Can immune thrombocytopenia be cured with medical therapy?

Abstract

Primary immune thrombocytopenia (ITP) in adults often assumes a chronic course that requires persistent monitoring and treatment. Medical therapy has traditionally been viewed as a means of temporarily raising the platelet count with little or no potential to induce long-term platelet responses off treatment. However, several recent studies have tested the hypothesis that intensive medical therapy administered early in the disease course may ameliorate or even cure ITP. In this review, we propose a biological rationale for medical intervention that simultaneously targets the innate and adaptive immune responses administered early in the course of disease. We also critically examine data on long-term outcomes after single-agent and multi-agent medical therapy. Intensive regimens that target inflammation and adaptive immunity (e.g., combination high-dose dexamethasone and rituximab) appear to improve response rates at 6 to 12 months compared with standard first-line therapy (e.g., prednisone, high-dose dexamethasone alone) in newly diagnosed patients. Controlled trials with extended follow-up are needed to determine whether these intensive regimens induce more cures compared with standard treatment or merely delay relapse at the expense of potentially greater toxicity.

Fig. 1

The generation of immunologic memory and persistence of ITP. A schematic of how the immune response may evolve over time in patients with ITP. We propose that most, if not all, patients with ITP initially respond to some type of exogenous antigen. During this initial priming phase, lasting 2–4 weeks, short-lived plasmablasts secrete antibodies and some of the antibodies that are produced happen to bind not only to the exogenous antigen but also to platelets. In many individuals, the priming phase ends and platelet counts increase without the need for further therapy as antigen is cleared. However, in some individuals, additional factors such as chronic inflammation, defective self-tolerance, or persistent antigenemia drive the adaptive immune response and over time this response evolves into a full-fledged memory response, with successive cycles of clonal expansion, somatic hypermutation, selection for high-affinity antibodies, and progressive diversification of responding antigen and T cell receptor repertoires (epitope spreading). The memory response is harder to eliminate than the primary response, because the number and diversity of responding clones is increased. Furthermore, the anatomic localization of the responding cells, their potentially lower threshold for activation, and increased resistance to apoptosis may make them harder to eliminate. These differences between primary and memory immune responses provide a biological rationale for the use of early and aggressive treatments that rapidly abrogate the priming immune response in the setting of initial disease before the memory response has a chance to become established. Ag, antigen; ITP, immune thrombocytopenia; SHM, somatic hypermutation. Different shades of the same color indicate different antibody (blue) or T cell receptor (red) clonotypes.