findings.htm

WORKSHOP FINDINGS, RECOMMENDATIONS, AND AGENCY RESPONSES This section summarizes the six major findings and recommendations that emerged during the workshop, and the responses to date from ATSDR, CDC, FDA, and the National Institutes of Health (NIH).

1. PERFORM ADDITIONAL STUDIES WITH A STANDARD CASE DEFINITION Finding The 11 cases described require more complete laboratory characterization to see if they satisfy stringent criteria for a case definition of BCML. Additional studies in other cohorts using the case definition for BCML are also required.
Recommendation

Establish a case definition based on laboratory criteria, then re-analyze samples from the cases and from other cohorts.

Agency Response

A case definition of BCML, as assessed by kappa/lambda analysis and/or a PCR-based detection of rearranged immunoglobulin heavy chain genes, has been established. A protocol (see Chapter 23) to characterize the eleven cases presented at the workshop and other individuals with high B-cell counts is in progress.

2. EVALUATE ENVIRONMENTAL RISK FACTORS Finding     Additional studies in well-defined exposure cohorts are required to investigate an association between BCML and exposure to environmental chemicals.
Recommendations     (1) Explore the possibility of using existing data sets to test the association between people living near hazardous waste sites and their risk for CLL or NHL.
    (2) Develop a questionnaire specifically addressing environmental risk factors among subjects with BCML, B-CLL or NHL and among control subjects.
    (3) Design additional cohort and case-control studies, including prospective longitudinal studies, to confirm findings and assess genetic and environmental risk factors.
Agency Response     (1) A joint protocol (see Chapter 22) to combine NCI data sets with ATSDR geographic information on hazardous waste site locations has been submitted for Institutional Review Board approval.
    (2) A questionnaire focusing on environmental risk factors and confounding variables is being developed (see Chapter 24).
    (3) Exposure cohorts (such as the ATSDR benzene and trichloroethylene exposure registries) are being explored as candidates for additional studies.
3. DETERMINE THE NATURAL HISTORY OF BCML Finding     The data presented on individuals with BCML followed longitudinally (see Chapter 6) validate BCML as a risk factor for B-CLL, but further analysis of these data and continued follow-up of this and other cohorts are necessary in order to determine the proportion of BCML that develops into B-CLL or other malignancies.
Recommendation     Conduct epidemiological review of the data acquired from the cohort described in Chapter 6 and update the data through continued follow-up of this cohort. Conduct new studies designed with a longitudinal component for follow-up.
Agency Response     This will require specific support at the agency or department level to provide competitive funding for peer-reviewed proposals.
4. CONDUCT STRATIFIED PREVALENCE STUDIES Finding     Data from these ATSDR studies and from independent investigations (see Chapter 10) suggest that the prevalence of BCML in a normal population of people above age 40 maybe on the order of 1%. This surprisingly high value must be confirmed and evaluated in demographically representative populations.
Recommendation     Develop the most effective screening procedures for evaluating the prevalence of BCML in large population studies. These procedures could should be designed for use in a randomized survey such as the Health and Nutrition Evaluation Survey (HANES).
Agency Response     CBER/FDA and EHLS/CDC will jointly develop the optimal screening procedures. The application of such procedures awaits technical development and the opportunity for collaboration with ongoing studies.
5. STANDARDIZE LABORATORY METHODS Finding     Consistent laboratory characterization of BCML will require the use of inter-laboratory studies to validate methods, establish technical sources of variability, and ensure laboratory proficiency.
Recommendations     Validate kappa/lambda analysis with methods that use at least two labeled antibodies and preferably three labeled antibodies to identify B-cells, kappa, and lambda expression. Single parameter (color) analyses are not recom-mended. Use B-cell “gating” (either live or software gates) to improve sensitivity. Establish a network to coordinate inter-laboratory studies.
Agency Response     CBER/FDA and EHLS/CDC will help develop standards for kappa/lambda analyses and PCR techniques used in heavy chain analysis.
6. ADDRESS MEDICAL AND ETHICAL ISSUES Finding     Because neither the clinical significance of BCML nor the prognosis of individuals with BCML is predictable at this time, the decision to report findings of BCML to study participants raises ethical questions, and our lack of knowledge about BCML reinforces the need for medical follow-up.
Recommendation

Ideally, an established centralized clinical facility such as the Family Studies Section Outpatient Clinic, NCI, NIH would follow and advise individuals identified with BCML in federally-supported studies. The larger ethical issues involved in identifying BCML should be closely examined and compared with issues involved in identifying risk factors for other diseases such as the use genetic markers to identify an increased risk of breast cancer. Findings from
the inter-agency workgroup in the Ethical, Legal and Social Issues branch of the National Center for Human Genome Research should be considered in the context of BCML.

Agency Response ATSDR medical officers had already contacted all participants identified as having a B-CLL-like phenotype and encouraged them to discuss these results with their personal physicians. In addition, ATSDR offered to help transport the 3 people with documented monoclonality to the outpatient clinic of the Family Studies Section, NCI, NIH. Arrangements for future studies are currently under discussion. Future studies should include consideration by an Institutional Review Board on the need for clinical follow-up and individual notification.
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