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Etanercept (Enbrel) in Children With Fanconi Anemia and Early Bone Marrow Failure: A Pilot Study

4 Years
Not Enrolling
Fanconi Anemia

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Trial Information

Etanercept (Enbrel) in Children With Fanconi Anemia and Early Bone Marrow Failure: A Pilot Study

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

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.

Inclusion Criteria:

1. Patients must have a diagnosis of FA proven by a DEB test conducted in the
cytogenetics lab of Dr. Arleen Auerbach, Rockefeller University Hospital.

2. Patients must have evidence of early marrow failure i.e. reduction in at least one
cell line on two separate occasions at least one month apart e.g. platelet count of <
100,000 per cubic millimeter, hemoglobin < 9 gm/dl and/or absolute neutrophil count
(ANC) of < 1000

3. Negative pregnancy test (conducted via serum β-HCG screen) - done before the first
dose of study drug in all women (except those surgically sterile, at least 5 years
postmenopausal, or under the age of 10 years)

4. Sexually active patients of childbearing potential must agree to use medically
acceptable form of contraception during screening and throughout the study

5. Patients or designees must have the ability to self-inject investigational product or
have a care giver at home who can administer subcutaneous injections

6. Patients or designees must be able and willing to give written informed consent and
comply with the requirements of the study protocol and must authorize release and use
of protected health information

7. Patients must have a negative TB skin test at entry into the study

Exclusion Criteria:

1. Patients < 4 yrs of age

2. Patients with advanced marrow failure i.e. transfusion dependent, will not be
eligible as we anticipate that stem cell depletion will already be advanced at this

3. Patients currently enrolled in another investigational device or drug trial(s)
(defined as a drug not approved by the FDA), or who have received other
investigational agent(s) within 28 days of baseline visit with the exception of CCHMC
IRB protocol # 03-9-11, "Thyroid Hormone in Children with Fanconi Anemia"

4. Patients on androgen therapy

5. Patients who have received immunosuppressive agents within the last 3 months prior to

6. Patients who have any grade 3 or 4 adverse event or laboratory toxicity other than in
Blood or Bone Marrow (as per the NCI CTC criteria) at the time of the screening
visit or at any time during the study, that in the opinion of the Investigator would
preclude participation in the study

7. Patients with active infections within 4 weeks before the screening/baseline visit

8. Patients with untreated Lyme disease

9. Patients with a recent or past history of fungal infection

10. Patients who have history of TB or TB exposure, chronic hepatitis B or hepatitis C,
SLE, history of multiple sclerosis, transverse myelitis, optic neuritis or epilepsy

11. Patients with known hypersensitivity to Etanercept (Enbrel) or any of its components
or who are known to have antibodies to Etanercept (Enbrel).

12. Patients who have received hematopoietic growth factor for greater than 3 consecutive
days in the 6 months before study enrollment (i.e., erythropoietin, filgrastim,
neupogen, sargramostin) for clinical purposes to improve bone marrow function.
Patients receiving hematopoietic growth factor for stem cell mobilization and
collection only are not excluded from this study.

13. Patients with an available matched sibling donor and clinically indicated need for
bone marrow transplant

14. Patients with renal failure requiring dialysis

15. Patients with a total bilirubin >3 mg/dl and/or SGPT >200 at time of enrollment

16. Patients who are pregnant or breastfeeding or are a female at risk of pregnancy and
are unable to practice safe sex during the length of the study

17. Patients who are HIV positive

18. Patients with severe co-morbidities (diabetes mellitus requiring insulin, CHF of any
severity, MI, CVA or TIA within 3 months of screening visit, unstable angina
pectoris, uncontrolled hypertension, oxygen-dependent severe pulmonary disease,
history of cancer within 5 years (other than resected cutaneous basal or squamous
cell carcinoma or in situ cervical cancer)

19. Patients who have any mycobacterial disease or known history of any other
immuno-suppressing disease

20. Patients with a history of recent alcohol or substance abuse (< 1 year)

21. Patients with a history of non-compliance with other therapies

22. Patients who have any condition judged by the patient's physician to cause this
clinical trial to be detrimental to the patient

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Health Services Research

Outcome Measure:

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

Outcome Time Frame:

24 months

Safety Issue:


Principal Investigator

Stella M. Davies, MBBSPhd MRCP

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Hospital Medical Center, Cincinnati


United States: Food and Drug Administration

Study ID:




Start Date:

October 2005

Completion Date:

October 2010

Related Keywords:

  • Fanconi Anemia
  • Fanconi Anemia
  • Hemic and Lymphatic Diseases
  • Anti-Rheumatic Agents
  • Anemia, Hypoplastic, Congenital
  • DNA Repair-Deficiency Disorders
  • Congenital, Hereditary, and
  • Neonatal Diseases and Abnormalities
  • Anemia
  • Fanconi Anemia
  • Fanconi Syndrome



Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039