Novel Therapies to Address Unmet Needs in ITP

Abstract

Primary immune thrombocytopenia (ITP) is an autoimmune disorder that causes low platelet counts and subsequent bleeding risk. Although current corticosteroid-based ITP therapies are able to improve platelet counts, up to 70% of subjects with an ITP diagnosis do not achieve a sustained clinical response in the absence of treatment, thus requiring a second-line therapy option as well as additional care to prevent bleeding. Less than 40% of patients treated with thrombopoietin analogs, 60% of those treated with splenectomy, and 20% or fewer of those treated with rituximab or fostamatinib reach sustained remission in the absence of treatment. Therefore, optimizing therapeutic options for ITP management is mandatory. The pathophysiology of ITP is complex and involves several mechanisms that are apparently unrelated. These include the clearance of autoantibody-coated platelets by splenic macrophages or by the complement system, hepatic desialylated platelet destruction, and the inhibition of platelet production from megakaryocytes. The number of pathways involved may challenge treatment, but, at the same time, offer the possibility of unveiling a variety of new targets as the knowledge of the involved mechanisms progresses. The aim of this work, after revising the limitations of the current treatments, is to perform a thorough review of the mechanisms of action, pharmacokinetics/pharmacodynamics, efficacy, safety, and development stage of the novel ITP therapies under investigation. Hopefully, several of the options included herein may allow us to personalize ITP management according to the needs of each patient in the near future.

Keywords: autoantibodies; immune thrombocytopenia; platelets; targeted therapies; thrombopoietin.

Figure 1

Mechanisms of platelet destruction in ITP. The immune imbalance leads to the excessive activation of cytotoxic T cells and autoreactive B cells. Plasma cell formation induces the release of antiplatelet autoantibodies. As a result, the opsonized platelets are destroyed by phagocytes, which can also present antigens to Th cells. Opsonized platelets can also be destroyed by the complement system; their surface glycoproteins are exposed to desialylation. This leads to subsequent platelet cleavage in the liver by Kupffer cells, after binding hepatocytes via Ashwell–Morell receptors. Finally, autoantibodies also interfere with platelet generation from megakaryocytes in the bone marrow. Note: APC, antigen presenting cell; KC, Kupffer cell.

Figure 2

Treatment preferences to manage ITP, according to the current guidelines. Splenectomy should not be considered an option during the first 12 months after diagnosis. Third-line treatments are not necessarily arranged according to hierarchy. Note: CLD, chronic liver disease; CTC, corticosteroids; ITP, primary immune thrombocytopenia; IVIGs, intravenous immunoglobulins; RTX, rituximab; TPO-RAs, thrombopoietin receptor agonists.