Hypereosinophilic Syndrome (HES)
What is an Eosinophil?
An eosinophil is a type of white blood cell that plays an
important role in the human immune system. For example, it helps us fight off
certain types of infections like parasites. Many different problems can cause
high numbers of eosinophils in the blood, including allergies, asthma, some
gastrointestinal disorders, parasitic infection, some blood/bone marrow
diseases, certain cancers, and other problems. When eosinophils occur in higher than normal numbers
in the blood, without a known cause and for a sustained period of time (more
than 6 months), an inate disorder of eosinophils may be present.
Eeosinophil, Courtesy of Dr. Margaret Collins
Normally, there are less than 3% eosinophils circulating in the
blood vessels because they migrate quickly into the tissues and organs of the
body. The highest concentration of
eosinophils is usually found in the gastrointestinal tract. There is a complex series of chemical events
that determine the levels of eosinophils in the blood and tissues. The proper balance and function of these
events determine eosinophil production, their activity, and their time to die.
Eosinophil production is governed by several chemicals in
blood called cytokines, including interleukin 3 (IL-3), interleukin 5 (IL-5),
and granulocyte-macrophage colony-stimulating factor (GM-CSF). Cytokines have many functions. They mediate
and regulate immunity, inflammation, and hematopoiesis (production of blood
cells) and different cytokines are produced in high amounts in different
diseases. IL-5 appears to be the most important and specific cytokine that is
responsible for the production and activity of eosinophils. Cytokines bind to specific chemicals on the
surface of cells, called membrane receptors, that initiate the cascade of
changes in other chemicals inside the cell leading toward the change in cell’s
behavior, including higher activity and multiplication. Many of the membrane
receptors and intracellular chemicals belong to a class of chemicals called
tyrosine kinases.
What is
HES?
HES is a group
of disorders in which there are very high numbers of eosinophils found in the
blood, for prolonged period of time (more than six months) for which a cause
cannot be found. The continuous presence of high number of eosinophils in blood
can eventually cause multiple organ tissue damage as these eosinophils
infiltrate different tissues and cause inflammation. HES can affect any organ
in the body, including the stomach and intestines, the heart, lungs, skin and
other organs.
Since many different problems can cause high numbers of
eosinophils in the blood, higher then normal blood eosinophil number alone does
not mean an individual has, or will develop, HES. Criteria has been developed
that must be fulfilled for an individual to be diagnosed with HES.
Criteria for
Diagnosis of HES
1. Peripheral
blood eosinophilia (high numbers of eosinophils in the blood); more than 1500
eosinophils/ml, for at least six months’
duration
2. End-organ (heart,
lungs, GI tract, brain, skin, etc) involvement with eosinophil tissue
infiltration (invasion) and injury
3. Exclusion of known
other causes for the eosinophilia such as parasitic infections and certain bone
marrow/blood diseases.
A bone marrow biopsy may be recommended in a patient
fulfilling these criteria and suspected of having HES.
Standard Treatments for HES
Treatment goals include decreasing blood eosinophil numbers,
preventing organ damage, and slowing disease progression.
Systemic steroids are often needed to treat HES
with organ involvement or with systemic symptoms, like severe rash, fluid
retention, and similar. Steroids are very effective for controlling eosinophil
numbers in blood and most patients can be maintained on oral steroid medication
(called prednisone) for long period of time with good control of the disease.
However, the blood eosinophils and disease symptoms generally return once
steroids have been stopped. Long-term steroid use (especially when used in high
doses) has, unfortunately, been associated with side effects.
Interferon alpha (IFNa) is used for a variety of
diseases including infections (like hepatitis) and malignancies (like certain
types of leukemia). IFNa has been shown to be effective in HES by suppressing
the symptoms related to the disease. Toxicity, however, is a major obstacle to
the use of this therapy. IFNa is
commonly injected into the fatty tissue under the skin 3-5 times a week. Upon
the initiation of therapy most patients experience influenza-like symptoms such
as fever, chills, muscle aches, headaches, and joint pain. Other side effects of IFNa are low blood
counts and elevated liver enzymes that require careful monitoring. These side effects usually lessen over time,
but other toxicities can manifest themselves in various forms after long-term
therapy. Overall experience with IFNa in
myeloproliferative diseases is that about 25-30% of patients require
discontinuation of therapy due to side effects. New long-acting forms of IFNa
(pegylated interferons) have been developed over last few years and are now approved
as therapy for hepatitis. These medications are administered only once a week
and may, therefore, be better tolerated.
yclosporine is a potent medication that suppresses the immune system and it is used
primarily to prevent organ rejection in people who have had organ transplants.
In some patients with HES there might be evidence that the immune cells have a
role in supporting the diseases existence (so called T cells) and cyclosporine
may have a role as therapy in such cases.
Anti-neoplastic agents provide an alternative
approach to therapy of advanced cases of HES. These are chemotherapeutic agents that may control the disease. They are
used to treat many malignancies and are not specific for eosinophilic disorders. They are potent medications that kill cells
that grow the fastest (eosinophils in HES) but may potentially have harmful
side effects and are reserved only for more severe cases. Careful monitoring
while taking these medications is essential. Hydroxyurea,
Methotrexate, Etoposide, Cyclophosphamide, Vincristine, and Cladribine.
As a result of cell growth research, scientists have been
able to develop a group of therapeutic agents known as tyrosine kinase inhibitors. By blocking the ability of tyrosine kinases
to function, these compounds provide a valuable tool for controlling malignant
cell growth. The novel approach for treating HES is to “target” specific
receptors on the eosinophil surface in order to interrupt their unregulated
replication. PDGF-R (platelet derived
growth factor receptor) is a receptor that is tyrosine kinase involved with the
maintenance of normal blood cell production, skin pigment production, formation
of female ova and male sperm, and the growth and activity of certain white
blood cells involved in allergy and immune response. Alteration in PDGF-R tyrosine kinase activity
is known to be responsible for disease onset and progression in some patients
with HES. Therefore, medications (tyrosine
kinase inhibitors) were developed to interfere with this process.
is a tyrosine kinase inhibitor that is known to inhibit
PDGF-R. Gleevec was developed for and is currently approved by the Food and
Drug Administration for use as a treatment for Chronic Myelogenous Leukemia
(CML); in this disease it blocks the activity of one other tyrosine kinase and
is very effective therapy. Gleevec may
eliminate disease in select HES patients, those having alteration in PDGF-R tyrosine
kinase activity. Therefore, it is mandatory that HES patients be tested for
this abnormality; there are 2 ways this can be accomplished, either using PCR
test for FIP1L1-PDGFRa gene rearrangement, or using FISH test for CHIC2 gene
deletion. Most HES patients do not have PDGF-R alteration, and some patient
without it may still respond to Gleevec therapy, by improving signs and
symptoms of the disease. Gleevec is given at a starting dose of 100 mg orally
daily, with a dose escalation up to 400 mg after one month if no response is
observed. Other tyrosine kinase
inhibitors are being evaluated as therapy for HES patients.
a tyrosine kinase inhibitor that was recently approved for
therapy of CML patients failing Gleevec. It may affect many different tyrosine
kinases and is being evaluated in a clinical study for HES patients not
responding to standard therapies.
Nilotinib is another tyrosine kinase
inhibitor that is also being developed for CML patients loosing a response to
Gleevec, but is not approved yet. This agent too is being evaluated in a
clinical study for HES patients not responding to standard therapies.
Mepolizumab is an investigational medication
for HES, not yet approved. It is a
medication given intravenously monthly, that binds to IL-5 which is primary
cytokine responsible for eosinophil growth. This therapy is being evaluated in
clinical trials for patients with HES and other eosinophilic diseases and the initial
results are encouraging.
Alemtuzumab is a monoclonal antibody reactive with several
cell populations carrying a particular molecule termed CD52. Recent reports have shown the usefulness of
alemtuzumab (anti-CD52) for the treatment of two female HES patients with
cutaneous manifestations, one with a CD3_ CD4+ T-cell population [30_,31_]. Although this
medication carries a black box warning because of hematological toxicity,
infusion reactions and opportunistic infections, it may have a place in the treatment
of certain HES patients who are resistant to other therapies.
Study Identifies New Treatment
For Hypereosinophilic Syndrome in Adults (PDF)
Several clinical studies with new medications for HES are
currently underway in the
USA
. Go to www.clinicaltrials.gov and enter “Hypereosinophilic Syndrome” to
find active studies. Clinical trials include:
1.
Dasatinib clinical study is currently accruing HES
patients at the MD Anderson Cancer Center,
Houston
,
Texas
. More
details can be found at: http://www.mdanderson.org/diseases/mpd/ under ‘Clinical Trials’
2.
Nilotinib clinical study is open at many centers in
the
USA
,
including MD Anderson Cancer Center in
Houston
,
Texas
.
http://www.amn107.com/clinical_en.jsp
3.
Mepolizumab clinical study is accessible at many
academic centers in the
USA
.
http://www.clinicaltrials.gov/ct/show/NCT00244686
Updated
10-14-06
, APFED, Wendy Book and Dr.
Verstovsek
