Chronic lymphocytic leukemia

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. This decrease in antibodies increases the patient's risk of recurrent infections and other autoimmune complications, such as autoimmune hemolytic anemia and immune thrombocytopenia. 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. 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 Gastrointestinal (GI) involvement can also rarely occur with chronic lymphocytic leukemia. ==Causes==

The exact cause of CLL is unknown. However, family history has been strongly correlated with disease development. 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. 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. 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. ==Diagnosis==

of a lymph node affected by B-CLL showing a characteristic proliferation center (right of image), composed of larger, lighter-staining cells, H&E stain 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. 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. This classification system is based on the number of body areas affected and the presence of anemia or thrombocytopenia. Molecular examination of peripheral blood and flow cytometry The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry to confirm clonality and molecular expression is needed to establish the diagnosis of CLL. Both are easily accomplished with a small sample of blood. A flow cytometer instrument can examine the expression of molecules on individual cells. This requires the use of specific antibodies to cell-surface molecules that have fluorescent tags that are recognized by the instrument. In CLL, the lymphocytes are all genetically identical since they are derived from the same B cell lineage. CLL cells can express the typical B-cell markers such as CD19 and CD20, as well as abnormal surface markers such as CD5 and CD23. Smudge cells are a result of CLL cells lacking vimentin, a type of cytoskeleton proteins which is a structural component in a cell which maintains the cell's internal shape and mechanical resilience). Surface markers The atypical molecular pattern on the surface of the cell includes the co-expression of cell surface markers clusters of differentiation 5 (CD5) and 23. In addition, all the CLL cells within one individual are clonal, that is, genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive antibody light chains, kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody-producing cells, resulting in a mixture of both kappa- and lambda-expressing cells. The lack of the normal distribution of these B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell non-Hodgkin lymphoma). The Matutes's CLL score allows the identification of a homogeneous subgroup of classical CLL, that differs from atypical/mixed CLL for the five markers' expression (CD5, CD23, FMC7, CD22, and immunoglobulin light chain) Matutes's CLL scoring system is very helpful for the differential diagnosis between classical CLL and the other B cell chronic lymphoproliferative disorders, but not for the immunological distinction between mixed/atypical CLL and mantle cell lymphoma (MCL malignant B cells). Discrimination between CLL and MCL can be improved by adding non-routine markers such as CD54 and CD200. Among routine markers, the most discriminating feature is the CD20/CD23 mean fluorescence intensity ratio. FMC7 expression can be misleading for borderline cases. Related diseases In the past, cases with a similar microscopic appearance in the blood but with a T-cell phenotype were referred to as T-cell CLL. However, these are now recognized as a separate disease group and are currently classified as T-cell prolymphocytic leukemias (T-PLL). An accurate diagnosis of T-PLL is important as it is a rare and aggressive disease. CLL should not be confused with acute lymphoblastic leukemia, a highly aggressive leukemia most commonly diagnosed in children, and highly treatable in the pediatric setting. Differential diagnosis Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B-cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma. • B cell prolymphocytic leukemia, a related, but more aggressive disorder, has cells with a similar phenotype, but are significantly larger than normal lymphocytes and have a prominent nucleolus. The distinction is important as the prognosis and therapy differ from CLL. • Hairy cell leukemia is also a neoplasm of B lymphocytes, but the neoplastic cells have a distinct morphology under the microscope (hairy cell leukemia cells have delicate, hair-like projections on their surfaces) and unique marker molecule expression. All the B-cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow, and occasionally lymph node cells by a pathologist with specific training in blood disorders. A flow cytometer is necessary for cell marker analysis, and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by FISH. ==Treatment==

CLL treatment focuses on controlling and limiting the progression of the disease and its symptoms, as it remains incurable . In patients with few to no symptoms, watchful waiting with close observation is generally appropriate. As of 2024, first-line treatment for CLL involves the use of targeted biological therapy. In special circumstances, patients can develop massive splenomegaly that may lead to the destruction of red blood cells, white blood cells, and platelets. Decision to treat While it is generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years—in some cases for decades. Because of its slow onset, asymptomatic early-stage CLL (Rai 0, Binet A) is, in general, not treated since it is believed that early-stage CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time to detect any change in the disease pattern. There are two widely used staging systems in CLL to determine when and how to treat the patient: The Rai staging system, used in the United States, and the Binet system in Europe. Both these systems attempt to characterize the disease based on the bulk and marrow failure. Monoclonal antibodies Anti-CD20 antibodies CD20 is a protein that is found on the surface of B-cells and thus serves as an important target in the treatment of many B-cell malignancies, including CLL. Chemoimmunotherapy with FCR has been shown to improve response rates, progression-free survival, and overall survival in a large randomized trial in CLL patients selected for good physical fitness. Stem cell transplantation Autologous stem cell transplantation, using the recipient's own cells, is not curative. Refractory CLL "Refractory" CLL is a disease that no longer responds favorably to treatment within six months following the last cancer therapy. ==Prognosis==

Prognosis can be affected by the type of genetic mutation that the person with CLL has. Some examples of genetic mutations and their prognoses are: mutations in the IGHV region are associated with a median overall survival (OS) of more than 20–25 years, while no mutations in this region is associated with a median OS of 8–10 years; deletion of chromosome 13q is associated with a median OS of 17 years; and trisomy of chromosome 12, as well as deletion of chromosome 11q, is associated with a median OS of 9–11 years. Telomere length has been suggested to be a valuable prognostic indicator of survival. In addition, a person's sex has been found to have an impact on CLL prognosis and treatment efficacy. More specifically, females have been found to survive longer (without disease progression) than males, when treated with certain medications. As of 2022, the most commonly used prognostic score is the CLL International Prognostic Index (CLL-IPI). This system takes into account the following factors: • TP53 gene deletion and/or mutation • Mutated immunoglobulin heavy chain variable (IGHV) • Serum B2-microglobulin levels • Clinical stage (see the Rai and Binet staging systems above) • Age ==Epidemiology==

CLL is the most common type of leukemia in the Western world compared to non-Western regions such as Asia, Latin America, and Africa. It is observed globally that males are twice as likely than females to acquire CLL. The median age of diagnosis is 70 years. In older people, however, this difference becomes less pronounced: after the age of 80 years, new cases of CLL are diagnosed equally between men and women. In Western populations, subclinical "disease" can be identified in 3.5% of normal adults, and in up to 8% of individuals over the age of 70. A low incidence is seen in Japanese immigrants to the US, and in African and Asian immigrants to Israel. People who live near areas with considerable industrial pollution have an elevated risk of developing leukemia, particularly CLL. ==Research directions==

In light of newer targeted therapies such as Bruton tyrosine kinase inhibitors and anti-CD20 monoclonal antibodies, the need for bone marrow transplants in patients with CLL has become rare. Bone marrow transplants are only recommended in specific cases when front-line therapies have either failed and/or the patient continues to relapse. Although this disease remains incurable, therapies such as Bruton tyrosine kinase inhibitors (including ibrutinib, acalabrutinib, and zanubrutinib), BCL-2 inhibitors (including venetoclax), and phosphatidylinositol 3-kinase inhibitors (including idelalisib and duvelisib) allow patients with CLL to now live longer. Despite the great success of these new targeted biological therapies so far, more research is needed in order to establish clearer guidelines on the optimal combination and sequence of these agents based on the patient's specific clinical presentation. Furthermore, for patients who do not respond to these agents, treatment options are limited. Thus, further research should be focused on discovering therapies that target other important chemical pathways. == Special Populations ==

Pregnancy Leukemia is rarely associated with pregnancy, affecting only about one in 10,000 pregnant women. Treatment for chronic lymphocytic leukemias can often be postponed until after the end of the pregnancy. If treatment is necessary, then giving chemotherapy during the second or third trimesters is less likely to result in pregnancy loss or birth defects than treatment during the first trimester. == See also ==