Leukemia

Acute Lymphoblastic Leukemia

Introduction
Background

Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers. The annual incidence rate for acute lymphoblastic leukemia is 30.9 cases per million population. The peak incidence occurs in children aged 2-5 years.

Although a few cases are associated with inherited genetic syndromes (ie, Down syndrome, Bloom syndrome, Fanconi anemia), the cause remains largely unknown. Many environmental factors (ie, exposure to ionizing radiation and electromagnetic fields, parental use of alcohol and tobacco) have been investigated as potential risk factors, but none has been definitively shown to cause acute lymphoblastic leukemia. Various viruses may be linked to the development of leukemia, particularly when prenatal viral exposure occurs in mothers recently infected with influenza or varicella. However, no direct link has been established between viral exposure and the development of leukemia.

Acute lymphoblastic leukemia may also occur in children with various congenital immunodeficiencies (ie, Wiskott-Aldrich syndrome, congenital hypogammaglobulinemia, ataxia-telangiectasia) that have an increased predisposition to develop lymphoid malignancies.

With improvements in diagnosis and treatment, overall cure rates for children with acute lymphoblastic leukemia now approach 80%. Further refinements in therapy, including the use of risk-adapted treatment protocols, may improve cure rates for patients at high risk while limiting the toxicity of therapy for patients with a low risk of relapse. This article summarizes advances in the diagnosis and treatment of childhood acute lymphoblastic leukemia.
Pathophysiology

In acute lymphoblastic leukemia, a lymphoid progenitor cell becomes genetically altered and subsequently undergoes dysregulated proliferation, survival, and clonal expansion. In most cases, the pathophysiology of transformed lymphoid cells reflects the altered expression of genes whose products contribute to the normal development of B cells and T cells. Several studies indicate that leukemic stem cells are present in certain types of acute lymphoblastic leukemia.1,2
Frequency
United States

Annually, 2500-3500 children are diagnosed with acute lymphoblastic leukemia.
International

Throughout the world, the incidence rate is thought to be similar to that in the United States.
Mortality/Morbidity

Overall cure rates for children with acute lymphoblastic leukemia now approach 80%. The 4-year event-free survival (EFS) rate for high-risk patients is approximately 65%.
Race

The overall incidence of acute lymphoblastic leukemia varies among different racial groups within the United States. White children are more frequently affected than black children.
Sex

Acute lymphoblastic leukemia occurs slightly more frequently in boys than in girls. This difference is most pronounced for T-cell acute lymphoblastic leukemia.
Age

The incidence of acute lymphoblastic leukemia peaks in children aged 2-5 years.
Clinical
History

Children with acute lymphoblastic leukemia (ALL) generally present with signs and symptoms that reflect bone marrow infiltration and extramedullary disease. Because leukemic blasts replace the bone marrow, patients present with signs of bone marrow failure, including anemia, thrombocytopenia, and neutropenia. Clinical manifestations include fatigue and pallor, petechiae and bleeding, and fever. In addition, leukemic spread may manifest as lymphadenopathy and hepatosplenomegaly. Other signs and symptoms of leukemia include weight loss, bone pain, and dyspnea.

Signs or symptoms of CNS involvement, even when it occurs, are rarely observed at the time of the initial diagnosis. The signs and symptoms include headache, nausea and vomiting, lethargy, irritability, nuchal rigidity, and papilledema. Cranial nerve involvement, which most frequently involves the seventh, third, fourth, and sixth cranial nerves, may occur. Also, leukemia can present as an intracranial or spinal mass, which causes numerous neurologic symptoms, most of which are due to nerve compression.

Testicular involvement at diagnosis is rare. However, if present, it appears as painless testicular enlargement and is most often unilateral.
Physical

Physical findings in children with acute lymphoblastic leukemia reflect bone marrow infiltration and extramedullary disease. Patients present with pallor caused by anemia and petechiae and bruising secondary to thrombocytopenia. They also have signs of infection because of neutropenia. In addition, leukemic spread may be seen as lymphadenopathy and hepatosplenomegaly.

Careful neurologic examination to look for CNS involvement is important because the treatment for leukemia with CNS involvement is different.

In male patients, testicular examination is necessary to look for testicular involvement of leukemia.
Causes

Although a small percentage of cases are associated with inherited genetic syndromes, the cause of acute lymphoblastic leukemia remains largely unknown.

http://emedicine.medscape.com/article/990113-overview

Acute Myelogenous Leukemia

Introduction
Background

Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education articles Leukemia and Bruises.
Pathophysiology

The underlying pathophysiology in acute myelogenous leukemia (AML) consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.1,2

This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.
Frequency
United States

Estimates of new cases of acute myelogenous leukemia (AML) in the United States in 2007 were 13,410 (7060 men; 6350 women).
International

Acute myelogenous leukemia (AML) is more commonly diagnosed in developed countries.
Mortality/Morbidity

* In 2007, an estimated 8990 deaths from acute myelogenous leukemia (AML) occurred in the United States. Of these, 5020 occurred in men and 3970 occurred in women.
* In adults, treatment results are generally analyzed separately for younger (18-60 y) and older (>60 y) patients with acute myelogenous leukemia (AML).
o With current standard chemotherapy regimens, approximately 30-35% of adults younger than 60 years survive longer than 5 years and are considered cured.
o Results in older patients are more disappointing, with fewer than 10% of surviving over the long term.

Race

* Acute myelogenous leukemia (AML) is more common in whites than in other populations.

Sex

* Acute myelogenous leukemia (AML) is more common in men than in women. The difference is even more apparent in older patients. This is likely because myelodysplastic syndromes (MDSs) are more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the increased prevalence of acute myelogenous leukemia (AML) in men may be related to occupational exposures.

Age

* The prevalence of acute myelogenous leukemia (AML) increases with age. The median age of onset is approximately 70 years. However, acute myelogenous leukemia (AML) affects all age groups.

Clinical
History

* Patients with acute myelogenous leukemia (AML) present with symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable.
o Some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks.
o Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder (AHD) such as MDS.
* Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia.
o The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks.
o Other symptoms of anemia include dyspnea upon exertion, dizziness, and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.
o Patients often have decreased neutrophil levels despite an increased total white blood cell (WBC) count.
o Patients with acute myelogenous leukemia (AML) present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ANCs) (ie, <500 cells/µL, especially <100 cells/µL) have the highest risk of infection.
o Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.
o Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both.
o Potentially life-threatening sites of bleeding include the lungs, gastrointestinal tract, and the central nervous system.
* Alternatively, symptoms may be the result of organ infiltration with leukemic cells.
o The most common sites of infiltration include the spleen, liver, gums, and skin.
o Infiltration occurs most commonly in patients with the monocytic subtypes of acute myelogenous leukemia (AML).
o Patients with splenomegaly note fullness in the left upper quadrant and early satiety.
o Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.
o Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that requires immediate intervention.
o Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.

Physical

* Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present in those with acute myelogenous leukemia (AML).
* Fever and other signs of infection can occur, including lung findings of pneumonia.
* Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. The petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder such as DIC. Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses.
* Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by acute myelogenous leukemia (AML) (granulocytic sarcoma).
* Signs relating to leukostasis include respiratory distress and altered mental status.

Causes

* Although several factors have been implicated in the causation of acute myelogenous leukemia (AML), most patients who present with de novo AML have no identifiable risk factor.
* Antecedent hematologic disorders
o The most common risk factor for acute myelogenous leukemia (AML) is the presence of an antecedent hematologic disorder, the most common of which is MDS. MDS is a disease of the bone marrow of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years.
o Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop acute myelogenous leukemia (AML), whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do develop AML.
o Other antecedent hematologic disorders that predispose patients to acute myelogenous leukemia (AML) include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.
* Congenital disorders
o Some congenital disorders that predispose patients to acute myelogenous leukemia (AML) include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis.
o Usually, these patients develop acute myelogenous leukemia (AML) during childhood; rarely, some may present in young adulthood.
o More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to acute myelogenous leukemia (AML). For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML.3 Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both. Likewise, polymorphisms in glutathione S -transferase are associated with secondary acute myelogenous leukemia (AML) following chemotherapy for other malignancies.4
* Familial syndromes
o Germ-line mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for myelogenous leukemia (AML), an autosomal-dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.
o Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein, alpha; a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by myelogenous leukemia (AML).5
o Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.
* Environmental exposures
o Several studies demonstrate a relationship between radiation exposure and leukemia.
o Early radiologists (before the use of appropriate shielding) were found to have an increased likelihood of developing leukemia.
o Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.
o Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.
o Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing myelogenous leukemia (AML). In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.
o Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.
* Previous exposure to chemotherapeutic agents for another malignancy
o As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with myelogenous leukemia (AML) increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.6
o Patients with previous exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with previous exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors.
o Patients with a previous exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase before the development of myelogenous leukemia (AML). Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).
o Patients with a previous exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves chromosome band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).7
o The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure, but it is only 9-12 months for topoisomerase inhibitors.

http://emedicine.medscape.com/article/197802-overview

Chronic Myelogenous Leukemia

Introduction
Background

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Leukemia.
Pathophysiology

Chronic myelogenous leukemia (CML) is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9; t(9;22). The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph) chromosome after the city of discovery.

This translocation relocates an oncogene called abl from the long arm of chromosome 9 to the long arm of chromosome 22 in the BCR region. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the chronic myelogenous leukemia (CML) phenotype through processes that are not yet fully understood.1,2,3,4,5,6,7,8

The presence of BCR/ABL rearrangement is the hallmark of chronic myelogenous leukemia (CML), although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML.
Frequency
United States

Chronic myelogenous leukemia (CML) accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Although uncommon, the disease also occurs in younger individuals.
International

Increased incidence of chronic myelogenous leukemia (CML) was reported among individuals exposed to radiation in Nagasaki and Hiroshima after the dropping of the atomic bomb.
Mortality/Morbidity

Generally, 3 phases of chronic myelogenous leukemia (CML) are recognized. The general course of the disease is characterized by an eventual evolution to a refractory form of acute myelogenous or, occasionally, lymphoblastic leukemia. The median survival of patients using older forms of therapy is 3-5 years.

* Most patients with chronic myelogenous leukemia (CML) present in the chronic phase, characterized by splenomegaly and leukocytosis (see image below) with generally few symptoms.
o

Blood film at 400X magnification demonstrates leu...
Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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Blood film at 400X magnification demonstrates leu...

Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
* This phase is easily controlled by medication. The major goal of treatment during this phase is to control symptoms and complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly. Newer forms of therapy aim at delaying the onset of the accelerated or blastic phase.
* After an average of 3-5 years, chronic myelogenous leukemia (CML) usually evolves into the blast crisis, which is marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft-tissue or skin leukemic infiltrates. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly. The manifestations of blast crisis are similar to those of acute leukemia. Treatment results are unsatisfactory, and most patients succumb to the disease once this phase develops.
* In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients, the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease. Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph chromosomes or other translocations.
* In many patients, an accelerated phase occurs 3-6 months before the diagnosis of blast crisis. Clinical features in this phase are intermediate between the chronic phase and blast crisis.

Age

* In general, chronic myelogenous leukemia (CML) occurs in the fourth and fifth decades of life.
* Younger patients aged 20-29 years may be affected and may present with a more aggressive form, such as in accelerated phase or blast crisis.
* Uncommonly, chronic myelogenous leukemia (CML) may appear as a disease of new onset in elderly individuals.

Clinical
History

* The clinical manifestations of chronic myelogenous leukemia (CML) are insidious and are often discovered incidentally when an elevated white blood cell (WBC) count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical examination.
* Nonspecific symptoms of tiredness, fatigue, and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.
* Patients often have symptoms related to enlargement of the spleen, liver, or both.
o The large spleen may encroach on the stomach and cause early satiety and decreased food intake. Left upper quadrant abdominal pain described as "gripping" may occur from spleen infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue.
o The enlarged liver may contribute to the patient's weight loss.
* Some patients with chronic myelogenous leukemia (CML) may have low-grade fever and excessive sweating related to hypermetabolism.
* The disease has 3 clinical phases, and chronic myelogenous leukemia (CML) follows a typical course of an initial chronic phase, during which the disease process is easily controlled; followed by a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal.
o Most patients are diagnosed while still in the chronic phase. The WBC count is usually controlled with medication (hematologic remission). This phase varies in duration depending on the maintenance therapy used. It usually lasts 2-3 years with hydroxyurea (Hydrea) or busulfan therapy, but the chronic phase has lasted for longer than 9.5 years in patients who respond well to interferon alfa therapy. Furthermore, the addition of imatinib mesylate in recent years has dramatically improved the duration of hematologic and, indeed, cytogenetic remissions.
o Some patients with chronic myelogenous leukemia (CML) progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of the blood counts with myelosuppressive medication and the appearance of peripheral blast cells (>15%), promyelocytes (>30%), basophils (>20%), and platelet counts less than 100,000 cells/μL unrelated to therapy. Promyelocytes and basophils are shown in the image below.
+

Blood film at 1000X magnification shows a promyel...
Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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Blood film at 1000X magnification shows a promyel...

Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
o Usually, the doses of the medications need to be increased. Splenomegaly may not be controllable by medications, and anemia can worsen. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the last phase. Thus, signs of transformation or accelerated phase in patients with chronic myelogenous leukemia are poor control of blood counts with myelosuppression or interferon, increasing blast cells in peripheral blood with basophilia and thrombocytopenia not related to therapy, new cytogenetic abnormalities, and increasing splenomegaly and myelofibrosis.
o Acute phase, or blast crisis, is similar to acute leukemia, and survival is 3-6 months at this stage. Bone marrow and peripheral blood blasts of 30% or more are characteristic. Skin or tissue infiltration also defines blast crisis. Cytogenetic evidence of another Ph-positive clone (double) or clonal evolution (other cytogenetic abnormalities such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y chromosome) is usually present.
* In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually associated with infections.

Physical

* Splenomegaly is the most common physical finding in patients with chronic myelogenous leukemia (CML).
o In more than 50% of the patients with CML, the spleen extends more than 5 cm below the left costal margin at time of discovery.
o The size of the spleen correlates with the peripheral blood granulocyte counts (see image below), with the largest spleens being observed in patients with high WBC counts.
+

Blood film at 1000X magnification demonstrates th...
Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

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Blood film at 1000X magnification demonstrates th...

Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
o A very large spleen is usually a harbinger of the transformation into an acute blast crisis form of the disease.
* Hepatomegaly also occurs, although less commonly than splenomegaly. Hepatomegaly is usually part of the extramedullary hematopoiesis occurring in the spleen.
* Physical findings of leukostasis and hyperviscosity can occur in some patients, with extraordinary elevation of their WBC counts, exceeding 300,000-600,000 cells/μL. Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages.

Causes

* The initiating factor of CML is still unknown, but exposure to irradiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki.
* Other agents, such as benzene, are possible causes.

http://emedicine.medscape.com/article/199425-overview

Chronic Lymphocytic Leukemia
Introduction
Background

Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is the most common form of leukemia found in adults in Western countries.1 See histologic sample in the image below.

Peripheral smear from a patient with chronic lymp...
Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.

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Peripheral smear from a patient with chronic lymp...

Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Leukemia and Lymphoma.
Pathophysiology

The cells of origin in the majority of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically in the peripheral blood, these cells resemble mature lymphocytes.

B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, CD21, and CD23 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone (MZ) of lymphoid follicles, B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is most likely a malignancy of an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies.

B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) cells express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM/IgD and IgD. Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).

An abnormal karyotype is observed in the majority of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Individuals showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis.

The presence of trisomy 12, which is observed in 15% of patients, is associated with atypical morphology and progressive disease. Deletion in the short arm of chromosome 17 has been associated with rapid progression, short remission, and decreased overall survival in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). 17p13 deletions are associated with loss of function of the tumor suppressor gene p53. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement, aggressive disease, and shorter survival.

More sensitive techniques have demonstrated abnormalities of chromosome 12. Forty to 50% of patients demonstrate no chromosomal abnormalities on conventional cytogenetic studies. However, 80% of patients will have abnormalities detectable by fluorescence in situ hybridization (FISH). Approximately 2-5% of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) exhibit a T-cell phenotype.

Studies have demonstrated that the protooncogene bcl2 is overexpressed in B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).2 The protooncogene bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of bcl-2 protein, genetic translocations that are known to result in the overexpression of bcl2, such as t(14;18), are not found in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Studies have shown that this upregulation in bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA).3,4 These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA. Deletions of miRNA15a and miRNA16-1 lead to overexpression of bcl2 through loss of downregulating miRNAs. Genetic analyses have demonstrated deletion or downregulation of these miRNA genes in 70% of cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Investigations have also identified a number of high-risk genetic features and markers that include germline immunoglobulin variable heavy chain (IgVH), IgVH V3-21 gene usage, increased CD38 expression, increased Zap70 expression, elevated serum beta-2-microglobulin levels, increased serum thymidine kinase activity, short lymphocyte doubling time (<6 mo), and increased serum levels of soluble CD23. These features have been associated with rapid progression, short remission, resistance to treatment, and shortened overall survival in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Germline IgVH has been shown to indicate a poor prognosis. Studies have shown that these patients also have earlier progression of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) after treatment with chemotherapy. The use of certain IgV H genes, V3-21, have also been associated with poor prognosis regardless of IgV H mutational status.

Zeta-associated peptide of 70 kilodaltons (Zap70) is a cytoplasmic tyrosine kinase whose expression has been associated with a poor prognosis. Cells with germline IgV H often have an increased expression of Zap70; however, studies have shown discordance rates of 10-20% between IgV H mutational status and Zap70 expression levels. Elevated levels of Zap70 are believed to decrease the threshold for signaling through bcl2, thereby facilitating the antiapoptotic effects of bcl2. Zap70 function also appears to be dependent on heat shock protein 90 (hsp90), whose inhibition may provide a future therapeutic option.

Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) should also be distinguished from prolymphocytic leukemia, in which more than 65% of the cells are morphologically less mature prolymphocytes.
Frequency
United States

More than 17,000 new cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are reported every year. The true incidence in the US is unknown and is likely higher, as estimates of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) incidence come from tumor registries, and many cases are not reported. One case series had the actual incidence at 38% higher than estimated from tumor registries.
International

Unlike the incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) in Western countries, which is similar to that of the United States, chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is extremely rare in Asian countries (ie, China, Japan), where it is estimated to comprise only 10% of all leukemias. However, underreporting and incomplete registry may significantly underestimate the true incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) in these countries.
Mortality/Morbidity

* The natural history of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is heterogeneous.
* Some patients die rapidly, within 2-3 years of diagnosis, because of complications from chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).
* The majority of patients live 5-10 years, with an initial course that is relatively benign but followed by a terminal, progressive, and resistant phase lasting 1-2 years. During the later phase, morbidity is considerable, both from the disease and from complications of therapy.5,6

Race

The incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is higher among whites compared with blacks.
Sex

The incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is higher in males than in females, with a male-to-female ratio of 1.7:1.
Age

* Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a disease that primarily affects elderly individuals, with the majority of cases reported in individuals older than 55 years. The incidence continues to rise in those older than 55 years.
* However, there are reports that individuals aged 35 years or younger are being diagnosed with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) more frequently.

Clinical
History

Patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) present with a wide range of symptoms and signs at presentation. Onset is insidious, and it is not unusual for chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be asymptomatic at time of presentation.

Symptoms and signs of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) may include the following:

* A predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster may be noted.
* Enlarged lymph nodes are the most common presenting symptom, seen in 87% of patients symptomatic at time of diagnosis.
* Early satiety and/or abdominal discomfort may be related to an enlarged spleen.
* Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia.
* Tiredness and fatigue may be present secondary to anemia.
* Fevers, chills, and night sweats and weight loss constitute B symptoms seen in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).
* Ten percent of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) will present with an autoimmune hemolytic anemia.

Physical

* Localized or generalized lymphadenopathy (80-90% of cases)
o Splenomegaly (30-54% of cases)
o Hepatomegaly (10-20% of cases)
o Petechiae
o Pallor

Causes

* As in the case of most malignancies, the exact cause of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is uncertain.
* The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells. In the majority of cases, this appears to be secondary to alterations in the expression of the miRNAs MIRN15a and MIRN16-1.
* Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is an acquired disorder, and reports of truly familial cases are exceedingly rare.7

http://emedicine.medscape.com/article/199313-overview