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Eltrombopag-based combination treatment for immune thrombocytopenia.

ABSTRACT: Immune thrombocytopenia (ITP) is a bleeding disorder caused by a decrease in platelet count resulting from increased destruction and insufficient production of platelets. Although impaired regulatory T-lymphocyte activity plays a critical role in platelet destruction, many other immunologic abnormalities are also likely to be involved. Importantly, patients with ITP appear to have defects in a thrombopoietin-mediated physiological mechanism that compensates for a decrease in platelet count by increasing platelet production. Thus, simultaneous treatment of multiple pathogenic pathways involved in ITP could potentially result in synergistic efficacy. While conventional treatments for ITP suppress or modulate the immune system to reduce platelet destruction, a unique class of ITP therapy, namely thrombopoietin receptor agonists (TPO-RAs), improves platelet production by activating the thrombopoietin pathway. As hypothesized, preliminary studies show that combinations of eltrombopag, an oral TPO-RA, with conventional treatments improve outcomes in both newly diagnosed and refractory patients. In this review, the clinical experience with eltrombopag-based combinations in patients with ITP is summarized and the implications of the available data are discussed.

SUBMITTER: Gomez-Almaguer D

PROVIDER: S-EPMC6187430 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Eltrombopag-based combination treatment for immune thrombocytopenia.

Gómez-Almaguer David D

Therapeutic advances in hematology 20181004 10

Immune thrombocytopenia (ITP) is a bleeding disorder caused by a decrease in platelet count resulting from increased destruction and insufficient production of platelets. Although impaired regulatory T-lymphocyte activity plays a critical role in platelet destruction, many other immunologic abnormalities are also likely to be involved. Importantly, patients with ITP appear to have defects in a thrombopoietin-mediated physiological mechanism that compensates for a decrease in platelet count by in ...[more]

PMID: 30344993

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Project description:Immune thrombocytopenia (ITP) is an autoimmune disorder that induces a decrease in the number of circulating platelets due to spleen destruction and inability of megakaryocytes to restore normal counts. Immunosuppressive therapy with glucocorticoid drugs constitutes the first line of treatment. However, lack of response to these agents is not uncommon, and the management of refractory patients is a matter of controversy. In fact, day-to-day clinical practice shows that, in spite of the current guidelines, splenectomy, which is currently considered a suitable second-choice therapy, is being replaced by treatment with thrombopoietin receptor agonists. These boost platelet production by megakaryocytes. The use of one of these, namely eltrombopag, has been permitted for ITP patients refractory to first-line drugs or splenectomy, for the last 10 years. This review summarizes the experience reported using eltrombopag in ITP, paying attention to efficacy and safety. Results from clinical trials will be discussed, and studies performed in the course of daily clinical practice will also be reviewed, as these are useful to assess the potential of the drug in real-world settings. The management of adverse events and the use of eltrombopag in particular situations will also be covered. The experience reported so far permits us to suggest that eltrombopag efficiently induces recovery of platelet counts. Furthermore, recent papers have demonstrated that a sustained response after discontinuation, initially thought to be problematic, may be possible in a nonnegligible number of cases. The safety profile is satisfactory, although patients presenting with thromboembolism risk factors should be treated with caution until the eltrombopag-associated prothrombotic risk is fully established. In summary, although larger studies are still needed to clarify some issues, eltrombopag may be a useful alternative tool for ITP patients refractory to conventional medical management or splenectomy.

Project description:Thrombopoietin (TPO) is the most potent cytokine stimulating thrombopoiesis. Therapy with exogenous TPO is limited by the formation of antibodies cross-reacting with endogenous TPO. Mimetics of TPO are compounds with no antigenic similarity to TPO. Eltrombopag is an orally-active nonpeptide small molecule that binds to the transmembrane portion of the TPO receptor MPL. Initial trials of eltrombopag have centered on immune thrombocytopenia (ITP), which is due to both increased destruction and decreased production of platelets. Eltrombopag at 25-75 mg/day has been shown to be highly effective in raising the platelet count in ITP with suboptimal response to immunosuppression and splenectomy. These successful results led to the exploration of eltrombopag in other thrombocytopenic disorders. In hepatitis C viral infection, eltrombopag raises the platelet count sufficiently enough to allow treatment with ribavirin and pegylated interferon. Because MPL is expressed on hematopoietic cells, eltrombopag use in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) might enhance leukemic proliferation. Clinical trials of eltrombopag in MDS and AML, however, have shown amelioration of thrombocytopenia without promoting disease progression. In severe aplastic anemia (SAA) not responding to immunosuppression with anti-thymocyte globulin (ATG) and cyclosporine, eltrombopag as a single agent at 150-300 mg/day results in an overall response rate of 40-70%. At high doses, adverse effects including pigmentation, gastrointestinal upset and hepatic derangement have become evident. Current studies have examined the first-line use of eltrombopag in combination with ATG in SAA. In a recent study, eltrombopag used at 150 mg/day with horse ATG resulted in an overall response rate of 90% in newly diagnosed SAA patients, with a complete response rate of about 50%. Clonal karyotypic aberrations are, however, found in 10-20% of SAA patients treated with eltrombopag. The safety and efficacy of eltrombopag in SAA require further evaluation, particularly when it is used with less intensive immunosuppression.

Dataset Information

Eltrombopag-based combination treatment for immune thrombocytopenia.

Publications

Eltrombopag-based combination treatment for immune thrombocytopenia.

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