expert roundtables

Necessary Clinical Updates in the Current Treatment Guidelines for the Management of Immune Thrombocytopenia

by Adam Cuker, MD, MS, Terry Gernsheimer, MD, Howard A. Liebman, MD

Overview

Published in 2011, the clinical treatment guidelines for immune thrombocytopenia (ITP) sponsored by the American Society of Hematology (ASH) are outdated and currently lagging behind clinical practice. At the time of their publication, there were limited long-term safety and efficacy data available on thrombopoietin receptor agonists (TPO-RAs), but there are now long-term study data on the clinical use of eltrombopag and romiplostim, as well as other advances that have changed the clinical landscape of ITP management. In 2015, ASH convened an expert panel to update the guidelines with a systematic review and evidence-based analysis of new clinical data. Our featured experts in the field discuss necessary clinical updates in the current treatment guidelines for the management of ITP.

Q: What clinical updates should be included in the current treatment guidelines for the management of ITP that are currently being revised?

Howard A. Liebman, MD

Donald I Feinstein Chair in Medicine
Professor of Medicine and Pathology
Jane Anne Nohl Division of Hematology
USC Norris Cancer Hospital
Los Angeles, CA

“I think that there are a couple of things that should and will be updated. There are now positive long-term extension data published on both of the approved TPO-RAs that were not available in 2011, so that will be added to the long-term treatment regimens. There are also additional long-term data about anti-CD20 monoclonal antibody treatment, which should hopefully lower the enthusiasm for that treatment regimen.”

Howard A. Liebman, MD

I think that there are a couple of things that should and will be updated. There are now positive long-term extension data published on both of the approved TPO-RAs that were not available in 2011, so that will be added to the long-term treatment regimens. There are also additional long-term data about anti-CD20 monoclonal antibody treatment, which should hopefully lower the enthusiasm for that treatment regimen. The recent anti-CD20 data include some results that suggest patients who might be a preferred population for anti-CD20 therapy if you are going to use it at all, with younger women having the best outcomes and older patients having much poorer outcomes. Overall, it all translates out to about 20% at 5 years and maybe a little over 30% at 1 year, which isn’t something to justify the enthusiasm for anti-CD20 therapy in the community. As far as pediatric patients are concerned, the randomized study from the Netherlands is going to reinforce the European opinion and support increased watchful waiting, with interventions only for children who might have issues with head trauma or more significant bleeding manifestations. I think that data should be included in the guidelines, but I am not sure if pediatricians in the United States will feel comfortable following European standards, with parents indicating their anxiety about their child walking around with 2000 platelets. There is nothing new on splenectomy since 2011, but I do not think that splenectomy is going to disappear from the guidelines because there is a population that probably does better, which are younger individuals. Much of the data about long-term response in splenectomy included a lot of young women who were in as early as 6 months of follow-up when it called ITP “chronic.” Therefore, doing splenectomy after 2 or 3 years is not as effective as it is claimed, and no doubt it is not as effective in the older patient population. Even with the coming updates, there are ongoing clinical trials of some newer agents that are being looked at as alternate therapies, such as a third-line agent, the highly purified Staph A, which is thought to be a potentially alternate approach early on. Clinical trials and research are ongoing in ITP, so we will see what happens next.

Terry B. Gernsheimer, MD

Director of the University of Washington
Medical Transfusion Service
Professor of Medicine, Division of Hematology
University of Washington
Seattle, WA

The safety of TPO-RAs in children will make the pediatric section and will include that as one of the recommendations because there are now positive randomized trial data on that. So, there should be pediatric recommendations for the use of the TPO-RAs. They will probably also include the fact that earlier use of the TPO-RAs may be appropriate because of the long-term data.”

Terry B. Gernsheimer, MD

One additional thing will be the randomized studies with the TPO-RAs, not just in adults but also in children. The safety of TPO-RAs in children will make the pediatric section and will include that as one of the recommendations because there are now positive randomized trial data on that. So, there should be pediatric recommendations for the use of the TPO-RAs. They will probably also include the fact that earlier use of the TPO-RAs may be appropriate because of the long-term data. Although there have been some good data showing that watchful waiting can be safe in children, I still was not as impressed that it is as safe as some say because they still had events. They could predict that the events would generally be seen in the children who had very low counts, but they still were events. I think that in Europe, it is partly economic because treating pediatric patients is more expensive than not treating them. Cost plays into why they are going to say that watchful waiting is probably okay in certain cases. Although I do not know whether or not they will address the data that keep coming out, I think that it might be interesting to discuss the use of indium platelet scanning and the usefulness of splenectomy, whether or not it can predict the response to splenectomy. There are clinicians who believe and who do not believe those data, but I’m hoping that the guidelines will at least touch on whether or not indium platelet scanning is useful. Another thing is that, because anti-D treatment is no longer available in Europe for the treatment of ITP, I am wondering what they are going to do with that. I do not know if they have completely taken it off the market because they may still be using it for other circumstances, where women may have either a bleed postpartum or whether somebody gets a unit of platelets or red cells that is Rh positive that they should not have gotten, but they may comment on the fact that anti-D is no longer used in Europe and is not recommended there. It is a good drug, it is just mostly that the way the US Food and Drug Administration has changed the labeling in terms of how long the time is that you have to infuse it over has taken away a lot of the advantage of it, although I think that the data still show that you get a longer duration of response with anti-D than with intravenous immunoglobulin G.

Adam Cuker, MD, MS

Assistant Professor of Medicine
Director, Penn Comprehensive Hemophilia and Thrombosis Program
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

“The recommendations from the 2011 guidelines regarding second-line therapy are outdated, and there needs to be new recommendations that acknowledge the expanding role of the TPO-RAs and the relatively diminishing role of splenectomy, and provide more clarity on the role of rituximab.”

Adam Cuker, MD, MS

By way of disclosure, I am on the ASH panel, so I already know what recommendations will be included. I will not answer as a panelist, but as a clinician who is interested and takes care of patients with ITP. One of the key issues is concerning the best treatment for first-line therapy, and whether standard-dose prednisone or high-dose dexamethasone should be used. The recommendations from the 2011 guidelines regarding second-line therapy are outdated, and there needs to be new recommendations that acknowledge the expanding role of the TPO-RAs and the relatively diminishing role of splenectomy, and provide more clarity on the role of rituximab. The 2011 guidelines did not come out strongly one way or another on rituximab, and it would be helpful to have more clarity on that. Another thing that I noticed when looking through the 2011 guidelines is that there is a recommendation on treating ITP in the background of hepatitis C that mentions interferon and its propensity for worsening thrombocytopenia, but that is really no longer a concern because interferon is not used in developed countries like the United States to treat hepatitis C because there are now highly effective oral therapies. Therefore, that is an obsolete recommendation. Looking through the recommendations regarding childhood ITP, the 2011 guidelines included no mention about the use of the TPO-RAs for second-line therapy in children and, clearly, that’s something that needs to be mentioned in the updated guideline because we now have evidence on that. Finally, one important issue that the 2011 guidelines do not address that I would like to see addressed in the updated guideline is recommendations on third-line therapy. For instance, what do you do if you’re in a country like the United States and your patient does not respond to or does not tolerate any of the second-line therapies? In addition, to make these guidelines more useful in parts of the world where rituximab or the TPO-RAs may not be widely available, what do you do in those countries where access to those drugs is limited if your patient needs treatment beyond standard first-line therapy? Those include some of the key points that I identified that I hope that the updated guidelines will address.

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