Researchers have shown that abnormal white blood cells can be present in patients' blood more than six years prior to the diagnosis of a chronic form of lymphocytic leukemia. This finding may lead to a better understanding of the cellular changes that characterize the earliest stages of the disease and how it progresses. The study, led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and the U.S. Food and Drug Administration, was published in the Feb. 12, 2009, issue of the New England Journal of Medicine.

"This finding emphasizes the need to better define predictors of cancer development," said NCI Director John E. Niederhuber, M.D. "Identifying the earliest indicators of cancer gives researchers an opportunity to study the window from the prediagnostic state to the transformation to disease. This may help define risk factors and may allow for the discovery of novel molecular targets for treatment of the disease."

Chronic lymphocytic leukemia (CLL) is a blood cancer that usually progresses slowly over many years. In this disease, abnormal white blood cells called B-cells accumulate in the blood and the bone marrow. The lymph nodes, spleen, and other organs may also be affected. Although CLL is the most common form of leukemia in adults in Western countries, little is known about what causes the disease or how it develops.

Previous research by the NCI/FDA team and others showed that some family members of CLL patients can have B-cells in their blood that have outer-surface proteins that are similar to proteins found on CLL cells. This abnormal condition, known as monoclonal B-cell lymphocytosis (MBL), occurs in over 10 percent of CLL family members and in about 3 percent to 5 percent of healthy adults over the age of 50, suggesting it might be a precursor of CLL.

In the current study, the research team identified 45 individuals among the more than 77,000 participants in the nationwide Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial who were cancer-free upon entering the trial, were later diagnosed with CLL, and had frozen blood samples available for analysis that had been collected upon their enrollment in PLCO. Using sophisticated laboratory techniques to analyze the blood samples, the researchers found that 44 of the 45 CLL patients had MBL between six months to more than six years prior to their CLL diagnosis. The MBL cells were identified by examining cell-surface proteins, or CLL markers, using a method called flow cytometry, and by using molecular techniques to confirm the presence of certain rearranged genes, known as immunoglobulin heavy variable (IGHV) group genes, found in CLL. In 41 patients, MBL was confirmed by both methods.

"Our findings indicate that MBL is present in virtually all of CLL patients prior to full-blown disease," said lead author Ola Landgren, M.D., Ph.D., of NCI's Division of Cancer Epidemiology and Genetics. "This important discovery provides novel insights into the natural history of CLL and will open new fields of investigation for understanding its causes." The risk of developing CLL for individuals with MBL appears to be low - on average, it is estimated that each year, only about one percent of them will develop CLL, he noted.

"Next, it will be important to isolate MBL cells and to conduct additional molecular analyses," says Gerald Marti, M.D., Ph.D., of the FDA's Center for Biologics Evaluation and Research, another study author. "This will provide insight into the differences in these cells that may influence why some transform into CLL whereas other do not."

Although the results might not have immediate implications for clinical practice, such as routine screening for MBL, the study will have an influence on CLL research. According to Neil Caporaso, M.D., another NCI author, "Identifying and studying MBL will provide insight that is not available when studying CLL itself. An important and unanswered question is what causes some individuals with MBL to progress to CLL while others remain disease free. Investigating MBL may help us to determine early risk factors for the disease and allows us to identify the precise molecular changes that occur in these cells that cause them to transform into CLL."

The NCI/FDA team says that the work underscores the importance of studying family history and progression of disease. Performing evaluations of members of cancer-prone families has been key to the identification and characterization of MBL; current work focuses on trying to identify molecular markers and environmental influences that predict risk and genes that influence CLL development. The team is working to characterize MBL better and to understand its biology to further define factors that lead to CLL. The team is also conducting studies that focus on related blood cancers and their precursors, including multiple myeloma and monoclonal gammopathy of undetermined significance.

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Landgren O, Albitar M, Ma W, Abbasi FR, Hayes RB, Ghia P, Marti GE, and Caporaso NE. B-Cell clones as early markers for chronic lymphocytic leukemia. New England Journal of Medicine. Vol. 360, No. 7.

For more information on Dr. Landgren's research, please go to http://dceg.cancer.gov/about/staff-bios/landgren-ola.

For more information on Dr. Caporaso's research, please go to http://dceg.cancer.gov/about/staff-bios/caporaso-neil.

For more information on Dr. Marti's research, please go to http://www.fda.gov/commissionersfellowships/marti_bio.html.

For more information about ongoing NCI family studies on CLL, please go to http://dceg.cancer.gov/geb/research/activeclinical/blood/cll-info.

The Center for Biologics Evaluation and Research (CBER) of FDA works to facilitate the development, evaluation, and availability of safe and effective vaccines, blood and blood products, and cellular, tissue, and gene therapies. Through mission-targeted, collaborative research, CBER develops new knowledge and tools to support its science-based regulatory decision making that protects and promotes health in the United States and globally, including protecting against emerging threats.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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