Eltrombopag Fills Unmet Need in Hematologic Disorders, But More Work Remains

Alvaro Jose Alencar, MD

The addition of eltrombopag (Promacta) offered patients with benign hematological disorders, such as immune thrombocytopenia (ITP) and aplastic anemia, another effective treatment option after failing available options, said Alvaro Jose Alencar, MD. However, while this was an important step forward in the clinical space, more work is required.

Historically, patients with these 2 disorders had been treated with immunosuppressive therapies. Patients with ITP would be given steroids, while those with aplastic anemia would be administered the combination of antithymocyte globulin (ATG) and cyclosporine. Better understanding of these disorders resulted in the development of thrombopoietin receptor agonists, such as eltrombopag.

“The therapies that used to be the standard until the application of eltrombopag for aplastic anemia were very effective, but there was still a very large group of patients who were failing this therapy; the same [was true with] ITP,” said Alencar. “With ITP, in the first-line setting, most patients respond to steroids, but sometimes they fail steroids and require more therapies.”

In November 2018, the FDA approved eltrombopag in combination with standard immunosuppressive therapy (IST) to include newly diagnosed adult and pediatric patients 2 years and older with severe aplastic anemia. The oral thrombopoietin receptor agonist was previously indicated for patients with severe aplastic anemia who have had an insufficient response to standard therapy, for adults and pediatric patients with chronic ITP who are refractory to other therapies, and for the treatment of thrombocytopenia in patients with chronic hepatitis C virus infection.

The most recent regulatory decision was based on positive data from an analysis showing that the combination resulted in an overall response rate of 79% (95% CI, 69%-87%) at 6 months. Moreover, 44% of IST-naïve patients achieved a complete response when IST was given concurrently with eltrombopag—a rate that was 27% higher than what was historically observed with IST alone. Now, according to Alencar, investigators are hoping to see similar success with the agent in the frontline setting as well.

OncLive: How has the treatment of immune-mediated hematological disorders evolved?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Alencar, an assistant professor of medicine at Sylvester Comprehensive Cancer Center, University of Miami Health System, highlighted advances made in the treatment of patients with these disorders, offered advice on how to choose between available agents, and shed light on future research.Alencar: ITP and aplastic anemia are 2 immune-mediated disorders that have mainly been treated with IST—steroids for ITP or the combination of ATG and cyclosporine for aplastic anemia. We are learning more that thrombopoietin is an extremely important stimulant or protein in these 2 disorders. Initially, it was thought to be associated with the stimulation of platelet production, but now we know that it's actually acting on the stem cells and has an important function in aplastic anemia. [There is] a use for thrombopoietin receptor agonists in the treatment of patients with ITP in the second-line setting, as well as the use of eltrombopag, the main thrombopoietin receptor agonist that has been evaluated in aplastic anemia.

What key trials do you wish to highlight in this area?

What unmet needs with these disorders still need to be addressed?

These are disorders that will significantly impact quality of life. Aplastic anemia, if left untreated, is a highly deadly disease; it typically will affect very young patients. Treatment will dramatically change their lifespan. Without treatment, they would die within a couple of years. With treatment, we will most likely cure the great majority of them. Therefore, it's fundamental that we have proper therapies. Understanding the disorders better and using more targeted agents will allow us to treat these patients better with less toxicity.There were phase III trials that evaluated the use of eltrombopag, as well as romiplostim (Nplate), versus standard of care [or] versus placebo in relapsed/refractory ITP. There were also studies that evaluated the use of fostamatinib (Tavalisse) in patients who were refractory to thrombopoietic medications. I spoke about the single-arm study evaluating eltrombopag in patients with relapsed/refractory aplastic anemia and the larger study in the first-line setting, which combined eltrombopag with an ATG and cyclosporine.For ITP, it's trying to see if there is a way that we can minimize the use of these drugs. Still, today, when we use these agents, patients have to stay on them forever. However, we know that some patients can discontinue and remain off therapy. We’re trying to understand if there's a way that we can minimize the use of these drugs instead of using them [indefinitely].

In aplastic anemia, the follow-up on the use of eltrombopag in the first-line setting is still relatively short, so we don't know if we're going to see different problems in the long run. We know that some of these patients can have new genetic abnormalities; potentially, they could [develop] a new problem, such as myelodysplastic syndrome or acute myeloid leukemia, in the future.

In second-line ITP treatment, how do you use patient selection to choose therapy?

More than anything, we need to understand how these [agents] are going to pan out in longer follow-up. We also know that some patients don't respond as well to IST, so using next-generation sequencing or molecular markers to determine whether there are patients who are more or less likely to respond to IST is needed in aplastic anemia.Romiplostim is a subcutaneous injection, which is pretty annoying because patients have to receive a weekly subcutaneous injection for the rest of their lives. That really limits the patient's quality of life; they have to come for an injection weekly. Some patients prefer not to take a pill and they may be happy with a subcutaneous injection, but they are still stuck with [having to do it on a] weekly.

Eltrombopag is a pill, so it's a little bit easier; patients can take it from home. However, there's a limitation [with this agent]: it has to be taken on an empty stomach. Therefore, there are some problems with the scheduling. Patients have to set a reminder on a daily basis regarding what time to take their pills or ensure that they are not taking them on a full stomach. As such, there is some impact on the lives of these patients.

What is your key takeaway to colleagues working in the field?

How do you envision the field shifting?

Avatrombopag (Doptelet) is a very interesting drug because it wasn't approved [by the FDA] for this setting, but it has the same mechanism as eltrombopag and it is not limited to [patients having to take it on an] empty stomach. Providers can use this agent in patients who are having a hard time keeping their stomach empty to take eltrombopag or those who don't want to receive a weekly shot. It's an off-label use, but it has demonstrated in 2 different ITP studies that it's just as effective and a little bit more convenient for patients.Everyone needs to have a better understanding of the use of thrombopoietic agents in ITP—the differences, the little nuances between each agent, the toxicities, and how to choose between 1 drug and the other. Although they all induce relatively similar responses, one drug might be better for an individual patient. Understanding better when and how to apply them [is necessary]. The data with eltrombopag in aplastic anemia is relatively new, so we really [need to reinforce] the importance of this agent. There weren’t any significant advances made in aplastic anemia for quite a long time until the recent data from the last 5 to 6 years with eltrombopag in both the relapsed and the first-line settings.The shift will be trying to see if we can use these agents early on in ITP the same way that they have been used in aplastic anemia. We have proven that eltrombopag has clear activity in the relapsed/refractory setting. When it was brought to the first-line setting, it dramatically improved responses. We can try to see if the same thing will happen in ITP. If we bring these agents into the first-line setting, can we improve responses or decrease the rate of relapses that are very high in patients getting steroids [upfront]? We have not seen dramatic changes so far, but that's where the field is heading: trying to use these very effective agents more effectively in the first-line setting.

FDA Approves Novartis Drug Promacta for First-Line SAA and Grants Breakthrough Therapy Designation for Additional New Indication. Novartis. Published November 16, 2018. https://bit.ly/2BbN587. Accessed March 28, 2019.