Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow produces too many lymphocytes, which are a type of white blood cell. B cell lymphocytes can begin to collect in the blood, spleen, lymph nodes, and bone marrow; these cells malfunction and crowd out healthy blood cells. CLL is divided into slow-growing (indolent) and fast-growing variants.
Most individuals have no symptoms when they are first diagnosed with CLL. Around five to 10% of patients may experience fever, fatigue, unexplained weight loss, loss of appetite, painless swelling of the lymph nodes, enlargement of the spleen, and/or anemia. These symptoms often worsen over time. Patients with CLL also have an increased risk of developing serious infections. The exact cause of CLL is unknown, but risk factors include a family history of CLL, tobacco use, or environmental exposure to Agent Orange, ionizing radiation and certain insecticides. Diagnosis is typically by testing the blood for high numbers of mature lymphocytes and "smudge cells".
Asymptomatic patients of CLL are often managed by watchful waiting and monitoring for infections. There is currently no evidence that early intervention can alter the course of the disease. Those with significant symptoms are treated with chemotherapy, immunotherapy, or a combination of both, depending on the individual's age, physical condition, and whether they have the del(17p) or TP53 mutations.
CLL is the most common type of leukemia in the Western world. It most commonly affects individuals over the age of 65 due to the accumulation of genetic mutations that occur over time. CLL is rarely seen in individuals younger than 40 years old. Men are more commonly affected than women, although the average lifetime risk for both genders is similar (around 0.5–1%). It represented less than 1% of deaths from cancer between 1980 and 2015.
Signs and symptoms Most people are diagnosed as having CLL based on the result of a routine blood test that shows a high white blood cell count, specifically a large increase in the number of circulating lymphocytes. Most commonly, patients have no symptoms at first. In a small number of cases, patients with CLL may present with enlarged lymph nodes, partially in areas around the neck, armpit, or groin. In rare circumstances, the disease is recognized only after the cancerous cells overwhelm the bone marrow, resulting in low red blood cells, neutrophils, or platelets. This can then result in symptoms such as fever, easy bleeding/bruising, night sweats, weight loss, and increased tiredness. In some instances, the cancerous cells can accumulate in the spleen and result in an enlarged spleen.
Complications About 25% of patients with CLL have very low levels of antibodies in their bloodstream (hypogammaglobulinemia) at diagnosis, with several more patients developing this throughout the course of their disease. This decrease in antibodies increases the patient's risk of recurrent infections and other autoimmune complications, such as autoimmune hemolytic anemia and immune thrombocytopenia. Autoimmune hemolytic anemia occurs in about 5-10% of CLL patients, which is when one's own immune system attacks its own red blood cells.
A more serious complication called Richter's transformation (RT) occurs in 2–10% of patients with CLL. This is a process in which the original CLL cells convert to a far more aggressive disease that has the biology and histopathology of diffuse large B cell lymphoma or less commonly Hodgkin's lymphoma. These patients typically present with a sudden clinical deterioration that can be characterized by unexplained fevers or weight loss, asymmetric and rapid growth of lymph nodes, and/or a significant drop in the number of white blood cells, red blood cells, or platelets. Treatment for RT typically consists of various chemotherapy/chemo-immunotherapy protocols.
CLL has also been reported to convert into other more aggressive diseases such as lymphoblastic lymphoma, hairy cell leukemia, high grade T cell lymphomas, acute myeloid leukemia, lung cancer, brain cancer, melanoma of the eye or skin, salivary gland tumors, and Kaposi's sarcomas. While some of these conversions have been termed RTs, the World Health Organization and most reviews have defined RT as a conversion of CLL/SLL into a disease with DLBCL or HL histopathology.
Gastrointestinal (GI) involvement can also rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis, and bleeding. Usually, GI complications with CLL occur after Richter transformation. Two cases to date have been reported of GI involvement in chronic lymphocytic leukemia without Richter's transformation.Bitetto AM, Lamba G, Cadavid G, Shah D, Forlenza T, Rotatori F, Rafiyath SM. Colonic perforation secondary to chronic lymphocytic leukemia infiltration without Richter transformation. Leuk Lymphoma. 2011 May;52(5):930-3.
Causes The exact cause of CLL is unknown. However, family history has been strongly correlated with disease development. Environmental factors may also play a role in the development of CLL. For instance, exposure to Agent Orange increases the risk of CLL, and exposure to hepatitis C virus may increase the risk. There is no clear association between ionizing radiation exposure and the risk of developing CLL. Blood transfusions have been ruled out as a risk factor.
Mechanism CLL results from an unusual growth and expansion of white blood cells. This manifestation typically begins with a single hematopoietic stem cell that acquires certain mutations over time that allows it to continue to expand and grow at a faster rate than other cells. Each patient with CLL may be affected by a different set of mutations, making these cells sometimes difficult to target and treat. Some of the most common mutations that have been found in CLL-affected cells include the following: NOTCH1, TP53, ATM, and SF3B1.
CLL can also be caused by several epigenetic changes, which are adaptations that add a tag to specific DNA sequences, rather than altering the sequence itself. In CLL, these changes can be classified into the addition of three different methyl subgroups (naïve B-cell-like, memory B-cell-like, and intermediate), which impact how much that DNA sequence is transcribed. Some relevant genetic mutations may be inherited. Since no single mutation is associated with CLL in all cases, an individual's susceptibility may be impacted when multiple mutations that are associated with an increased risk of CLL are co-inherited. Up until 2020, 45 susceptibility loci have been identified. Of these loci, 93% are linked to the alteration of 30 gene expressions involved in immune response, cell survival, or Wnt signaling.
As CLL cells accumulate, they promote inflammation and an immunosuppressive environment by releasing chemical signals.
CLL is commonly preceded by a pre-cancerous state known as monoclonal B-cell lymphocytosis (MBL). This occurs when there is an increase in a specific type of white blood cells, but the number remains less than 5 billion cells per liter (L) (5 billion/L) of blood. This subtype, termed chronic lymphocytic leukemia-type MBL (CLL-type MBL), is an asymptomatic, indolent, and chronic disorder in which people exhibit a mild increase in the number of circulating B-cell lymphocytes. These B-cells are monoclonal, which means a single ancestral B-cell produced them. They share some of the same cell marker proteins, chromosome abnormalities, and gene mutations that are found in CLL.
CLL-type MBL can be separated into two groups:
Low-count MBL has monoclonal B-cell blood counts of <0.5 billion cells/liter (i.e. 0.5 billion/L) High-count MBL has blood monoclonal B-cell counts ≥0.5 billion/L but <5 billion/L.
Low-count MBL rarely if ever progresses to CLL, while high-count CLL/SLL MBL does so at a rate of around 1% per year. Thus, CLL may present in individuals with a long history of having high-count MBL. There is no established treatment for these individuals except monitoring for development of the disorder's various complications (see treatment of MBL complications) and for their progression to CLL.
Diagnosis
The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of cell-surface molecules. CLL is usually first suspected by a diagnosis of lymphocytosis, an increase in a type of white blood cell, on a complete blood count test. This is frequently an incidental finding on a routine physician visit. Most often, the lymphocyte count is greater than 5000 cells per microliter (μL) of blood, but it can be much higher. The presence of lymphocytosis in a person who is elderly should raise a strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.
Classification To be diagnosed with CLL, the patient must have a white blood cell count greater than 5 billion cells per liter (L) (5 billion/L) of blood. If CLL-type cells are mainly found in the lymph nodes or lymphoid tissue (such as the spleen), a diagnosis of small lymphocytic lymphoma (SLL) is made. When these cancerous cells appear mostly in the blood, the disease is classified as CLL.
Clinical staging
Staging, which helps determine the extent of the disease, is done using one of two systems: the Rai staging system (most commonly used in the United States) or the Binet classification(most commonly used in Europe). These systems are simple, requiring the use of only physical examination and blood test results.
Rai staging system Source:
Low-risk disease (formerly Stage 0): characterized by lymphocytosis with cancer cells in the blood and/or bone marrow without lymphadenopathy, enlargement of the liver and spleen, anemia, or thrombocytopenia Intermediate-risk disease (formerly Stage I/II): characterized by lymphocytosis, swollen lymph nodes (may be palpable or not), spleen enlargement, and/or liver enlargement High-risk disease (formerly Stage III/IV): characterized by lymphocytosis with associated anemia (hemoglobin <11 g/dL) OR thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly (liver enlargement), splenomegaly (spleen enlargement), or anemia.
Binet classification Source:
This classification system is based on the number of body areas affected and the presence of anemia or thrombocytopenia. Areas of involvement include the (1) head and neck (considered one), (2) one or both of the armpits, (3) the groin, (4) the spleen, and (5) the liver. They are considered affected if a lymph node greater than 1 cm in diameter is present and/or the spleen or liver is palpable. Clinical stage A: characterized by no anemia (Hb > 10 g/dL) or thrombocytopenia (platelets > 100 billion/L) and no greater than two areas of lymphoid involvement (described above) Clinical stage B: characterized by no anemia (Hb > 10 g/dL) or thrombocytopenia (platelets > 100 billion/L) with three or more areas of lymphoid involvement Clinical stage C: characterized by anemia (Hb < 10 g/dL) and/or thrombocytopenia (platelets < 100 billion/L) regardless of the number of areas of lymph node or organ enlargement
Array-based karyotyping
Array-based karyotyping is a cost-effective alternative to FISH for detecting chromosomal abnormalities in CLL. Several clinical validation studies have shown >95% concordance with the standard CLL FISH panel.
Molecular examination of peripheral blood and flow cytometry