Pilot Study of Etanercept (Enbrel) in Children With Fanconi Anemia

Patients with FA are treated with blood products (transfusions), injections to stimulate
white blood cell production, and/or androgen therapy once they reach advanced stages of bone
marrow failure. Although these therapies lead to temporary improvement in the blood counts,
they are associated with potential serious side effects. Currently, the only known potential
cure for bone marrow failure in Fanconi Anemia is a stem cell transplant, which is usually
done at the late stages of bone marrow failure and is again associated with significant
toxicity.

Studies show that patients with FA are very sensitive to and produce unusually high levels
of a protein called tumor necrosis factor alpha (TNF-α) that causes bone marrow cells to
die. We will study whether a drug called Etanercept that reduces levels of TNF-α will delay
or prevent the progressive bone marrow failure associated with FA. Etanercept has been
successfully used in children with arthritis.

Primary Objectives:

1. To assess toxicity of Etanercept (Enbrel) in children with Fanconi Anemia (FA) and
early marrow failure.

2. To assess efficacy of Etanercept (Enbrel) in improving hematopoiesis (i.e. peripheral
counts) in patients with FA.

Secondary Objectives:

1) Correlation of biological studies to measure the impact of Etanercept (Enbrel) on Tumor
Necrosis Factor - α (TNF-α) production.

Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone
marrow failure, variable congenital abnormalities and a predisposition to malignancy,
particularly acute myeloid leukemia (AML) 1. Cells from FA patients exhibit
hypersensitivity to alkylating agents such as mitomycin C and diepoxybutane (DEB).
Currently, FA is diagnosed by testing for chromosome breakage after lymphocyte stimulation
and exposure to mitomycin C (MMC) or diepoxybutane (DEB) 2. Chromosome fragility, defined
by an increased percentage of chromosome breaks, is diagnostic for FA3. Although it is the
most common form of constitutional aplastic anemia it is very uncommon and the true
incidence of FA is not known. A total of 754 patients from North America with the DEB
confirmed diagnoses of FA were registered into the International Fanconi Anemia registry
(IFAR) by 2001. The major cause of morbidity and mortality for children with FA is bone
marrow failure that occurs in the majority of children in the first and second decades of
life. Attempts to culture bone marrow progenitors in vitro from FA patients demonstrate
decreased numbers of myeloid and erythroid colonies, which is consistent with clinical bone
marrow failure.

Current treatment for FA relies upon hematological support in the form of transfusions once
advanced marrow failure occurs. Patients with FA do not respond to anti-thymocyte globulin
or cyclosporine (typical treatments for acquired aplastic anemia), but 50% improve with
androgen preparations, with a median prolongation of life of 2 years in responders (from 16
years to 18 years of age at death) although relapses are inevitable. Androgen therapy
causes significant liver toxicity, virilization and risk of hepatic adenoma or carcinoma.
Patients who do not respond to these modalities are treated with stem cell transplantation,
with its associated toxicities from the transplant conditioning regimens, graft-versus-host
disease and increased risk of post transplant malignancy compared to patients without FA.
Five-year survival after a matched sibling transplant is approximately 65%. After an
unrelated donor transplant, five-year survival is about 30%. The natural history of this
disease is one of eventual death by age 10 to 20 years from progressive marrow failure or
from conversion to AML (in approximately 10% of patients). Thus there is clearly a need for
an effective and early therapy with better toxicity profile.

Studies in both animals and human subjects indicate that high levels of systemic TNF-α and
increased sensitivity of hematopoietic progenitors to TNF-α plays a key role in pathogenesis
of bone marrow failure in patients with FA. This suggests a possible benefit in supporting
hematopoiesis with anti-TNF-α receptor Fc fusion protein (Etanercept; Enbrel) in children
with FA. This study proposes to treat patients with FA and early marrow failure with
Etanercept (Enbrel), a medication used to treat rheumatoid arthritis. The results of the
proposed project will use important preclinical data (see below) to support the development
of a novel therapeutic approach for treatment of marrow failure in FA. Etanercept (Enbrel)
will prevent the progressive marrow failure and associated complications without the need
for transplant and if found to be effective, this treatment can be included in standard
clinical care of FA patients, potentially for many years.