Adherence to ITP guidelines and adequate immunotherapy

In this issue of Blood Advances, Gunn et al¹ present a multicenter observational study comparing 2 consecutive cohorts of children with newly diagnosed immune thrombocytopenia (ITP) and no or mild bleeding signs. The aim was to optimize adherence to the American Society of Hematology ITP guidelines by implementation of a clinical pathway with initial management decisions based on a low bleeding score instead of platelet count. The main message from the analyses demonstrates a markedly increased rate of observation alone (watch and wait) in the second prospective cohort with adherence to the 2019 ASH ITP guidelines.² In addition, management decisions based on bleeding score showed a low rate of IV immunoglobulin (IVIG) administration compared with the retrospective cohort with adherence to the 2011 ASH ITP guidelines³ and management according to low platelet count.

In both the ASH ITP guidelines observation alone (watch and wait) was recommended, and if treatment was required, the 2011 ASH ITP guidelines suggested either administration of a single dose of IVIG/anti-D or a short course of corticosteroids, whereas the 2019 guidelines suggested corticosteroids over IVIG/anti-D. These different recommendations between the 2 cohorts resulted in an increase of the rate of observation alone from 37% to 61% and a decrease of IVIG/anti-D administration from 51% to 15%, whereas the clinical outcome within the first 6 months after diagnosis remained comparable with no increase of bleeding events or hospitalizations and with similar remission rates.

Guidelines for other hematological disorders experienced poor adherence, that is, for children with sickle cell disease⁴ or for adults undergoing thrombophilia testing, which poorly influenced anticoagulation therapies.⁵ In contrast, the successful adherence to the ASH ITP guidelines is based on a close collaboration and horizontal communication across the various 12 centers of the ITP Consortium of North America (ICON). The project leaders initiated a structured cooperation sharing experiences with local physicians and trainees, organizing regular data review meetings and inducing awareness of quality improvement.

ITP is a rare bleeding disorder in individuals characterized by transient and/or long-term imbalanced immune system. Antibody coated platelets are removed from the circulation by early immune elimination. In children, ITP often occurs as a transient postinfection/vaccination phenomenon. The heterogeneity of ITP is high concerning age, sex, bleeding manifestation, pathogenesis, spontaneous remission, treatment response, and follow-up. In children, spontaneous remission is more frequent than in adolescents and adults.⁶ In recent years registries analyzed worldwide data of children and adults resulting in new definitions of ITP⁷, in heterogeneities,⁸ in the rates of remission (platelet count of >100 × 10⁹/L) in children were 77% at 24 months, 50% in adolescents, and 30% in adults⁶; from another registry the bleeding manifestations initially and during the follow-up and the management were analyzed.⁹

This study exhibits some limitations concerning overall comparability of the retrospective and prospective cohort and the 2 different versions of guidelines. Specifically, the eligible subgroup of ITP covering all ages of children including very young children and adolescents, the management decisions based either on the degree of platelet count or on bleeding score and the study duration was limited (6 months). Furthermore, the unknown numbers of patients who are participating in other clinical trials parallel to this study, and deviations due to fearful bleeding symptoms and/or to adverse effects of immunosuppressive treatments disturbing the health-related quality of life reduced the adherences to guidelines.

ICON now has the potential to perform controlled randomized studies, in which the limitations of the present observational study could be resolved in part, by parallel analyses, by restricted eligibility of heterogenous ITP, by confirmation of new decision-making based on a bleeding scores vs platelet counts in parallel and by long-term follow-up of patients with persistent and chronic ITP.

This study of children with no or mild bleeding symptoms confirms that IVIG should mainly be an indication in prevention and treatment of severe bleedings. Within the last 40 years IVIG administration has become a favored treatment option in patients with ITP characterized by rapid platelet increases, immunomodulation in ITP and in other chronic inflammatory and autoimmune disorders and more acceptable adverse effects. However, the half-life of IVIG is short (21 days), the relapses in chronic ITP are frequent and the financial expenses are high. But ITP became a model disorder for IVIG in autoimmune disorders. Firstly, the observation of a boy with severe refractory ITP and secondary hypogammaglobulinemia due to long-term immunosuppressive treatment leads to a pilot study in children with ITP which opened the door to other IVIG–immunomodulatory indications.¹⁰ The polyvalent immunoglobulin G (IgG) concentrate from tens of thousands of healthy blood or plasma donations influences the various, complex cellular and humoral immune components of the disturbed immune system in a synergistic way (see figure).¹¹ In clinical studies a wide range of indications in chronic inflammatory and autoimmune diseases with similar immune pathogeneses demonstrated beneficial IVIG results and reached registration by authorities; however, real dose-finding studies do not exist. The global human derived IgG demand and supply are increasing every year.¹² Therefore, adequate indications of immunotherapy should be elaborated. In addition, the polyclonal mechanisms of action of IVIG stimulated the development of targeted monoclonal antibodies, agonists, and antagonists, such as targeted monoclonal antibodies for blockade of neonatal Fc receptor on B cells, reducing autoantibody production, targeting complement inhibition, and thrombopoietin receptor agonists stimulating platelet production; all of these may influence the future demand of IVIG. Other indications besides the classic IgG substitution in patients with primary and secondary immune deficiencies¹³ will remain a domain of IVIG such as heparin-induced and vaccine-induced immune thrombocytopenia and thrombosis,¹⁴ autoimmune disorders in neurology and dermatology, Kawasaki disease, Guillain-Barré syndrome, and others.¹²

Synergistic (arrows) interactions of the complex immune system¹¹ reflect the mechanisms of action of IVIG administration in ongoing or chronic ITP and other autoimmune disorders. Disturbances appear to be transient in patients with newly diagnosed ITP who have no or low bleeding signs and observation only, and who spontaneously recover, as discussed in.¹ MHC-I, major histocompatibility complex class I.

Let us close with a fascinating new aspect. Besides their hemostatic functions, platelets also have immunologic properties¹⁵ which raises the question: do patients with autoimmune disease and platelet involvement profit from early aggressive platelets treatment together with concomitant therapies¹⁶ contribute to a synergistic immunomodulation (see figure)?

Conflict-of-interest disclosure: The author declares no competing financial interests.