expert roundtables

Clinical Trials in Immune Thrombocytopenia

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

Overview

New therapies and treatment recommendations for chronic immune thrombocytopenia (ITP) have emerged in the last decade, including the thrombopoietin receptor agonists (TPO-RAs) eltrombopag and romiplostim. These treatments have provided important clinical trial data regarding the long-term treatment of chronic ITP. Although recent studies have improved treatment outcomes for patients with chronic ITP, several clinical trials are being conducted to assess new treatments for the disorder, including nonspecific immunosuppressant therapy, molecule targeting therapy, and platelet- increasing therapies. These additional prospective clinical trials may lead to improved outcomes in patients with chronic ITP.

Q: What ongoing clinical trials are being performed that use novel agents to improve patient outcomes in chronic ITP, and what additional clinical trials are needed?

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

“The standard has been set by the TPO-RAs, so new agents will need to have extension studies to document the long-term safety and efficacy of these agents to get a good sense of how patients do with long-term use of these drugs.”

Howard A. Liebman, MD

The most recent trial that has been completed, and the data are sitting at the US Food and Drug Administration (FDA), is for the oral spleen tyrosine kinase (Syk) inhibitor fostamatinib for ITP. I think that long-term data for anything are going to be required, and any clinical data package that makes it to being considered for FDA approval in the United States is based on phase 3 studies. The standard has been set by the TPO-RAs, so new agents will need to have extension studies to document the long-term safety and efficacy of these agents to get a good sense of how patients do with long-term use of these drugs. All of the other investigational agents that I am aware of are very early on in their studies, so we do not know outcomes yet. However, some seem very promising in early presentations of phase 1 and 2 data, such as the FcRn inhibitors. Extension studies will be needed on all of these investigational agents if they make it through a phase 3 study, and most of the groups that are moving along are allowing redosing in their phase 2 trials to support a phase 3 trial.

In addition, finding patients with ITP to include in clinical studies is very hard nowadays because there are so many effective therapies that can maintain a good platelet count, such as the TPO-RAs. This has changed the story with clinical trials. Therefore, it is now more difficult to conduct and recruit for clinical studies, and study populations end up being very refractory patients or those patients who have complications related to the therapy, including complications on TPO-RAs. So, a more difficult-to-treat patient group is being studied with the new agents, compared to the patients studied in the romiplostim trial, which is the first of the TPO-RAs.

Adam Cuker, MD, MS

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

“One question to study is, could we improve upfront response rates, reduce toxicity, and improve quality of life in patients with ITP simply by going straight to a TPO-RA in the front line? And then these trials where we test the first-line use of a TPO-RA will also help to answer the question of whether TPO-RAs can induce remission compared with just using steroids alone in the first line.”

Adam Cuker, MD, MS

One thing that I think we need to do is to get to a place where we can test strategies of using biomarkers to guide treatment decisions. I would love someday to have a clinical trial where we identify, for example, a biomarker that predicts responsiveness to rituximab. In one arm of the study, the patients are all treated with rituximab, and in the other arm, the patients are tested with this biomarker. And only those with a certain result could go on to receive rituximab, while those with another result might go on to receive, for example, a TPO-RA. My hypothesis is that if we do a study such as this correctly, we can improve the response rates to the different treatments by matching a patient’s individual pathophysiology with the right treatment choice for that patient. So, sort of a form of personalized medicine. That is one category of clinical trials that we really have never done in ITP, which is an important aspiration for the future.

Another trial that I’m very interested in, that companies are working on, are trials of using TPO-RAs as part of upfront therapy for ITP. Right now, TPO-RAs are used as second-line therapy. To some degree, I think that there’s a fallacy to the way we treat ITP. We currently use steroids first-line, and patients hate steroids because of all of the side effects they experience, and, although most patients do respond to steroids, most of them will lose their response when the steroids are tapered, and then we need to go on to second-line therapy. The question then becomes, why are we putting patients through this? We treat them with steroids, we know that they are not going to like them, we think that they are probably going to respond, and, when they lose their response, we put them on something else, such as a TPO-RA, which is generally more tolerable and has good response rates. One question to study is, could we improve upfront response rates, reduce toxicity, and improve quality of life in patients with ITP simply by going straight to a TPO-RA in the front line? And then these trials where we test the first-line use of a TPO-RA will also help to answer the question of whether TPO-RAs can induce remission compared with just using steroids alone in the first line. That is another kind of clinical trial that I am very interested in.

Then, of course, there are novel agents being developed for ITP (eg, drugs that block the neonatal endothelial Fc receptor). There are several companies in this space that have their eye on ITP. There are other drugs that block pathways within the platelet after an immunoglobulin G antibody binds to the platelet, such as Syk inhibitors and other drugs in this space that I am aware of as well. There is a need to continue to develop new agents and to test them in ITP, although I will say that I think it’s getting harder and harder to do that because the TPO-RAs are so effective that we have fewer and fewer patients who do not respond to and do not tolerate standard second-line therapies and who would be the patients you might target for phase 1 trials with those novel agents.

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 bar has been raised really high now because of the TPO-RAs, so it is much harder to find patients for clinical studies in ITP. It is difficult to try an experimental agent on a patient when he or she is responding nicely to a TPO-RA and is not having any bad reactions or side effects from treatment.”

Terry B. Gernsheimer, MD

The bar has been raised really high now because of the TPO-RAs, so it is much harder to find patients for clinical studies in ITP. It is difficult to try an experimental agent on a patient when he or she is responding nicely to a TPO-RA and is not having any bad reactions or side effects from treatment. Understand that the TPO-RA, when those studies were getting done, we didn’t have anything that really was good that didn’t have tons of side effects when used long-term. So, it’s going to take a lot longer to get these studies done and to convince people that these agents are worth using because we don’t have as many refractory patients, meaning patients who are unresponsive, anymore. We are down to a much lower percentage of patients, probably less than 20%, who are not going to respond to TPO-RAs or cannot take a TPO-RA for some reason, or patients who just do not want to continue on them and want to try something else.

References

Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161(3):411-423.

Neunert CE. Management of newly diagnosed immune thrombocytopenia: can we change outcomes? Blood Adv. 2017;1(24):2295-2301.

Nomura S. Advances in diagnosis and treatments for immune thrombocytopenia. Clin Med Insights Blood Disord. 2016;9:15-22.

Saleh MN, Bussel JB, Cheng G, et al; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121(3):537-545.

Wong RSM, Saleh MN, Khelif A, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study [published correction appears in Blood. 2018;131(6):709]. Blood. 2017;130(23):2527-2536.

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