Chronic Lymphocytic Leukemia Disease Background

Introduction

Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder characterized by the progressive accumulation of monoclonal B-cell lymphocytes found in the blood and bone marrow. 

Epidemiology

It is the most common form of adult leukemia in the Western world with an incidence of roughly 4.2 per 100,000 people per year. In the United States (U.S.) alone there were an estimated 215,107 people living with CLL in 2021. In contrast, the incidence of CLL is extremely low in Asian countries, such as in China and Japan, where estimated frequency is approximately 10% of that seen in its Western counterparts. Worldwide, there are as many as 191,000 cases and 61,000 deaths attributed to CLL every year.  

CLL is considered a disease of older adults, with an average age of diagnosis at 70 years of age. However, as much as 10% of CLL cases are reported to be younger than 55 years. CLL has a slightly higher incidence in males than in females, but studies show that the latter would show a more aggressive form of the disease. Lastly, CLL is reported to have some genetic basis for susceptibility, as family members of patients with CLL may have as much as a 9-fold increased risk for the disease. 

Pathophysiology

Pathophysiology of CLL involves processes that lead to the clonal replication of malignant B lymphocytes in the blood, bone marrow, lymph nodes, and the spleen. The first of these is the development of monoclonal B-cell lymphocytosis (MBL) due to multiple factors such as antigenic stimulation, genetic mutations, and cytogenic. MBL is defined by a monoclonal population of B lymphocytes <5,000 cells/µL in the peripheral blood without any symptoms or features of a B cell lymphoproliferative disorder. Abnormalities that promote the development of MBL include large chromosomal changes (eg deletions in chromosome 13q and 11q, trisomy 12) and mutations in the genes NOTCH1, MYD88, TP53, ATM, and POT1, to name a few. This then is followed by the progression of MBL to CLL due to additional insult to the B-cell clone, either from more genetic abnormalities or changes in the bone marrow microenvironment. A critical step in the pathogenesis of CLL is the induction of an antigen-independent cell-autonomous signaling of the B-cell antigen receptor (BCR). Ultimately, due to the accumulation of incompetent, neoplastic B cells, some patients develop signs and symptoms related to suppression of normal organ function (eg lymphadenopathy, hepatosplenomegaly, cytopenias, infections). 

Chronic Lymphocytic Leukemia_Disease Background

Risk Factors

The following are the risk factors for the development of CLL:

• Chemical exposure
• Family history: First-degree relatives (6- to 9-fold increased risk)
• Race: Higher incidence in Caucasians compared to African Americans and Asians
• Gender: Increased incidence in men compared to women

Commonly associated genetic aberrations in CLL includes the following:

• Good prognosis: Deletions of chromosome 13q 
• Poor prognosis: 17p, 11q chromosomal deletion, trisomy 12, TP53, NOTCH1, SF3B1, RPS15 gene mutations, ATM mutations with or without BIRC3 deletion, CD49d, CD38 expression, ZAP-70 expression