Cancer in Inherited Bone Marrow Failure Syndromes

Fanconi Anemia Clinical Trial

Official title:

Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00027274
• Other study ID #: 020052
• Secondary ID: 02-C-0052
• Status: Recruiting
• Start date: November 28, 2001

Study information

• Verified date: April 2, 2024
• Source: National Institutes of Health Clinical Center (CC)
• Contact: NCI Family Study Referrals
• Phone: (800) 518-8474
• Email: ncifamilystudyreferrals[@]mail.nih.gov
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Background: A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders. Pathogenic variant(s) in IBMFS genes are relevant to carcinogenesis in sporadic cancers. Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. Carriers of IBMFS pathogenic variant(s) are at increased risk of cancer. The prototype disorder is Fanconi's Anemia (FA); other IBMFS will also be studied. Objectives: To determine the types and incidence of specific cancers in patients with an IBMFS. To investigate the relevance of IBMFS pathogenic variant(s) in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers. To identify risk factors for IBMFS-related cancers in addition to the primary germline pathogenic variant(s). To determine the risk of cancer in IBMFS carriers. Eligibility: North American families with a proband with an IBMFS. IBMFS suspected by phenotype, confirmed by pathogenic variant(s) in an IBMFS gene, or by clinical diagnostic test. Fanconi's anemia: birth defects, marrow failure, early onset malignancy; positive chromosome breakage result. Diamond-Blackfan anemia: pure red cell aplasia; elevated red cell adenosine deaminase. Dyskeratosis congenita: dysplastic nails, lacey pigmentation, leukoplakia; marrow failure. Shwachman-Diamond Syndrome: malabsorption; neutropenia. Amegakaryocytic thrombocytopenia: early onset thrombocytopenia. Thrombocytopenia absent radii: absent radii; early onset thrombocytopenia. Severe Congenital Neutropenia: neutropenia, pyogenic infections, bone marrow maturation arrest. Pearson's Syndrome: malabsorption, neutropenia, marrow failure, metabolic acidosis; ringed sideroblasts. Other bone marrow failure syndromes: e.g. Revesz Syndrome, WT, IVIC, radio-ulnar synostosis, ataxia-pancytopenia. First degree relatives of IBMFS-affected subjects as defined here, i.e. siblings (half or full), biologic parents, and children. Grandparents of IBMFS-affected subjects. Patients in the general population with sporadic tumors of the types seen in the IBMFS (head and neck, gastrointestinal, and anogenital cancer), with none of the usual risk factors (e.g. smoking, drinking, HPV). Design: Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory test, review of medical records, cancer surveillance. Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS. Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

Description:

Study Description: This is a natural history study involving questionnaires, clinical and research evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance. A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders. Pathogenic variant(s) in IBMFS genes are relevant to carcinogenesis in sporadic cancers. This study will determine whether patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. Carriers of IBMFS gene pathogenic variant(s) are at increased risk of cancer. The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied. Objectives: To determine the types and incidence of specific cancers in patients with an IBMFS. To investigate the relevance of IBMFS gene pathogenic variants in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers. To identify risk factors for IBMFS-related cancers in addition to the primary germline pathogenic variant(s). To determine the risk of cancer in IBMFS carriers. Endpoints: Primary Endpoint: -All cancers, solid tumors, and cancers specific to each type of IBMFS. Secondary Endpints: -Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

Other known NCT identifiers

• NCT00056121

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 4000
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

• INCLUSION CRITERIA:

The participants will be affected by an IBMFS, or be members of a family with an IBMFS, and be at risk of being affected or carriers of the syndrome. Except for the rare X-linked recessive disorder (e.g. some dyskeratosis congenita patients), there should be equal numbers of male and female probands and family members. These IBMFS have been reported in most racial and ethnic groups, and thus all such groups will be included. The age range will be from birth to old age (grandparents of probands). The majority of the probands will be children (10-20% will be adults), and their parents and grandparents will be adults. All racial/ethnic groups are eligible.

INCLUSION CRITERIA for Patients:

• Fanconi s anemia.
• Diamond Blackfan anemia.
• Dyskeratosis congenita.
• Shwachman Diamond Syndrome.
• Amegakaryocytic thrombocytopenia.
• Thrombocytopenia absent radii.
• Severe Congenital Neutropenia.
• Pearson Syndrome.
• Other bone marrow failure syndromes. Family Members of IBMFS - Affected Subjects: -Family members include first degree relatives of IBMFS-affected subjects as defined here, i.e. siblings (half or full), biologic parents, and children. Grandparents of IBMFS-affected subjects are also included, specifically for Hypothesis 4. The age range will be from birth to old age (grandparents of probands). Patients in the general population: -Patients in the general population with sporadic tumors of the types seen in the IBMFS (head and neck, gastrointestinal, and anogenital cancer), with none of the usual risk factors for those tumors (e.g. smoking, drinking, HPV). These patients will be further evaluated for an IBMFS by the referring physician under the guidance of the study investigators and if diagnosed with an IBMFS or if not diagnosed but highly suspicious for an IBMFS, would be eligible for inclusion in the Field and Clinic Center cohorts. EXCLUSION CRITERIA: -Affected: An individual who meets any of the following criteria will be excluded from

participation in this study:

• Evidence that the hematologic disorder is acquired rather than genetic. Such evidence includes temporal relation of the aplastic anemia to known marrow suppressant drugs, chemicals, toxins, or viruses (in the absence of evidence indicative of an inherited marrow failure disorder).
• Known causes of cytopenias such as autoantibodies to red cells, platelets, or neutrophils, viruses (especially hepatitis), micronutrient deficiencies, transient erythroblastopenia of childhood, and cyclic neutropenia.
• Assignment of the patient s physical findings to other syndromes or causes that are not part of the IBMFS disease spectrum.
• Inability of the participant or LAR to understand and be willing to sign a written informed consent document.
• Unwillingness to permit access to medical records and pathology specimens. There are no other exclusion parameters not related to the primary disease. -Unaffected/Family Members: An individual who meets any of the following criteria will be

excluded from participation in this study:

• If there is no affected individual in the family who meets the inclusion criteria
• Inability of the participant or LAR to understand and be willing to sign a written informed consent document.
• Unwillingness to permit access to medical records and pathology specimens.

Related Conditions & MeSH terms

• Anemia
• Anemia, Aplastic
• Anemia, Diamond-Blackfan
• Bone Marrow Failure Disorders
• Congenital Bone Marrow Failure Syndromes
• Diamond Blackfan Anemia
• Dyskeratosis Congenita
• Fanconi Anemia
• Fanconi Syndrome
• Hemoglobinuria, Paroxysmal
• Inherited Bone Marrow Failure Syndrome, Aplastic Anemia
• Pancytopenia
• Shwachman Diamond Syndrome
• Shwachman-Diamond Syndrome
• Syndrome

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	National Cancer Institute - Shady Grove	Rockville	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018 Jan;103(1):30-39. doi: 10.3324/haematol.2017.178111. Epub 2017 Oct 19. — View Citation

Alter BP, Rosenberg PS, Giri N, Baerlocher GM, Lansdorp PM, Savage SA. Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica. 2012 Mar;97(3):353-9. doi: 10.3324/haematol.2011.055269. Epub 2011 Nov 4. — View Citation

Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood. 2012 Apr 19;119(16):3815-9. doi: 10.1182/blood-2011-08-375972. Epub 2012 Feb 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohort of Families with IBMFS	Establish a cohort of families with IBMFS	Ongoing
Primary	Biology of Patients Compared with Healthy Controls	Compare biology of IBMFS patients with general populations	Ongoing
Primary	Differences Between Patients and Healthy Controls	Identify differences between patients with IBMFS who develop cancer and those who don't	Ongoing
Primary	Risk of Cancer with Specific Mutations	Determine risk of cancer in IBMFS patients with specific gene mutations	Ongoing

External Links

•   NIH Clinical Center Detailed Web Page