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
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
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.
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
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?
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.
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.
patients go for more information about eltrombopag and its use in treating severe
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.