expert roundtables

Choosing Between Thrombopoietin Receptor Agonists as Second-line Therapy in Chronic Immune Thrombocytopenia

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

Overview

Clinical trials have demonstrated that thrombopoietin receptor agonists (TPO-RAs) are safe and effective in the treatment of chronic immune thrombocytopenia (ITP) in adults and children. Some patients experience a sustained response and can enter into remission and postpone splenectomy with TPO-RA treatment. In the long-term, open-label EXTEND (Eltrombopag Extended Dosing) study, median platelet counts in adults increased with eltrombopag treatment, with patients experiencing safe and effective sustained treatment response for up to 8 years. Romiplostim was also shown to be effective and well tolerated for up to 5 years of continuous treatment in adults with chronic ITP. Although eltrombopag is the only TPO-RA that is currently approved by the US Food and Drug Administration for use in pediatric patients, analyses have been conducted to assess the efficacy and safety of both of the TPO-RAs in children with chronic ITP and have found TPO-RAs to be effective and safe in pediatric patients, with eltrombopag associated with lower rates of rescue medication use and bleeding events. A meta-analysis of 13 randomized controlled trials to determine the efficacy and safety of TPO-RAs in adults and children with ITP concluded that both TPO-RAs are effective and safe in the treatment of primary ITP. In the absence of direct head-to-head comparison studies, our featured experts discuss choosing between the TPO-RAs in the management of patients with chronic ITP.

Q: What efficacy and safety data should be considered when choosing between the TPO-RAs as second-line therapy for patients with chronic ITP?

Adam Cuker, MD, MS

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

“These are some of the differentiators that I think about when choosing, but I would say that, when we are making that initial treatment decision for a patient who has not previously been on a TPO-RA, route of administration is the major differentiator.”

Adam Cuker, MD, MS

When I talk to patients about the 2 TPO-RA treatment options, eltrombopag and romiplostim, the main differentiator that we discuss is the route of administration. Romiplostim is a once-weekly subcutaneous injection that, for most patients, needs to be given in a doctor’s office. So, that can impose a certain level of inconvenience for some patients, although we have had success getting home administration for some of our patients. Eltrombopag is a once-daily pill, but it, too, has inconveniences because the pill has to be timed appropriately so that it is not taken in proximity to other polyvalent cations, such as magnesium or calcium. It has to be taken apart from dairy because that will interfere with absorption of the drug. It has to be taken apart from iron because that will also interfere with absorption of the drug. So, we discuss the issues related to the route of administration with patients, and very often, in my experience, patients will develop a preference for 1 based on that discussion.

There are other things that also play a role for me in choosing between the TPO-RAs. Comorbidities can play a role. One example would be that, in a minority of patients, eltrombopag is associated with hepatobiliary laboratory abnormalities and hepatotoxicity. If I have a patient with liver disease, I would probably be more inclined to choose romiplostim over eltrombopag. In addition, it is my sense that there is greater platelet count fluctuation with romiplostim than with eltrombopag, but that is not in every patient. We have some patients on romiplostim who have very steady platelet counts, but we have others who have major swings in their platelet counts. Because eltrombopag is taken once a day rather than given once a week, it has been my experience that we do not tend to see such large platelet count fluctuations with eltrombopag. For some patients, that might be a relevant differentiator.

Lastly, there is published literature—and I have personal experience with this as well—where there is a fairly high rate of patients who, when they switch from 1 TPO-RA to another, respond to the second agent even when the reason for switching was lack of response to the first agent. This might be because they have somewhat different mechanisms of action. The 2 drugs bind to different parts of the thrombopoietin receptor. It might also have to do with potency. It is my sense that the highest doses of romiplostim are more potent than that highest approved doses of eltrombopag. These are some of the differentiators that I think about when choosing, but I would say that, when we are making that initial treatment decision for a patient who has not previously been on a TPO-RA, route of administration is the major differentiator.

Terry B. Gernsheimer, MD

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

“Due to similar efficacy and safety, the choice between eltrombopag and romiplostim frequently comes down to what the patient wants concerning the route of administration.”

Terry B. Gernsheimer, MD

The efficacy and safety data are similar for these 2 drugs, and I think that these 2 drugs are neck and neck. There are data from meta-analyses suggesting that eltrombopag may reduce the risk of bleeding more than romiplostim, but I certainly do not think that that is actually accurate. Due to similar efficacy and safety, the choice between eltrombopag and romiplostim frequently comes down to what the patient wants concerning the route of administration. For example, with romiplostim you must consider whether the patient wants to come in weekly to get an injection, but, hopefully, we are going to see the ability to do self-injection in the near future. I have a few insurance companies here that are now allowing that, but, for now, most patients who are on romiplostim have to come in weekly, and that could be a real disadvantage for some people. Interestingly, I have some patients who like coming in—they prefer to do that versus oral therapy with eltrombopag.

The other consideration is whether the patient can take an agent such as eltrombopag, which has dietary restrictions. Some patients cannot have that period, which is going to be a good 3 to 4 hours of fasting when they take the drug, and this fasting can be difficult for patients. There are some drugs that are coming down the pike that are similar to eltrombopag but without the dietary restrictions. That will change the algorithm. For now, I think that is what we have in terms of choosing between those 2 drugs.

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 agree that these agents have similar efficacy and safety, and the choice is usually made based on patient preference. In addition, there is also the issue of reimbursement and insurance coverage. Some patients can get injections of romiplostim in the office, and it will be covered by insurance. Those same patients will not have adequate coverage for eltrombopag as an outpatient oral medication due to the co-pay being too high. So, in addition to other treatment considerations, cost and reimbursement is 1 of the issues that still emerges in some patients when choosing a TPO-RA. 

References

Agnelli Giacchello J, Valeri F, Boccadoro M, Borchiellini A. Thrombopoietin receptor agonists in patients with persistent or chronic immune thrombocytopenia. Eur J Haematol. 2018;100(3):304-307.

Ghadaki B, Nazi I, Kelton JG, Arnold DM. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists. Transfusion. 2013;53(11):2807-2812.

Guo JC, Zheng Y, Chen HT, et al. Efficacy and safety of thrombopoietin receptor agonists in children with chronic immune thrombocytopenia: a meta-analysis. Oncotarget. 2017;9(6):7112-7125.

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.

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.

Vishnu P, Aboulafia DM. Long-term safety and efficacy of romiplostim for treatment of immune thrombocytopenia. J Blood Med. 2016;7:99-106.

Wang L, Gao Z, Chen XP, et al. Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: a systematic review and meta-analysis. Sci Rep. 2016;6:39003.

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.

Zhang J, Liang Y, Ai Y, et al. Eltrombopag versus romiplostim in treatment of children with persistent or chronic immune thrombocytopenia: a systematic review incorporating an indirect-comparison meta-analysis. Sci Rep. 2018;8(1):576.

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