thrombopoietin receptor agonist that stimulates proliferation and differentiation of megakaryocytes, the bone marrow cells that produce blood platelets. This drug is effective in increasing platelet count in healthy volunteers, as well as in patients affected by some acquired thrombocytopenias, such as idiopathic thrombocytopenic purpura and HCV related thrombocytopenia. The purpose of this study is to determine if eltrombopag, administered orally at the dose of 50 or 75 mg/daily for up to 6 weeks, is effective in increasing platelet count of patients affected by MYH9RD. Further aims of this study are to test if eltrombopag is effective in reducing bleeding tendency of MYH9RD patients; to evaluate safety and tolerability of eltrombopag in patients with MYH9RD; to evaluate in vitro function of platelets produced during therapy in patients responding to this drug.

Inclusion Criteria:

• Age 16 years or more
• Confirmed diagnosis of MYH9-related disease
• Average platelet count for the previous year less than 50x10e9/L
• Written informed consent

Exclusion Criteria:

• Diseases known to involve the risk of thromboembolic events (e.g. atrial fibrillation)
• History of thrombosis within 1 year
• Use of drugs that affect platelet function (including but not limited to, aspirin, clopidogrel or NSAIDS) or anti-coagulants
• Females who are pregnant or nursing (a negative pregnancy test in required before enrollment of fertile women)
• Formal refusal of any recommendation of a safe contraception
• Alcohol or drug addiction
• Altered renal function as defined by creatinine of 20 mg/L or more
• Any other disease or condition that by the advise of the responsible physician would make the treatment dangerous for the patient or would make the patient ineligible for the study, including physical, psychiatric, social and behavioral problems. HCV positivity and liver diseases will not be considered an exclusion criterion since a phase II study showed that eltrombopag was effective and safe in this patient population.