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INTRODUCTION

Chronic lymphocytic leukemia (CLL) is a monoclonal proliferation of mature B lymphocytes defined by an absolute number of malignant cells in the blood (5 × 109/mL). The presence of malignant B cells under this count in the blood without nodal, spleen, or liver involvement and absent cytopenias is a precursor of this disease called monoclonal B-cell lymphocytosis (MBL) with ~1–2% chance per year of progressing to overt CLL. CLL is a heterogeneous disease in terms of natural history, with some patients presenting asymptomatically and never requiring therapy, whereas others present with symptomatic disease, require multiple lines of therapy, and eventually die of their disease. Over the past 10–15 years, the understanding of CLL origin and biology has grown exponentially, leading first to more refined disease definition, prognostic markers, and, subsequently, introduction of novel therapies that have significantly changed the natural history of this disease. In this chapter, we review the epidemiology, biology, and management of CLL, with a focus on new knowledge that is currently changing standards of care.

EPIDEMIOLOGY

CLL is primarily a disease of older adults, with a median age at diagnosis of 71 and an age-adjusted incidence of 4.5/100,000 people in the United States. The prevalence of CLL has increased over the past decades due to improvements in therapy for this disease and also survival of older patients from other medical ailments. In 1980, the 5-year overall survival of patients was 69%, and this increased to 87.9% in 2007 and is likely even higher today. The male:female ratio is 2:1; however, as patients age, the ratio becomes more even, and over the age of 80, the incidence is equal between men and women. The disease is most common in Caucasians, less common in Hispanic and African Americans, and is rare in the Asian population.

Unlike many other malignancies, there have been no definitive links between CLL and exposures. Indeed, CLL is one of the only types of leukemia not linked to radiation exposure. Agent Orange exposure has been implicated, and CLL is thus a service-connected condition for those who were exposed to Agent Orange in the Vietnam conflict.

CLL is one of the most familial-associated malignancies, and the first-degree relative of a CLL patient has an 8.5-fold elevated risk of developing CLL than the general population. MBL is also more common in families with two first-degree relatives having CLL, further supporting a genetic predisposition of this disease. Despite this, specific genes conferring risk in the familial setting outside of specific families have been difficult to identify. In genome-wide association studies (GWAS), ~30 SNPs have been identified, which is estimated to account for 19% of the familial risk of CLL. Genes involved in apoptosis, telomere function, B-cell receptor (BCR) activation, and B cell differentiation have all been implicated in GWAS. Variants in shelterin complex proteins involved in telomere maintenance such as POT1 have been identified ...

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