Eltrombopag for the Treatment of the Inherited Thrombocytopenia Deriving From MYH9 Mutations
Authors: Pecci Alessandro , Klersy Catherine , Gresele Paolo , Savoia Anna , Fierro Tiziana , Bozzi Valeria , Mezzasoma Anna Maria , Melazzini Federica , Balduini Carlo Luigi 
Published: October 2019

Abstract
Abstract 2533
MYH9-Related Disease (MYH9-RD) is one of the less rare forms of inherited thrombocytopenia. It derives from mutations of the gene MYH9 for the heavy chain of nonmuscle myosin IIA and is characterized by congenital macrothrombocytopenia variably associated with young-adult onset of hearing loss, cataract, and a severe proteinuric nephropathy.
Only platelet transfusions are available for increasing platelet counts in this condition, but they expose to the risks of acute reactions, transmission of infectious diseases, and refractoriness to subsequent platelet transfusions. Moreover, this treatment suffers from scarceness of blood donors.
Novel thrombopoiesis-stimulating agents have been developed and 2 of them, eltrombopag and romiplostin, have been approved for increasing platelet count in a few forms of acquired thrombocytopenia. Since it has been recently shown that megakaryocytes of patients with MYH9-RD respond in vitro to TPO stimulation, we reasoned that TPO-mimetics could be effective also in this condition and decided to test the effect of eltrombopag.
Therefore, we performed a phase II, multicentre, open-label, dose escalation trial. Twelve adult patients with a platelet count lower than 50×10e9/L and a diagnosis of MYH9-RD confirmed by identification of the causative MYH9 mutations received orally eltrombopag 50 mg daily for 21 days (Revolade®, GSK). Patients with platelet counts lower than 100×10e9/L at day 21 increased eltrombopag to 75 mg daily for 21 additional days. Patients with platelet counts between 100 and 150×10e9/L at day 21 continued eltrombopag 50 mg daily for the following 21 days, while patients with more than 150×10e9 platelets/L stopped therapy.
The primary endpoints were the achievement of a platelet count over 100×10e9/L or at least three times the baseline value (major response), or at least twice the baseline value but less than major response (minor response). Secondary end points included safety and tolerability, and the reduction of bleeding tendency.
After 3 weeks at the eltrombopag dose of 50 mg daily, 3 patients achieved platelet counts of 150×10e9/L or more and stopped therapy. Two had a platelet counts between 100 and 150×10e9/L and continued treatment at the same dosage, while 7 had less than 100×10e9 platelets/L and received eltrombopag 75 mg daily for 3 weeks.
A major response was obtained in 8 patients (67%), in 5 of them after 3 weeks of eltrombopag 50 mg daily, and in 3 cases after 3 additional weeks at the dose of 75 mg. Three patients (25%) achieved a minor response, 1 after 3 weeks at 50 mg daily, and 2 after 3 additional weeks at 75 mg. In one patient the treatment resulted in no response.
Mean platelet count at the end of treatment was significantly higher than at baseline (105 versus 31×10e9 platelets/L, p=0.0022). In the 11 patients that achieved major or minor responses, mean platelet count was still higher than baseline 15 days after discontinuation of the drug, while it returned to levels near baseline 15 days later.
Platelet size did not change either during treatment or after its cessation, and this indicates that the increases in platelet count were paralleled by corresponding increases in total platelet mass.
The extent of platelet aggregation was within the normal range after all tested agonists in 5 of the 7 patients that achieved platelet counts higher than 100×10e9/L, while it was slightly reduced after ADP and collagen in 2 patients.
Mean serum TPO level was higher than the normal range and this figure did not change neither during treatment with eltrombopag nor after its discontinuation.
Ten of 12 patients had grade 1 or 2 bleeding symptoms, as measured by the WHO bleeding scale, at baseline, while 2 were asymptomatic. Upon treatment, bleeding diathesis quickly ameliorated and disappeared in 8 cases, while it remained unchanged in the only patient with no response to eltrombopag and in another one with a minor response. The benefit in terms of bleeding diathesis lasted well beyond treatment discontinuation.
Treatment was well tolerated in all cases, with only two patients reporting mild and transient headache and one patient suffering from transient dry mouth at the beginning of treatment.
In conclusion, 50–75 mg of eltrombopag per day increased platelet count and reduced bleeding tendency in most patients with MYH9-RD. Further research is required to ascertain whether TPO mimetics are effective also in other forms of inherited thrombocytopenia.

Disclosures:
Off Label Use: Eltrombopag for MYH9-related disease.