IP: Dr. Tomás José González López

Resumen del proyecto: Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder caused by platelet autoantibodies. This disease is characterized not only by an accelerated platelet destruction in the reticuloendothelial system but also by an inhibition of proliferation and maturation of bone marrow megakaryocytes with impaired production of platelets. Incidence in adults has been estimated between 1.6 and 3.95 x 100 000 subjects per year, depending on the selected diagnostic cut-off, ranging from <150 to <50 x 109/L. The signs and symptoms of ITP and its clinical course vary from subject to subject. The severity of hemorrhage not completely correlates with bleeding risk. The treatment goal in ITP is to control and prevent bleeding increasing and maintaining platelet count within a safe range. Corticosteroids continue to be first-line therapy. Thrombopoietin receptor agonists (TPO-RAs),romiplostim and eltrombopag, are currently used to treat patients with ITP who are at risk of bleeding and who have already failed at least one ITP therapy. Eltrombopag is an oral, nonpeptide TPO-RA that activates the thrombopoietic receptor and stimulates human megakaryocytes. Clinical trials have demonstrated that eltrombopag is effective and safe in adults with chronic ITP, (response rates between 59 and 88%) with high long-term (up to three years) treatment responses. On the other hand, platelet counts usually return to baseline within 2 weeks if eltrombopag is stopped, but a non-determined proportion of patients that discontinue eltrombopag is able to maintain platelet count above baseline values without additional lTP treatment. ITP diagnosis keeps on being of exclusion. Molecular biology studies in ITP were anecdotal until few years ago probably because of lack of accurate techniques able to study the etiopathology of ITP. Actually, one of new goals in ITP investigation is to discover valid genetic markers for diagnosis of ITP and/or to find predictors of response to drugs. One pioneer study already demonstrated in 2013 the potential utility of genetic studies in ITP. They reported a Beta-Tubulin SNP (single-nucleotide polymorphism) related to treatment refractoriness in ITP. Since then, new and cheaper molecular biology tools have been developed. Currently, the new massive sequencers with their "next generation sequencing (NGS)" techniques allow us now to implement this technology, as other hematological diseases, in ITP molecular pathophysiology investigation. NGS usefulness in hematology is trending topic actually. However, use of genetics in ITP is still emerging. In ASH 2015 we could attend to an oral presentation reporting discovery of genes related to development and severity of chronic ITP in a pediatric population. Nevertheless,there are not many studies regarding molecular characteristics of our adult ITP patients at diagnosis that could differentiate ITP from other related diseasesas myelodisplastic (MDS) syndromes or thrombopathies. Same happens with likely genetic alterations related with the possibility of discontinuation of eltrombopag after a short-medium term use. We don't know much of possible SNPs and/or mutations involved in refractoriness to thrombopoietin-receptor analogs (TPO-RAs) either. Spanish ITP group recently developed REVOES (Spanish Eltrombopag Registry) to obtain safety and efficacy data of Eltrombopag use in real life conditions. So far we have identified at least 35 patients refractory to eltrombopag and other drugs like steroids, immunoglobulins, romiplostim, ...; For that reason, our NGS technology planned study will make use of REVOES data to, if possible, identify molecular markers of refractoriness in this Eltrombopag refractory population This study aims, therefore, to describe possible SNPs and/or mutations directly related with clinical refractoriness to eltrombopag treatment in clinical practice of our Spanish ITP patients. We expect to analyze about 100 genes in 35 eltrombopag refractory ITPs.These genes are directly related with eltrombopag downstream signaling, cytokine networks, cytotoxic routes, growth factors, adhesion molecules, apoptotic mechanisms and physiological platelet production mechanisms.

Entidad financiadora: Novartis Farmaceútica S.A.