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

2014-08-27 03:19:46 | BioPortfolio


The purpose of this research study is to evaluate the safety of the drug Etanercept (Enbrel) and to determine if this drug can help in the treatment of early bone marrow failure in patients 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.

Study Design

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


Fanconi Anemia




Cincinnati Children's Hospital Medical Center
United States




Children's Hospital Medical Center, Cincinnati

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:19:46-0400

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Medical and Biotech [MESH] Definitions

A Fanconi anemia complementation group protein that undergoes PHOSPHORYLATION by CDC2 PROTEIN KINASE during MITOSIS. It forms a complex with other FANCONI ANEMIA PROTEINS and helps protect CELLS from DNA DAMAGE by genotoxic agents.

A Fanconi anemia complementation group protein that is the most commonly mutated protein in FANCONI ANEMIA. It undergoes PHOSPHORYLATION by PROTEIN KINASE B and forms a complex with FANCC PROTEIN in the CELL NUCLEUS.

A Fanconi anemia complementation group protein that contains an N-terminal DNA-binding region and seven, C-terminal, WD REPEATS. It is an essential factor in HOMOLOGOUS RECOMBINATION DNA REPAIR through its interactions with BRCA2 PROTEIN; RAD51 RECOMBINASE; and BRCA1 PROTEIN. It functions as a molecular scaffold to localize and stabilize these proteins at homologous recombination sites. Mutations in the PALB2 gene are associated with FANCONI ANEMIA complementation group N; type 3 PANCREATIC NEOPLASMS; and susceptibility to BREAST CANCER.

A diverse group of proteins whose genetic MUTATIONS have been associated with the chromosomal instability syndrome FANCONI ANEMIA. Many of these proteins play important roles in protecting CELLS against OXIDATIVE STRESS.

An E3 UBIQUITIN LIGASE that plays a key role in the DNA damage response pathway of FANCONI ANEMIA PROTEINS. It is associated with mono-ubiquitination of FANCD2 PROTEIN and the redistribution of FANCD2 to nuclear foci containing BRCA1 PROTEIN.

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