Identifying and treating refractory ITP: difficulty in diagnosis and role of combination treatment

Abstract

Immune thrombocytopenia (ITP) is the most common acquired thrombocytopenia after chemotherapy-induced thrombocytopenia. Existing guidelines describe the management and treatment of most patients who, overall, do well, even if they present with chronic disease, and they are usually not at a high risk for bleeding; however, a small percentage of patients is refractory and difficult to manage. Patients classified as refractory have a diagnosis that is not really ITP or have disease that is difficult to manage. ITP is a diagnosis of exclusion; no specific tests exist to confirm the diagnosis. Response to treatment is the only affirmative confirmation of diagnosis. However, refractory patients do not respond to front-line or other treatments; thus, no confirmation of diagnosis exists. The first section of this review carefully evaluates the diagnostic considerations in patients with refractory ITP. The second section describes combination treatment for refractory cases of ITP. The reported combinations are divided into the era before thrombopoietin (TPO) and rituximab and the current era. Current therapy appears to have increased effectiveness. However, the definition of refractory, if it includes insufficient response to TPO agents, describes a group with more severe and difficult-to-treat disease. The biology of refractory ITP is largely unexplored and includes oligoclonality, lymphocyte pumps, and other possibilities. Newer treatments, especially rapamycin, fostamatinib, FcRn, and BTK inhibitors, may be useful components of future therapy given their mechanisms of action; however, TPO agents, notwithstanding failure as monotherapy, appear to be critical components. In summary, refractory ITP is a complicated entity in which a precise specific diagnosis is as important as the development of effective combination treatments.

Graphical abstract

Figure 1.

An estimate of the incidence of primary ITP vs other diagnoses in patients defined as having “refractory ITP.” These percentages may vary considerably depending on the clinical setting and geographical location. BMF, bone marrow failure syndromes.

Figure 2.

Flowchart for the identification and treatment of patients with refractory ITP. Ag, antigen; ANA, anti-nuclear antibodies; CMP, comprehensive metabolic panel; CRP; C-reactive protein; CMV, cytomegalovirus; ESR, erythrocyte sedimentation rate; Eval, evaluation; HCV, hepatitis C virus; H pylori, Helicobacter pylori; plt/Plt, platelets; PT, prothrombin time; PTT, partial thromboplastin time; TIBC, total iron binding capacity; Tx, treatment.

Figure 3.

Illustration of the different mechanisms of action of ITP medications. Immunosuppressive agents are also listed. Ab, antibody; BTK inh, BTK inhibitor; c-MpL, thrombopoietin receptor; IL, interleukin; MMF, mycophenolate mofetil; PC, plasma cell; Plt, platelets; Th, helper T cell; TLR-4, Toll-like receptor-4; TNF-α, tumor necrosis factor-α; Treg, regulatory T cell.