Chronic lymphocytic leukemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

Chronic lymphocytic leukemia arises from pre-follicular, center B cells, which are normally involved in the process of human immunoglobulins production. Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells. Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include chromosome 13q deletion, chromosome 17p deletion, and chromosome 11q deletion. On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include small lymphoid cells, thin cytoplasmic border, lack of nucleolus, and the presence of smudge cells. The first comprehensive clinical report of chronic lymphocytic leukemia was published in 1924 by Dr. George Minot, an American physician. Chronic lymphocytic leukemia must be differentiated from other diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukaemia, prolymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. The most potent risk factor in the development of chronic lymphocytic leukemia is advanced age. Other risk factors include male gender, positive family history, and exposure to certain chemicals. The majority of patients with chronic lymphocytic leukemia are asymptomatic at the time of diagnosis. If left untreated, patients with chronic lymphocytic leukemia may progress to develop weight loss, fever, and lymphadenopathy. Common complications of chronic lymphocytic leukemia include immunodeficiency, warm autoimmune hemolytic anemia, and Richter’s transformation. Prognosis is generally good, and the 5-year survival rate of patients with chronic lymphocytic leukemia is approximately 81.7%. Physical examination of patients with chronic lymphocytic leukemia is usually remarkable for skin pallor, palpable cervical lymph nodes, and hepatomegaly. Laboratory findings consistent with the diagnosis of chronic lymphocytic leukemia include abnormal complete blood count, immunohistochemistry, and electrophoresis. Monoclonality of kappa and lambda producing B cells is a key diagnostic feature among patients with chronic lymphocytic leukemia. According to the Rai Staging System, there are five stages of chronic lymphocytic leukemia based on the degree of lymphocytosis, hemoglobin concentration, platelets concentration, presence of splenomegaly, and presence of lymphadenopathy. While according to the Binet Staging System, there are three stages of chronic lymphocytic leukemia based on the degree of lymphocytosis, the presence of anemia or thrombocytopenia, and the involvement of three or more lymph node regions. Bone marrow biopsy and lymph node biopsy may be helpful in the diagnosis of chronic lymphocytic leukemia. Karyotyping and fluorescent in situ hybridization detect any chromosomal mutations involved in the development of chronic lymphocytic leukemia. The tumor stage is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients. The mainstay of therapy for symptomatic chronic lymphocytic leukemia patients is immunochemotherapy.

The first comprehensive clinical report of chronic lymphocytic leukemia was published in 1924 by Dr. George Minot, an American physician.

There is no classification system established for chronic lymphocytic leukemia. Staging systems for chronic lymphocytic leukemia can be viewed here.

Chronic lymphocytic leukemia arises from pre-follicular, center B cells, that are normally involved in the process of human immunoglobulins production. Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells. Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include chromosome 13q deletion, chromosome 17p deletion, and chromosome 11q deletion. On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include small lymphoid cells, thin cytoplasmic border, lack of nucleolus, and the presence of smudge cells.

There are no established direct causes for chronic lymphocytic leukemia. Common genetic mutations involved in the development of chronic lymphocytic leukemia can be found here.

Chronic lymphocytic leukemia must be differentiated from other diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukaemia, prolymphocytic leukaemia, follicular lymphoma, and mantle cell lymphoma.

In 2011, the age-adjusted incidence of chronic lymphocytic leukemia was 4.82 per 100,000 individuals in the United States. Chronic lymphocytic leukemia is a disease of the elderly and is rarely encountered in individuals under the age of 40. The majority of patients who are newly diagnosed with chronic lymphocytic leukemia are over the age 50 years. Males are more commonly affected with chronic lymphocytic leukemia than females.

The most potent risk factor in the development of chronic lymphocytic leukemia is advanced age. Other risk factors include male gender, positive family history, and exposure to certain chemicals.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for chronic lymphocytic leukemia.

Most patients with chronic lymphocytic leukemia are asymptomatic at the time of diagnosis. If left untreated, patients with chronic lymphocytic leukemia may progress to develop weight loss, fever, and lymphadenopathy. Common complications of chronic lymphocytic leukemia include immunodeficiency, warm autoimmune hemolytic anemia, and Richter’s transformation. Prognosis is generally good, and the 5-year survival rate of patients with chronic lymphocytic leukemia is 81.7%.

According to the Rai Staging System, there are five stages of chronic lymphocytic leukemia based on the degree of lymphocytosis, hemoglobin concentration, platelets concentration, presence of splenomegaly, and presence of lymphadenopathy. While according to the Binet Staging System, there are three stages of chronic lymphocytic leukemia based on the degree of lymphocytosis, the presence of anemia or thrombocytopenia, and the involvement of three or more lymph node regions. The tumor stage is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.

Symptoms of chronic lymphocytic leukemia include fever, weight loss, night sweats, and recurrent bleeding.

Physical examination of patients with chronic lymphocytic leukemia is usually remarkable for skin pallor, palpable cervical lymph nodes, and hepatomegaly.

Laboratory findings consistent with the diagnosis of chronic lymphocytic leukemia include abnormal complete blood count, immunohistochemistry, and electrophoresis. Monoclonality of kappa and lambda producing B cells is a key diagnostic feature among patients with chronic lymphocytic leukemia.

There are no X ray findings associated with chronic lymphocytic leukemia.

CT scan is not required to confirm the diagnosis of chronic lymphocytic leukemia.

MRI may be performed to detect spinal cord bone infiltration among chronic lymphocytic leukemia patients.

There are no ultrasound findings associated with chronic lymphocytic leukemia.

There are no other imaging studies needed to confirm the diagnosis of chronic lymphocytic leukemia.

Bone marrow biopsy and lymph node biopsy may be helpful in the diagnosis of chronic lymphocytic leukimea. Karyotyping and fluorescent in situ hybridization detect any chromosomal mutations involved in the development of chronic lymphocytic leukemia.

The mainstay of therapy for symptomatic chronic lymphocytic leukemia patients is immunochemotherapy. Asymptomatic chronic lymphocytic leukemia patients are managed with observation and follow-up, whereas symptomatic chronic lymphocytic leukemia patients are treated with immunochemotherapy. Immunochemotherapies used for the treatment of chronic lymphocytic leukemia patients include purine analogues, alkylating agents, monoclonal antibodies, corticosteroids, tyrosine kinase inhibitors, and B-cell receptor pathway inhibitors. Radiation therapy is not recommended for the management of chronic lymphocytic leukemia patients.

Surgical intervention is not recommended for the management of chronic lymphocytic leukemia patients.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shalinder Singh, M.B.B.S.[2] Haytham Allaham, M.D. [3]

The first comprehensive clinical report of chronic lymphocytic leukemia was published by Dr. George Minot in 1924, an American physician.

• The pathology of leukemia was first described in 1845 by Dr. John Hughes Bennett and Dr. Rudolph Virchow.^[1][2]
• In 1889, the first subdivision of leukemia into acute and chronic subtypes was first proposed by Dr. Wilhelm Ebstein.^[3][4]
• In 1893, clinical data and case studies were developed by Dr. Hans Kundrat, to diagnose chronic lymphocytic leukemia as an independent pathological entity.
• The first comprehensive clinical report of chronic lymphocytic leukemia was published by Dr. George Minot in 1924, an American physician.^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

There is no classification system established for chronic lymphocytic leukemia. Staging systems for chronic lymphocytic leukemia can be found here.^[1]

There is no classification system established for chronic lymphocytic leukemia. Staging systems for chronic lymphocytic leukemia can be found here.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shalinder Singh, M.B.B.S.[2] Haytham Allaham, M.D. [3]

Chronic lymphocytic leukemia arises from pre-follicular, center B cells, that are normally involved in the process of human immunoglobulin production. Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells. Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include chromosome 13q deletion, chromosome 17p deletion, and chromosome 11q deletion. On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include small lymphoid cells, thin cytoplasmic border, lack of nucleolus, and the presence of smudge cells.

• The pathology of chronic lymphocytic leukemia can be understood as follows:^{[1][2][3][4][5][6][7]}
  • Chronic lymphocytic leukemia is defined as clonal proliferation of incompetent B-cells.
  • Chronic lymphocytic leukemia arises from pre-follicular, center B cells that are normally involved in the process of human immunoglobulins production.
  • Chronic lymphocytic leukemia cells are clonal B cells, and their differentiation is halted between the pre-B cells and mature B cells.
  • Pre-malignant B cell proliferation precedes chronic lymphocytic leukemia/small lymphocytic leukemia and is known as monoclonal B cell lymphocytosis (MBL).
  • There are multiple factors leading to production of MBL, which involves antigen stimulation, gene mutation, environment factors, immunologic and cytogenetic modifications.
  • Repeated results from these factors lead to advancement of MBL to chronic lymphocytic leukemia.
  • Most of the patients of chronic lymphocytic leukemia are asymptomatic, until the incompetent lymphocytes start to accumulate and infiltrate organ systems.
  • Malignant lymphocytic cells infiltrate hematopoietic sites, such as the bone marrow, where they interfere with the production of red blood cells and platelets.
  • Chronic lymphocytic leukemia may also infiltrate the lymph nodes, spleen, and liver.
  • Immune deficiency may occur in chronic lymphocytic leukemia as the majority of cases develop hypogammaglobulinemia.
  • Warm autoimmune hemolytic anemia may develop due to the production of IgA and IgG autoantibodies among certain cases of chronic lymphocytic anemia.
  • Autoimmune thrombocytopenia may develop due to the production of auto-antibodies.
  • Production of cytokines, angiogenic factors, and chemokines by the surrounding macrophages and T cells provide important stimuli for malignant B cells proliferation in chronic lymphocytic leukemia.
  • Richter’s transformation represents the conversion of chronic lymphocytic leukemia into a more aggressive and rapidly growing large B cell lymphoma.
  • Richter’s transformation may occur among 1-5% of chronic lymphocytic leukemia cases.

• Chronic lymphocytic leukemia cells express B cell surface antigens such as CD19, CD20, CD21 and CD23 monoclonal antibodies.^[8][9]
• They also express CD5, which is a T cell antibody.^[10]
• Chronic lymphocytic leukemia cells also express decreased level of B cell surface antigens IgM and IgD immunoglobulin.^[11]

• Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells.
• Structural genetic mutations and associated features involved in the pathogenesis of chronic lymphocytic leukemia include:^{[12][13][14][15][16]}
  • Chromosome 11 long arm deletion (11q22-q23):
    • Relapsing disease, refractory to initial therapy, poor prognosis, large-scale lymph node involvement and shorter survival
  • Chromosome 13 long arm deletion (most common genetic mutation):
    • Better prognosis
  • Chromosome 17p13 deletion:
    • Tumor suppressor gene TP53 deletion, relapsing disease and refractory to initial therapy
  • Trisomy 12:
    • Increased proliferation and advanced disease

• Somatic genetic mutations and associated factors involved in the pathogenesis of chronic lymphocytic leukemia include:^{[17][18][19][20]}

• SF3B1 gene located on chromosome 2 (Poor prognosis)
• B cell receptor (BCR) signaling
• FBXW7 gene located on chromosome 4
• MYD88 gene located on chromosome 3
• TP53 gene located on chromosome 7
• NOTCH1 gene located on chromosome 9^[20]
• ATM gene located on chromosome 11
• CHD2 gene located on chromosome 15
• MicroRNA

• The type of the genetic mutation is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.

• On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include:

• Small lymphoid cells
• Thin cytoplasmic border
• Dense nucleus
• Lack of nucleolus
• Clumped chromatin aggregates
• The presence of smudge cells
• The presence of Gumprecht nuclear shadows

• On immunohistochemistry, characteristic findings of chronic lymphocytic leukemia include:

• CD5 +ve
• CD19 +ve
• CD20 +ve
• CD23 +ve/-ve
• CD38 +ve/-ve
• CD43 +ve
• Cyclin D1 -ve

• Illustrated below is a series of microscopic images observed in chronic lymphocytic leukemia:

• 
  Chronic lymphocytic leukemia illustrated on low magnification^[21]
• 
  Chronic lymphocytic leukemia illustrated on intermediate magnification^[21]
• 
  Chronic lymphocytic leukemia illustrated on high magnification^[21]
• 
  Chronic lymphocytic leukemia illustrated on very high magnification^[21]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

There are no established direct causes for chronic lymphocytic leukemia. Common genetic mutations involved in the development of chronic lymphocytic leukemia can be found here.^[1]

There are no established direct causes for chronic lymphocytic leukemia. Common genetic mutations involved in the development of chronic lymphocytic leukemia can be found here.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Syed Hassan A. Kazmi BSc, MD [3]

Chronic lymphocytic leukemia must be differentiated from other diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukaemia, prolymphocytic leukaemia, follicular lymphoma, and mantle cell lymphoma.

Chronic lymphocytic leukemia must be differentiated from other diseases that cause weight loss, night sweats, hepatosplenomegaly, and palpable lymph nodes, such as hairy cell leukaemia, prolymphocytic leukaemia, follicular lymphoma, and mantle cell lymphoma.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Rim Halaby, M.D. [3]; Haytham Allaham, M.D. [4]

The age-adjusted incidence of chronic lymphocytic leukemia is 4.7 per 100,000 individuals in the United States. Chronic lymphocytic leukemia is a disease of the elderly and is rarely encountered in individuals under the age of 40 years. Most patients who are newly diagnosed with chronic lymphocytic leukemia are over the age 50 years. Males are more commonly affected with chronic lymphocytic leukemia than females. The number of deaths from chronic lymphocytic leukemia is 1.3 per 100,000 individuals in the United States.

• The prevalence of chronic lymphocytic leukemia ranges from a low of 10 to 50 cases per 100,000 individuals, with an average prevalence of 30 per 100,000 individuals.

• The incidence of chronic lymphocytic leukemia in developed countries is 4 per 100,000 individuals. It increases to more than 30 per 100,000 individuals at the age of 80 years.^[1]
• In 2011, the age-adjusted incidence of chronic lymphocytic leukemia was 4.82 per 100,000 individuals in the United States.^[2]

• Thereafter, the incidence of chronic lymphocytic leukemia increases with age.^[3]
• Chronic lymphocytic leukemia is a disease of the elderly and is rarely encountered among individuals under the age of 40 years.
• Most patients who are newly diagnosed with chronic lymphocytic leukemia are over the age 50.
• While the overall age-adjusted incidence of chronic lymphocytic leukemia in the United States is 4.4 per 100,000, the age-adjusted incidence of chronic lymphocytic leukemia by age category is:^[2]

• 1.4 per 100,000 individuals among individuals younger than 65 years of age.
• 25.2 per 100,000 individuals among individuals older than 65 years of age.

• Males are more commonly affected with chronic lymphocytic leukemia than females. (1.7:1)
• In the United States, the age-adjusted incidence of chronic lymphocytic leukemia by gender on 2011 is:^[2][4]
  • 6.44 per 100,000 individuals among males.
  • 3.51 per 100,000 individuals among females.

• Chronic lymphocytic leukemia usually affects individuals of the Caucasian race. African American individuals are slightly less likely to develop chronic lymphocytic leukemia.^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

• The most potent risk factor in the development of chronic lymphocytic leukemia is advanced age. Other risk factors include male gender, positive family history, and exposure to certain chemicals.

• The most potent risk factor in the development of chronic lymphocytic leukemia is advanced age. Other risk factors include male gender, positive family history, and exposure to certain chemicals.

• The table below lists the risk factors involved in the development of chronic lymphocytic leukemia:^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for chronic lymphocytic leukemia.^[1]

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for chronic lymphocytic leukemia.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

Most patients with chronic lymphocytic leukemia are initially asymptomatic. If left untreated, patients with chronic lymphocytic leukemia may progress to develop weight loss, fever, and lymph nodes swelling. Common complications of chronic lymphocytic leukemia include immunodeficiency, warm autoimmune hemolytic anemia, and Richter’s transformation. Prognosis is generally good, and the 5-year survival rate of patients with chronic lymphocytic leukemia is 81.7%.

• Most patients with chronic lymphocytic leukemia are initially asymptomatic.
• If left untreated, patients with chronic lymphocytic leukemia may progress to develop weight loss, fever, and lymph nodes swelling.

• Common complications of chronic lymphocytic leukemia include:^[1][2][3][4]

• Richter’s transformation
• Recurrent infections
• Anemia
  • Autoimmune thrombocytopenia
  • Red cell aplasia
  • Chemotherapy-induced anemia
• Immune thrombocytopenia
• Colitis
• Intussusception
• Small intestinal bacterial contamination
• Tumor lysis syndrome
• Constrictive pericarditis

• Prognosis is generally good, and the 5-year survival rate of patients with chronic lymphocytic leukemia is 81.7%.^[5]
• Common prognostic factors for chronic lymphocytic leukemia patients include age, tumor stage, and the presence of certain genetic mutations.^[6]
• The table below lists prognostic factors for chronic lymphocytic leukemia patients:^[7][8][1]

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