Natural History Study for BEN

Sponsor

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00059423

Collaborator

(none)

178

Enrollment

Location

204.8

Actual Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In recent decades, hematologists have noticed that persons of African descent sometimes have lower white blood cell counts of a certain type, called granulocytes. These cells help to fight infections. The lower number of granulocytes in this situation does not appear to lead to more infections, and these individuals do not have any symptoms. This condition is called benign ethnic neutropenia (BEN), and is observed in a small percentage of individuals of African descent. This study will investigate the condition by studying people with and without BEN.

The goals of this study are to:

identify individuals of African descent with BEN.
determine the effects of two drugs, G-CSF and dexamethasone, on granulocyte production and movement.
determine whether there are differences in those with and without BEN in the way genes are stimulated after the administration of G-CSF and dexamethasone.

Study participants will be asked to interview with the research team, undergo physical exams, donate a blood sample, and receive G-CSF by injection, followed by dexamethasone (orally) about three weeks later. They also will be required to undergo apheresis three times, a procedure in which blood is drawn from a donor and separated into its components. Some components are retained for research analyses, such as granulocytes, and small amount of blood; the remainder is returned by transfusion to the donor. This procedure will be required of participants before they receive G-CSF, the day after they receive G-CSF, and the day after they receive dexamethasone. Gene messages (mRNA will be isolated from granulocytes, and analyzed to better understand granulocyte growth and movement.

Condition or Disease	Intervention/Treatment	Phase
Neutropenia Agranulocytosis Hematologic Diseases Leukocyte Disorders Leukopenia

Detailed Description

Benign ethnic neutropenia (BEN) is defined by peripheral blood absolute neutrophil count less than 1.5 x 10 (9) per liter without an increase in infections. This condition has been described in individuals of African descent. Although these individuals have normal myeloid maturation on bone marrow examinations, they appear to release fewer neutrophils into the circulation when stimulated by hydrocortisone, compared to normal controls. This suggests that there may be differences in the regulation of neutrophil release or trafficking. In the past decade, granulocyte-colony stimulating factor (G-CSF) has been widely used in a variety of clinical settings, from patients with chemotherapy-induced neutropenia to normal volunteers for peripheral blood stem cell collection. G-CSF, however, has not been used in individuals with BEN. Furthermore, gene expression in neutrophil proliferation and trafficking has not been studied in these individuals. The purpose of this study are to (1) identify individuals with BEN; (2) follow the natural history of BEN; (3) determine if there is a familial inheritance pattern; (4) characterize and compare neutrophil response to dexamethasone and G-CSF; (5) compare the pattern of neutrophil gene expression by microarray analyses; and (6) determine if mutations are present at the DNA level to account for gene expression pattern differences in individuals of African descent with and without BEN at baseline, post dexamethasone, and post G-CSF stimulation.

Study Design

Study Type:

Observational

Actual Enrollment :

178 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Natural History and Molecular Characterization of Benign Ethnic Neutropenia in Individuals of African Descent

Actual Study Start Date :

Jun 3, 2003

Actual Primary Completion Date :

Apr 23, 2019

Actual Study Completion Date :

Jun 26, 2020

Arms and Interventions

Arm	Intervention/Treatment
1 Individuals of African descent with benign ethnic neutropenia (BEN) at baseline
2 Individuals of African descent without benign ethnic neutropenia (BEN) at baseline

Outcome Measures

Primary Outcome Measures

Serial blood counts in BEN [Ongoing]
In our study, we hope to further elucidate the etiology of BEN in research subjects by isolating granulocyte mRNA after G-CSF and dexamethasone stimulation, applying microarray analyses to screen for gene expression differences, and confirming expression pattern differences by DNA analyses. We will focus on genes that are important in the proliferation and trafficking of neutrophils,such as PRV-1, elastase, myeloblastin, transcription factor PU.1, CAAT enhancing binding protein-alpha (C /EBP), stromal derived factor-1 (SDF-1), and CXC receptor-4 (CXCR4).

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA:
Individuals of African descent of age 5 or greater
Normal renal function: creatinine <1.5 mg/dL and proteinuria <1+
Normal liver function: bilirubin <1.5 mg/dL and transaminases within normal limits
For control subjects: WBC within normal range (3,300-9,600/mm3), granulocytes/neutrophils greater than or equal to 2,000/mm3, platelets >150,000/mm3, hemoglobin > 11.5g/dL and normal MCV
For benign ethnic neutropenic subjects: two blood counts, at least 1 month apart, with granulocytes/neutrophils <1,500/mm3, platelet >150,000/mm3, hemoglobin >12.5g/dL, and normal MCV. We will also follow subjects whose neutrophil counts are between 1500 and 2000/mm3 in a separate cohort periodically (e.g. once every 1-2 years) to see if their blood counts behave more like BEN or normal subjects.
Female volunteers of childbearing age should not be pregnant
Meets NIH Department of Transfusion Medicine (DTM) eligibility criteria for blood component donation for in vitro research uses (negative serologic tests for syphilis, hepatitis B and C, HIV, and HTLV-1)
Ability to give informed consent to participate in the protocol

EXCLUSION CRITERIA:

Any underlying hematologic disorder including anemia, and sickle cell disease. Subjects with thalassemia or sickle cell trait are not excluded.
Current use of corticosteroids, e.g. prednisone, dexamethasone, or hydrocortisone. Corticosteroids must be discontinued at least one month prior
Active or chronic viral, bacterial, fungal, or parasitic infection. Any antibiotic use should be discontinued at least one month prior
History of autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus, or positive anti-nuclear antibody (ANA ELISA) of 3 E.U. (ELISA units) or greater.
Low B12 or folate levels, or abnormal thyroid function tests
History of cancer or chemotherapy, except squamous carcinoma of the skin and cervical carcinoma in situ
Pregnant woman or positive urine pregnancy test
History of clinically significant cardiovascular disease (cardiology consultation may be obtained when clinically indicated)
Any positive serum screening test as listed below
Allergy to G-CSF or bacterial E. coli products
Active pulmonary disease or a pulse-ox level of less than 95% on screening exam