Chronic lymphocytic leukemia
Encyclopedia
B-cell chronic lymphocytic leukemia (B-CLL), also known as chronic lymphoid leukemia (CLL), is the most common type of leukemia
. Leukemias are cancers of the white blood cell
s (leukocytes). CLL affects B cell
lymphocyte
s. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by producing antibodies. In CLL, the DNA of a B cell is damaged, so that it cannot produce antibodies. Additionally, B cells grow out of control and accumulate in the bone marrow and blood, where they crowd out healthy blood cells. CLL is a stage
of small lymphocytic lymphoma (SLL), a type of B-cell lymphoma
, which presents primarily in the lymph nodes. CLL and SLL are considered the same underlying disease, just with different appearances.
CLL is a disease of adults, but, in rare cases, it can occur in teenagers and occasionally in children (inherited). Most (>75%) people newly diagnosed with CLL are over the age of 50, and the majority are men.
Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but, as it advances, CLL results in swollen lymph nodes, spleen
, and liver
, and eventually anemia
and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies
.
DNA analysis has distinguished two major types of CLL, with different survival times. CLL that is positive for the marker ZAP-70
has an average survival of 5 years. CLL that is negative for ZAP-70 has an average survival of more than 25 years. Many patients, especially older ones, with slowly progressing disease can be reassured and may not need any treatment in their lifetimes.
, an increase in one type of white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per microliter (µl) of blood, but can be much higher. The presence of a lymphocytosis in an elderly individual should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.
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 molecules on the cell surface. This atypical molecular pattern includes the coexpression of cells surface markers cluster of differentiation
5
(CD5
) and cluster of differentiation
23
(CD23
). 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 kappa and lambda producing 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 combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry
to confirm clonality and marker molecule expression is needed to establish the diagnosis of CLL. Both are easily accomplished on a small amount of blood. A flow cytometer is an instrument that can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (express marker molecules cluster of differentiation
19
(CD19
) and CD20
), and characteristically express the marker molecules CD5
and CD23
. These B cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells (smudge cells).
(IgVH) gene mutation status. High risk patients have an immature cell pattern with few mutations in the DNA in the IgVH antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.
Since assessment of the IgVH antibody DNA changes is difficult to perform, the presence of either cluster of differentiation
38
(CD38
) or Z-chain–associated protein kinase-70 (ZAP-70
) may be surrogate markers of high risk subtype of CLL. Their expression correlates with a more immature cellular state and a more rapid disease course.
(FISH). Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.
.
s.
CLL should not be confused with acute lymphoblastic leukemia
(ALL), a highly aggressive and highly treatable leukemia most commonly diagnosed in children.
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
.
, radiation therapy
, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy
removal of enlarged spleen) or by radiation therapy
("de-bulking" swollen lymph nodes).
Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy.
The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.
Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.
Although the purine analogue fludarabine
was shown to give superior response rates to chlorambucil
as primary therapy, there is no evidence early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.
Alkylating agents approved for CLL include bendamustine
and cyclophosphamide
.
Monoclonal antibodies
, such as alemtuzumab
(directed against CD52
) and rituximab
and ofatumumab
(directed against CD20
), are also used.
Younger patients that are at high risk for dying from CLL might consider hematopoietic stem cell transplantation (HSCT). Autologous stem cell transplantation
, a lower-risk form of treatment using the patient's own blood cells, is not curative. Myeloablative (bone marrow killing) forms of allogeneic stem cell transplantation
, a high-risk treatment using blood cells from a healthy donor, may be curative for some patients, but most patients cannot tolerate the treatment. An intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients.
, flavopiridol, and bone marrow (stem cell) transplantation, are considered. The monoclonal antibody, alemtuzumab
(directed against CD52
), may be used in patients with refractory, bone marrow-based disease.
, prolymphocytic leukemia
, Hodgkin's lymphoma
, or acute leukemia
in a patient who has chronic lymphocytic leukemia. Its incidence is estimated to be around 5%.
Gastrointestinal (GI) involvement can rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis and others. Usually, GI complications with CLL occur after Richter transformation. There have been two case reports to date of GI involvement in chronic lymphocytic leukemia without Richter's transformation.
In the United States
during 2009, about 16,000 new cases are expected to be diagnosed, and 4,400 patients are expected to die from CLL. Because of the prolonged survival, which was typically about ten years in past decades, but which can extend to a normal life expectancy, the prevalence
(number of people living with the disease) is much higher than the incidence
(new diagnoses).
Subclinical "disease" can be identified in 3.5% of normal adults, and in up to 8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.
Of all cancers involving the same class of blood cell
, 7% of cases are CLL/SLL.
Complications include hypogammaglobulinemia leading to recurrent infection, warm autoimmune hemolytic anaemia in 10–15% of patients, transformation to high grade lymphoma, and Richter's transformation.
Rates of CLL are somewhat elevated in people exposed to certain chemicals. Under U.S. Department of Veterans' Affairs regulations, Vietnam veterans who served in-country or in the inland waterways of Vietnam and who later develop CLL are presumed to have contracted it from exposure to Agent Orange
and may be entitled to compensation.
(all forms of CLL together) is about 50%.
Researchers at the Abramson Cancer Center of the University of Pennsylvania School of Medicine
reported preliminary success in the use of gene therapy
, through genetically modified T cell
s, to treat CLL. The findings, which were published in August 2011, were based on data from three patients who had modified T cells injected into their blood. The T cells had been modified to express genes that would allow the cells to proliferate in the body and destroy B cells including those causing the leukemia. Two patients went into remission, while the presence of leukemia in the third patient reduced by 70 percent. One of the patients had been diagnosed with CLL for 13 years, and his treatment was failing before he participated in the clinical trial. One week after the T cells were injected, the leukemia cells in his blood had disappeared. The T cells were still found in the bloodstream of the patients six months after the procedure, meaning they would be able to fight the disease should leukemia cells return. This was the first time scientists "have used gene therapy to successfully destroy cancer tumors in patients with advanced disease". One editorial in The New England Journal of Medicine also urged caution because only more trials would indicate whether the findings are "an authentic advance toward a clinically applicable and effective therapy".
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
. Leukemias are cancers of the white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s (leukocytes). CLL affects B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by producing antibodies. In CLL, the DNA of a B cell is damaged, so that it cannot produce antibodies. Additionally, B cells grow out of control and accumulate in the bone marrow and blood, where they crowd out healthy blood cells. CLL is a stage
Cancer staging
The stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...
of small lymphocytic lymphoma (SLL), a type of B-cell lymphoma
B-cell lymphoma
The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph glands. They develop more frequently in older adults and in immunocompromised individuals ....
, which presents primarily in the lymph nodes. CLL and SLL are considered the same underlying disease, just with different appearances.
CLL is a disease of adults, but, in rare cases, it can occur in teenagers and occasionally in children (inherited). Most (>75%) people newly diagnosed with CLL are over the age of 50, and the majority are men.
Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but, as it advances, CLL results in swollen lymph nodes, spleen
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
, and liver
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
, and eventually anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
.
DNA analysis has distinguished two major types of CLL, with different survival times. CLL that is positive for the marker ZAP-70
ZAP-70
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
has an average survival of 5 years. CLL that is negative for ZAP-70 has an average survival of more than 25 years. Many patients, especially older ones, with slowly progressing disease can be reassured and may not need any treatment in their lifetimes.
Symptoms and signs
Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count. Less commonly, CLL may present with enlarged lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as small lymphocytic lymphoma. In some individuals the disease comes to light only after the neoplastic cells overwhelm the bone marrow resulting in anemia producing tiredness or weakness.Diagnosis
The disease is easily diagnosed. CLL is usually first suspected by the presence of a lymphocytosisLymphocytosis
Lymphocytosis is an increase in the number or proportion of lymphocytes in the blood, usually detected when a complete blood count is routinely obtained. Lymphocytes normally represent 20 to 40% of circulating white blood cells...
, an increase in one type of white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per microliter (µl) of blood, but can be much higher. The presence of a lymphocytosis in an elderly individual should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.
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 molecules on the cell surface. This atypical molecular pattern includes the coexpression of cells surface markers cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
5
CD5 (protein)
CD5 is a cluster of differentiation found on a subset of IgM-secreting B cells called B-1 cells, and also on T cells. B-1 cells have limited diversity of their B-cell receptor due to their lack of the enzyme terminal deoxynucleotidyl transferase and are potentially self-reactive...
(CD5
CD5 (protein)
CD5 is a cluster of differentiation found on a subset of IgM-secreting B cells called B-1 cells, and also on T cells. B-1 cells have limited diversity of their B-cell receptor due to their lack of the enzyme terminal deoxynucleotidyl transferase and are potentially self-reactive...
) and cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
23
CD23
CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin...
(CD23
CD23
CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin...
). 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
Immunoglobulin light chain
]The immunoglobulin light chain is the small polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains.-In humans:...
, 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 kappa and lambda producing 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 combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
to confirm clonality and marker molecule expression is needed to establish the diagnosis of CLL. Both are easily accomplished on a small amount of blood. A flow cytometer is an instrument that can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (express marker molecules cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
19
CD19
B-lymphocyte antigen CD19 also known as CD19 , is a protein that in humans is encoded by the CD19 gene.- Function :...
(CD19
CD19
B-lymphocyte antigen CD19 also known as CD19 , is a protein that in humans is encoded by the CD19 gene.- Function :...
) and CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
), and characteristically express the marker molecules CD5
CD5 (protein)
CD5 is a cluster of differentiation found on a subset of IgM-secreting B cells called B-1 cells, and also on T cells. B-1 cells have limited diversity of their B-cell receptor due to their lack of the enzyme terminal deoxynucleotidyl transferase and are potentially self-reactive...
and CD23
CD23
CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin...
. These B cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells (smudge cells).
Clinical staging
Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification (see details) and is based primarily on the presence, or not, of a low platelet or red cell count. Early stage disease does not need to be treated.Gene mutation status
Recent publications suggest that two or three prognostic groups of CLL exist based on the maturational state of the cell. This distinction is based on the maturity of the lymphocytes as discerned by the immunoglobulin variable-region heavy chainHeavy chain
]The immunoglobulin heavy chain is the large polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains. Several different types of heavy chain exist that define the class or isotype of an antibody. These heavy chain types vary...
(IgVH) gene mutation status. High risk patients have an immature cell pattern with few mutations in the DNA in the IgVH antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.
Since assessment of the IgVH antibody DNA changes is difficult to perform, the presence of either cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
38
CD38
CD38 , also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells , including CD4+, CD8+, B and natural killer cells...
(CD38
CD38
CD38 , also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells , including CD4+, CD8+, B and natural killer cells...
) or Z-chain–associated protein kinase-70 (ZAP-70
ZAP-70
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
) may be surrogate markers of high risk subtype of CLL. Their expression correlates with a more immature cellular state and a more rapid disease course.
Fluorescence in situ hybridization
In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as fluorescent in situ hybridizationFluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
(FISH). Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.
- Deletions of part of the short arm of chromosome 17 (del 17p), which target the cell cycle regulating protein p53 are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5–10% of patients with CLL.
- Deletions of the long arm on chromosome 11 (del 11q) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5–10%).
- Trisomy 12, an additional chromosome 12, is a relatively frequent finding occurring in 20–25% of patients and imparts an intermediate prognosis.
- Deletion of the long arm of chromosome 13 (del 13q) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment coding for microRNAs miR-15a and miR-16-1.
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. See also Virtual KaryotypeVirtual Karyotype
Virtual karyotype detects genomic copy number variations at a higher resolution level than conventional karyotyping or chromosome-based comparative genomic hybridization .-Background:...
.
Related diseases
In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. These so-called T-cell CLLs, however, are now recognized as a separate disease group and are currently classified as T-cell prolymphocytic leukemiaT-cell prolymphocytic leukemia
T-cell-prolymphocytic leukemia is a mature T-cell leukemia with aggressive behavior and predilection for blood, bone marrow, lymph nodes, liver, spleen, and skin involvement. T-PLL is a very rare leukemia, primarily affecting adults over the age of 30. It represents 2% of all small lymphocytic...
s.
CLL should not be confused with acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
(ALL), a highly aggressive and highly treatable leukemia most commonly diagnosed in children.
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 (B PLL), a related, but more aggressive disorder, has cells with similar phenotype, but are significantly larger than normal lymphocytes and have a prominent nucleolus. The distinction is important as the prognosis and therapy differs from CLL.
- Hairy cell leukemiaHairy cell leukemiaHairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid 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 surface) 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
Fluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
.
Treatment
CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
removal of enlarged spleen) or by radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
("de-bulking" swollen lymph nodes).
Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy.
Decision to treat
While 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, early-stage CLL is, in general, not treated since it is believed that early 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.The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.
Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.
Chemotherapy
Combination chemotherapy regimens are effective in both newly-diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:- FC (fludarabineFludarabineFludarabine or fludarabine phosphate is a chemotherapy drug used in the treatment of hematological malignancies. It has been unofficially and casually referred to as "AIDS in a bottle" amongst healthcare professionals due to its significant immunosuppresive activity.-Indications:Fludarabine is...
with cyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
) - FR (fludarabineFludarabineFludarabine or fludarabine phosphate is a chemotherapy drug used in the treatment of hematological malignancies. It has been unofficially and casually referred to as "AIDS in a bottle" amongst healthcare professionals due to its significant immunosuppresive activity.-Indications:Fludarabine is...
with rituximabRituximabRituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
) - FCR (fludarabineFludarabineFludarabine or fludarabine phosphate is a chemotherapy drug used in the treatment of hematological malignancies. It has been unofficially and casually referred to as "AIDS in a bottle" amongst healthcare professionals due to its significant immunosuppresive activity.-Indications:Fludarabine is...
, cyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, and rituximabRituximabRituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
) - CHOP (cyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, doxorubicinDoxorubicinDoxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
, vincristineVincristineVincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
and prednisolonePrednisolonePrednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
)
Although the purine analogue fludarabine
Fludarabine
Fludarabine or fludarabine phosphate is a chemotherapy drug used in the treatment of hematological malignancies. It has been unofficially and casually referred to as "AIDS in a bottle" amongst healthcare professionals due to its significant immunosuppresive activity.-Indications:Fludarabine is...
was shown to give superior response rates to chlorambucil
Chlorambucil
Chlorambucil is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia...
as primary therapy, there is no evidence early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.
Alkylating agents approved for CLL include bendamustine
Bendamustine
Bendamustine is a nitrogen mustard used in the treatment of chronic lymphocytic leukemias and lymphomas. It belongs to the family of drugs called alkylating agents...
and cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
.
Monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
, such as alemtuzumab
Alemtuzumab
Alemtuzumab is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia , cutaneous T-cell lymphoma and T-cell lymphoma...
(directed against CD52
CD52
CD52 is a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes were derived.It also is found in monocytes and dendritic cells....
) and rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
and ofatumumab
Ofatumumab
Ofatumumab is a human monoclonal antibody which appears to inhibit early-stage B lymphocyte activation...
(directed against CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
), are also used.
Stem cell transplantation
Allogeneic bone marrow (stem cell) transplantation is rarely used as a first-line treatment for CLL due to its risk. There is increasing interest in the use of reduced-intensity allogeneic stem cell transplantation, which offers the prospect of cure for selected patients with a suitable donor.Younger patients that are at high risk for dying from CLL might consider hematopoietic stem cell transplantation (HSCT). Autologous stem cell transplantation
Autologous stem cell transplantation
Autologous stem cell transplantation is a medical procedure in which blood-forming stem cells are removed, stored, and later given back to the same person.- External link :...
, a lower-risk form of treatment using the patient's own blood cells, is not curative. Myeloablative (bone marrow killing) forms of allogeneic stem cell transplantation
Allogeneic stem cell transplantation
Allogeneic stem cell transplantation is a procedure in which a person receives blood-forming stem cells from a genetically similar, but not identical, donor. This is often a sister or brother, but could be an unrelated donor...
, a high-risk treatment using blood cells from a healthy donor, may be curative for some patients, but most patients cannot tolerate the treatment. An intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients.
Refractory CLL
"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including lenalidomideLenalidomide
Lenalidomide , initially known as CC-5013 and marketed as Revlimid by Celgene, is a derivative of thalidomide introduced in 2004....
, flavopiridol, and bone marrow (stem cell) transplantation, are considered. The monoclonal antibody, alemtuzumab
Alemtuzumab
Alemtuzumab is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia , cutaneous T-cell lymphoma and T-cell lymphoma...
(directed against CD52
CD52
CD52 is a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes were derived.It also is found in monocytes and dendritic cells....
), may be used in patients with refractory, bone marrow-based disease.
Complications
Chronic lymphocytic leukemia may transform into Richter's syndrome, a term used to describe the development of fast-growing diffuse large B cell lymphomaDiffuse large B cell lymphoma
Diffuse large B-cell lymphoma is a type of aggressive non-Hodgkin lymphoma. It accounts for approximately 40% of lymphomas among adults. The median age at diagnosis is 70 years, but it also occurs in children and young adults...
, prolymphocytic leukemia
B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia is a more aggressive, but still treatable, form of leukemia. The malignant B cells are larger than average. The name is commonly abbreviated B-PLL.It can involve deletions from chromosome 11 and chromosome 13....
, Hodgkin's lymphoma
Hodgkin's lymphoma
Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes...
, or acute leukemia
Acute leukemia
Acute leukemia or acute leukaemia is a generic term used to describe a family of serious medical conditions relating to an original diagnosis of leukemia...
in a patient who has chronic lymphocytic leukemia. Its incidence is estimated to be around 5%.
Gastrointestinal (GI) involvement can rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis and others. Usually, GI complications with CLL occur after Richter transformation. There have been two case reports to date of GI involvement in chronic lymphocytic leukemia without Richter's transformation.
Epidemiology
CLL is a disease of older adults and is rarely encountered in individuals under the age of 40. Thereafter, the disease incidence increases with age.In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
during 2009, about 16,000 new cases are expected to be diagnosed, and 4,400 patients are expected to die from CLL. Because of the prolonged survival, which was typically about ten years in past decades, but which can extend to a normal life expectancy, the prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
(number of people living with the disease) is much higher than the incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
(new diagnoses).
Subclinical "disease" can be identified in 3.5% of normal adults, and in up to 8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.
Of all cancers involving the same class of blood cell
Lymphoproliferative disorders
Lymphoproliferative disorders refer to several conditions in which lymphocytes are produced in excessive quantities. They typically occur in patients who have compromised immune systems...
, 7% of cases are CLL/SLL.
Complications include hypogammaglobulinemia leading to recurrent infection, warm autoimmune hemolytic anaemia in 10–15% of patients, transformation to high grade lymphoma, and Richter's transformation.
Rates of CLL are somewhat elevated in people exposed to certain chemicals. Under U.S. Department of Veterans' Affairs regulations, Vietnam veterans who served in-country or in the inland waterways of Vietnam and who later develop CLL are presumed to have contracted it from exposure to Agent Orange
Agent Orange
Agent Orange is the code name for one of the herbicides and defoliants used by the U.S. military as part of its herbicidal warfare program, Operation Ranch Hand, during the Vietnam War from 1961 to 1971. Vietnam estimates 400,000 people were killed or maimed, and 500,000 children born with birth...
and may be entitled to compensation.
Prognosis
Prognosis depends on the subtype. The overall five-year survival rateFive-year survival rate
The five-year survival rate is a term used in medicine for estimating the prognosis of a particular disease.Analysis performed against the Surveillance, Epidemiology, and End Results database facilitates calculation of Five-year survival rates....
(all forms of CLL together) is about 50%.
Research directions
Considerable research activity, studying the many treatments individually or in combination, is ongoing. Current research is comparing different forms of bone marrow transplants to determine which patients are the best candidates and which approach is best in different situations.Researchers at the Abramson Cancer Center of the University of Pennsylvania School of Medicine
University of Pennsylvania School of Medicine
The Perelman School of Medicine , formerly the University of Pennsylvania School of Medicine, was founded in 1765, making it the oldest American medical school. As part of the University of Pennsylvania, it is located in the University City section of Philadelphia, Pennsylvania. It is widely...
reported preliminary success in the use of gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
, through genetically modified T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s, to treat CLL. The findings, which were published in August 2011, were based on data from three patients who had modified T cells injected into their blood. The T cells had been modified to express genes that would allow the cells to proliferate in the body and destroy B cells including those causing the leukemia. Two patients went into remission, while the presence of leukemia in the third patient reduced by 70 percent. One of the patients had been diagnosed with CLL for 13 years, and his treatment was failing before he participated in the clinical trial. One week after the T cells were injected, the leukemia cells in his blood had disappeared. The T cells were still found in the bloodstream of the patients six months after the procedure, meaning they would be able to fight the disease should leukemia cells return. This was the first time scientists "have used gene therapy to successfully destroy cancer tumors in patients with advanced disease". One editorial in The New England Journal of Medicine also urged caution because only more trials would indicate whether the findings are "an authentic advance toward a clinically applicable and effective therapy".
In pregnancy
Leukemia is rarely associated with pregnancy, affecting only about 1 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.External links
- Chronic Lymphocytic Leukemia at American Cancer SocietyAmerican Cancer SocietyThe American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
- CLL booklet from Leukemia & Lymphoma SocietyLeukemia & Lymphoma SocietyThe Leukemia & Lymphoma Society , founded in 1949, is the world's largest voluntary health organization dedicated to funding blood cancer research, education and patient services. LLS's mission is to cure leukemia, lymphoma, Hodgkin's disease and myeloma, and to improve the quality of life of...
- General information about CLL from the US National Cancer InstituteNational Cancer InstituteThe National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...