Eltrombopag: Recent Discoveries on Potential New Applications for Aplastic Anemia | Aplastic Anemia and MDS International Foundation

Eltrombopag: Recent Discoveries on Potential New Applications for Aplastic Anemia

Dr. Townsley is a staff physician and clinical investigator in the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI) at the Clinical Center of the National Institutes of Health (NIH) in Bethesda, Maryland. She conducts her clinical and laboratory research in the department of Dr. Neal Young, Chief of the Hematology Branch of NHLBI. Dr. Townsley is currently the principal investigator for multiple trials investigating new approaches to the treatment of bone marrow failure, primarily severe aplastic anemia. Her research interests include the pathophysiology of marrow failure syndromes and the use of eltrombopag, a blood growth factor to treat aplastic anemia. She receives research funding support from Glaxo SmithKline, the manufacturer of eltrombopag (Promacta®).

What is eltrombopag and how does it work when applied to aplastic anemia ?

This is a drug that is already FDA-approved to treat another blood disorder called Immune Thrombocytopenia Purpura (ITP) – a blood condition that occurs when the body makes antibodies against platelets and destroys them very quickly, resulting in low platelet counts. Eltrombopag (Promacta®) was originally developed to treat this condition, and has been available for about six years for that clinical indication. It is a medication that can be taken by mouth that mimics the action of the hormone thrombopoietin, a substance made by the body that is know to be very important to stimulate production of platelets, and thus it is termed a “thrombopoietin mimetic.” Since then, we designed a pilot trial to test its use in patients with severe aplastic anemia (SAA) who had failed other treatments, which were most often multiple rounds of immunosuppressive therapy. This is known as refractory SAA. When tested in this setting, it was found to not only improve platelet counts in some patients, but also improve white and red blood cell counts. This was a surprising finding, as the drug was really designed to improve platelet counts.

Based on that, when we looked closely at the biology of the way the drug works, we knew that it could potentially be stimulating the stem cells – these are the cells in the bone marrow that give rise to all blood cells.

What were the circumstances that led to its being tested in clinical trials for aplastic anemia?

Originally we weren't that hopeful that eltrombopag would be useful in aplastic anemia, because the drug is only used as a growth factor for platelet growth. We knew that other growth factor types of drugs were tried in aplastic anemia and they had not been successful. So we weren’t hopeful, but since eltrombopag is a pill and is easy to administer, the NIH decided to embark on a trial to prove or disprove its efficacy because there are few therapies available to patients with refractory aplastic anemia.  Additionally, we thought it would be likely that physicians would be using it even without data. We wanted some data to show whether or not it would be useful, but also it was a low-risk intervention that happened to have unexpectedly good results.

What is meant by the “breakthrough therapy” designation given to eltrombopag for use in severe aplastic anemia?

The FDA recently granted eltrombopag a ‘breakthrough therapy’ designation. This is part of a new FDA program that is aimed at accelerating development and review time of drugs needed for serious, or life threatening conditions.  In this case, it was not for newly diagnosed SAA, but specifically for patients with SAA whose disease was refractory to immunosuppression. The important thing to understand is that the designation does not mean the FDA has already approved its use, rather the designation only shortens the usual review time and approval process. Even if it is eventually approved, this approval at least initially will only apply to patients with refractory SAA -- not other patients with aplastic anemia.

What were the primary discoveries in these research studies on eltrombopag when used for treating aplastic anemia?

The primary observation was that around 40% of patients on the NIH trial who were refractory to immunosuppression did have a response to eltrombopag, whether platelets, white or red blood cells or any combination. Some actually were tri-lineage, meaning responses in all three cell types, some had two cell lines improve, and others were just one of the three. But 40% had a response of some kind that was clinically meaningful, for instance being able to discontinue red cell or platelet transfusions.

What general new insights into aplastic anemia gained through these studies?

This was a big insight – we didn’t think that additional growth factors for this disease would be helpful. Many researchers had totally abandoned the idea. If you measure the level of growth factors involved in stimulating blood cell production from the bone marrow, including thrombopoietin, in the bloodstream of patients with aplastic anemia, they are already quite high in comparison to healthy people.  The hypothesis that driving already high levels even higher with a drug didn’t make sense to us – we just did not think additional growth factors would be helpful, particularly outside the platelet lineage.  So the result we obtained was very surprising to us.

Is use of eltrombopag suited for all classifications of aplastic anemia (moderate, severe, very severe)?

    Right now we’d say the use of eltrombopag is not suited to any of those classifications, unless it’s part of a clinical trial.  That’s what’s important about the FDA designation. It’s not saying that it’s approved. We are hopeful but have to remain cautious about the use of this drug until the ongoing trials are completed. We want to discourage physicians from treating patients with this drug, unless it is part of a clinical trial.

    How does eltrombopag fit in with existing treatments for aplastic anemia? For example, is it used in conjunction with ATG and cyclosporine?

    We have a clinical trial going on now where we are trying eltrombopag in patients with newly diagnosed severe aplastic anemia, as a combination therapy -- this is in conjunction with horse ATG and cyclosporine which is the standard immunosuppressive treatment.  Our current trial is asking whether eltrombopag is effective if given at the beginning of the disease alongside with the usual therapy, for instance whether it will speed the pace of recovery, or increase the percentage of patients that respond. There should be some results from this trial that will be published by the end of the year. Whether or not we will be able to definitely say if it will be useful by the end of the year is not known, but we can at least give initial findings from the current clinical trial.

      Is eltrombopag something patients should bring to the attention of their hematologist?

        We think this is something patients should make known to their hematologist, in the sense that it is a newer therapy that is only available as part of a clinical trial. We strongly encourage hematologists to refer patients for clinical trials -- especially for aplastic anemia patients, as it is rare disease and we need more patients to capture enough data.

        Also although we are excited and hopeful, and although we have had encouraging results, we have to be cautious. This is why the very close monitoring of patients that is part of a clinical trial is so important. We’re seeing patients not in a clinical trial being put on the drug, but at the wrong dose and for the wrong time period.  This is important because we are giving eltrombopag at very different doses than what is given for the FDA approved use for ITP. We are finding that some physicians are prescribing it, even though it is not yet approved. Without the clinical trials completed, physicians won’t know how to effectively and safely administer the drug. 

          Where can patients go for more information about eltrombopag and its use in treating severe aplastic anemia?

            Of course www.clinicaltrials.gov is a good place for patients to see what trials are available in their area, or at the NIH and it lists the eligibility requirements for each one. But patients who are further interested can read the original primary paper that appeared in the NEJM in 2012 (Olnes MJ, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. NEJM 2012 Jul 5]. This paper documents the trial for patients with refractory SAA where a response of 44% was obtained. There’s a more recent publication that was about a follow-up trial with an expanded group of patients and the result here was the 40% that I mentioned earlier. This was in in Blood, (Desmond, Townsley, and Dunbar), published December 2013.


            Danielle Townsley, MD, MSc

            Position / Title: 
            Staff Clinician and Primary Investigator
            National Heart Lung and Blood Institute

            Dr. Danielle Townsley is a Staff Clinician and Primary Investigator in the Hematology Branch of the National Heart Lung and Blood Institute (NHLBI) at the Clinical Center of the National Institutes of Health in Bethesda, Maryland. She received a Bachelor’s Degree at the University of California, San Diego in 1999 and a Master’s Degree in Epidemiology from the University of Edinburgh, Scotland in 2002. She completed her MD in 2006 and a residency in Internal Medicine at George Washington University in 2009.  In 2011, she completed her hematology fellowship at the NIH where she trained under the mentorship of Drs. Neal Young and Phillip Scheinberg.

            Currently she conducts her research in the laboratory of Dr. Neal Young, Chief of the Hematology Branch of NHLBI. Dr. Townsley’s research interests include the pathophysiology of marrow failure syndromes and the use of eltrombopag, a blood growth factor to treat aplastic anemia. She also studies familial causes of bone marrow failure, such as telomere diseases or dyskeratosis congenita, and the impact of inherited and acquired gene mutations on the pathophysiology of bone marrow failure. She is the principle investigator for multiple trials that utilize eltrombopag for aplastic anemia and myelodysplastic syndromes, as well as clinical trials administering the sex hormone, danazol for patients with telomere disorders.