Immune thrombocytopenia guidelines get an annual checkup

In this issue of Blood Advances, Neunert et al¹ report on their systematic review of the literature performed to determine the need to revise or update the 2019 American Society of Hematology guidelines for immune thrombocytopenia (ITP).² In this field with multiple novel therapies on the horizon and many new publications reporting on potential important mechanisms of disease and targets for therapy,^3,4 the group looked to reassess the validity of the provided guidance. The findings indicate that although new evidence has emerged, it is insufficient to dramatically change the current guidelines or justify a full guideline revision. This article discusses the results of the literature review and the recommendations for changes to the guideline, especially suggesting clarification of second-line therapies in adults with ITP and updates to several other recommendations.

One of the major criticisms of the 2019 guidelines has been that clinicians are rarely in the position of deciding only between 2 treatments that is thrombopoietin (TPO) receptor agonist (RA) or splenectomy/rituximab or TPO RA, but the available methodology at the time did not have viable way to compare more treatment options. Since then, new methodologies have been developed, and a focused update to allow for updated guidance is proposed in this review, based on the available literature. Most of the other updates, based on a total of 54 studies, are not going to change the take home points of the original 2019 guidelines.

For example, although 2 new systematic reviews and 1 new randomized clinical trial looked at corticosteroids, the results of these studies did not provide sufficient difference to change the strength or direction of the 2019 guideline recommendation of a single course of either prednisone or dexamethasone as first-line therapy. In addition, although the authors found no new trials addressing the addition of rituximab to first-line therapy, they did identify trials of combination therapy of corticosteroids paired with other treatments: TPO-RAs, all-trans retinoic acid, and mycophenolate mofetil, which make up a new category of therapeutic options but do not overall change recommendations for preferred therapeutic options.

One of the most exciting parts of the ITP therapeutic landscape is the emergence of novel therapies, and the review acknowledges these developments. The novel TPO-RA (avatrombopag approved by the Food and Drug Administration and hetrombopag approved in China) are already addressed in current guideline language, and the additional literature for new drugs in this class did not alter recommendations for safety or efficacy in adults with persistent or chronic ITP. Meanwhile, the spleen tyrosine kinase inhibitor fostamatinib has mainly been studied in patients who are highly refractory, making generalizability difficult, but there has been new literature to support this therapeutic option in a more general ITP population. We can expect a focused update to help clarify second-line therapies and also using new methodologies to potentially examine multiple treatment types limiting analysis to pairwise comparisons.

Overall, the authors give the pediatric guidelines a clean bill of health. The authors acknowledge newly published work investigating intravenous immunoglobulin vs observation in children with newly diagnosed ITP and note small trials of sirolimus, cyclosporine, and hydroxychloroquine in children with non–life-threatening mucosal bleeding and/or diminished health–related quality of life. The updated guidelines are not likely to be very different but will have further support for observation of patients without bleeding symptoms based on the results of the randomized clinical trial for intravenous immunoglobulin.

Underlying this report is an important question: how often should guidelines be reviewed or revised? Benchmarks developed by the Institute of Medicine Committee on Standards for Developing Trustworthy Clinical Practice Guidelines include regular “updating” as a criterion by which clinical practice guidelines may be judged.⁵ But the interval at which guidelines should be reviewed is intentionally left vague, because the benefits of review must be weighed against the time, effort, and resources needed to enact them. Timing of review is also dependent on the speed of research in a given field. By committing to yearly reviews, the authors underscore the pace at which new evidence is being generated in the field of ITP.

In conclusion, Neunert et al demonstrate that although progress has been made in ITP, the 2019 guidelines remain pertinent. We look forward to a focused update or clarification on second-line therapy for adults, particulary because of discordant recommendations in the last guideline. However, this literature review demonstrated that despite a large body of work in ITP since the publication of the last guidelines, all the prior recommendations remain relevant, and a complete guideline revision is not necessary. As research moves apace and medical literature ever expands, it becomes critical for guidelines to remain dynamic. An annual and focused approach to updating the ITP guidelines will create a flexible resource that all practitioners can trust.

Conflict-of-interest disclosure: M.P.L. is an advisory board member for Octapharma, Dova, Principia, Rigel, Argenx, Platelet Disorder Support Association (PDSA), 22qSociety, and CdLS Foundation; a consultant for Novartis, Dova, Principia, Argenx, Rigel, Sobi, Sanofi, and Janssen; and has received research funding from the Foundation For Women and Girls with Blood Disorders, PDSA, National Institutes of Health, Sysmex, Novartis, Principia, Argenx, Dova, Octapharma, and Sanofi. P.M.G. declares no competing financial interests.