ITP Definitions: Time for an Update.

The last 15 years have shown great progress in the management of immune thrombocytopenia (ITP), ranging from the introduction and licensing of two thrombopoietin receptor agonists (TPORA), eltrombopag and romiplostim, to more recently, a Syk tyrosine kinase inhibitor (fostamatinib) and two other TPORA (avatrombopag and hetrombopag). Novel therapies are being evaluated in phase 3 studies (inhibitors of BTK, FcRn and BAFF) while others have also been evaluated in clinical trials (e.g. Mycophenolate Mofetil, ATRA and oseltamivir).1 These advances have dramatically altered ITP management. Splenectomy, previously standard secondline therapy, is now rarely performed.2 In many parts of the world, patients are being treated with TPORA which are as effective as splenectomy but often require continuous administration. With the growing number of medical options, substantially fewer patients are becoming “refractory.” These advances mandate reassessment of the following conceptual definitions and goals in the treatment of ITP: disease phases, treatment response, remission, refractory, treatment goals and acceptable target platelet levels. The International Consensus Report3 and the American Society of Hematology (ASH) guidelines,4 together with an international working group (IWG) document on standardisation of terminology, definitions and outcome criteria5 define the management of ITP in much of the world. While developing recommendations can be prolonged and resourceintensive, they can also become quickly outdated. Current classification is into three phases: newly diagnosed (0– 3 m), persistent (>3– 12 m) and chronic (>12 m). The stated aim was guiding clinicians to defer splenectomy until the potential for spontaneous remission is over.5 However, patients in newly diagnosed or persistent phases have been excluded from some trials of novel treatments. Authorities licence successful therapies accordingly, thus introducing timedependent limits on access to treatment because reimbursement by health care systems is likely to be rejected outside the phases examined in trials. Phase boundaries are arbitrary cutoffs and are not based on pathophysiology. The use of these phases, which are discouraged for autoimmune haemolytic anaemia terminology,6 may no longer serve our patients. In contrast, the clinically pragmatic IWG definition of response: platelets >30 × 109/L, double baseline and absence of bleeding, has not been widely adopted in trials.7 Instead, studies designed for regulatory approval often require sustained platelets >50 × 109/L, potentially underestimating the clinical value of lower platelet targets. But even the IWG “response” may be inadequate when treatment is personalised. For example, other clinical variables affecting bleeding risk (age, prior bleeding events, anticoagulant use) may require a different “haemostatic” response, say >50 × 109/L for patients on dual antiplatelet therapy. Finally, the IWG threshold of complete response (platelets >100 × 109/L) may not be useful or predictive of bleeding risk. Also infrequently reported but of equal relevance for clinical outcome is the “durability” of treatment response. IWG proposed “proportion of cumulative time spent with response” for maintenance treatment. If this was measured as the percentage of weeks with a response, this is clinically relevant in comparing treatments. An acceptable definition of “remission” has not been created but is variably reported in studies. In many diseases, this term reflects the absence of disease activity, and the absence of concurrent therapy may not be critical. In this quest for clarity, whether “response”, “durability” or “remission” is the result of ongoing maintenance treatment is relevant given that many ITP therapies such as the TPORA may be ongoing. The likelihood of successfully discontinuing a maintenance treatment is of great interest to patients and providers of health care resources. Further confounding the concept of “maintenancefree” is that some treatment effects persist after the treatment ends; Bcell depletion may last for months or years after rituximab and splenectomy creates a lifelong disorder of asplenia. Does an ITP patient with a normal platelet count after splenectomy have an unmaintained remission? The exact meaning of a “line” of treatment, has not yet been addressed by the IWG. If the patient initially receives prednisolone and IVIg together, is that one line of combination treatment, one line and one rescue or two lines? If they then receive romiplostim and then rituximab, have they received second and third line, or two “second line” treatments? The International Consensus eschewed the concept of “lines” and simply referred to “initial” then “subsequent therapy”. As use of splenectomy declines, the definition of “refractory” ITP, which currently requires patients to be nonresponders or losing splenectomy response, needs updating. The standardisation of terminology within a field should be the domain of a single IWG, seeking broad Received: 4 March 2023 | Accepted: 23 March 2023