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Chronic Lymphocytic Leukemia

Last updated May 18, 2018

Approved by: Krish Tangella MD, MBA, FCAP

Chronic Lymphocytic Leukemia (CLL) is a type of blood cancer due to abnormal lymphocytes, typically affecting elderly adults. The condition is termed so when the malignant cells are present in the peripheral blood; the malignant lymphocytes (cancer cells) are predominantly found in blood and bone marrow.


What are the other Names for this Condition? (Also known as/Synonyms)

  • CLL (Chronic Lymphocytic Leukemia)

What is Chronic Lymphocytic Leukemia? (Definition/Background Information)

  • Chronic Lymphocytic Leukemia (CLL) is a type of blood cancer due to abnormal lymphocytes, typically affecting elderly adults. The condition is termed so when the malignant cells are present in the peripheral blood; the malignant lymphocytes (cancer cells) are predominantly found in blood and bone marrow
  • The terminology of Chronic Lymphocytic Leukemia and small lymphocytic lymphoma (SLL) can be confusing, but they are both the same type of cancer. In SLL, the cancer cells are predominantly found in the tissues of the lymph nodes, bone marrow, spleen, and liver
  • The cause of Chronic Lymphocytic Leukemia is generally unknown, though certain genetic mutations may be involved. Currently, no specific risk factors have been identified for CLL
  • The signs and symptoms of Chronic Lymphocytic Leukemia are commonly dependent upon the site of involvement of the cancer. There may be general symptoms such as fatigue, weight loss, and frequent infections. Significant complications may occur due to reduced levels of red blood cells, white blood cells, and platelets, may also be present
  • The healthcare provider may initially undertake a ‘wait and watch’ approach, in the absence of significant symptoms. Chemotherapy, radiation therapy, or targeted therapy may be employed in case the condition progresses. Nevertheless, despite suitable treatment measures, the prognosis of Chronic Lymphocytic Leukemia is guarded

General information on lymphoma and lymphocytes:

  • Lymphoma is a type of cancer stemming from uncontrollably dividing lymphocytes (type of white blood cells). There are two types of lymphomas:
    • Hodgkin lymphoma
    • Non-Hodgkin lymphoma
  • Lymphocytes are the main white blood cells found in the lymph, which is the fluid of the lymphatic system; just as blood is the fluid of the circulatory system. Lymphocytes are made in bone marrow, and can develop into either B-cells or T-cells
  • Lymph results from filtration of blood as it travels to and from tissues. Lymph is colorless because it lacks red blood cells; instead, it contains lymphocytes. It is central to the immune system
  • There are 3 different kinds of lymphocytes:
    • T-lymphocytes or T cells: They help combat infections and abnormalities within the cells (cell-mediated immunity). They fight viruses and cancerous cells
    • B-lymphocytes or B cells: They produce antibodies that are bodily defense proteins, which target foreign invaders outside the cells (humoral immunity). They fight bacterial cells, cell fragments, and other immunogenic elements
    • Natural killer cells or NK cells: They perform diverse functions related to both cell-mediated and humoral immunity. They also scout for cancer cells, a process called immune surveillance

Who gets Chronic Lymphocytic Leukemia? (Age and Sex Distribution)

  • Chronic Lymphocytic Leukemia is generally found in elderly adults over the age of 65 years; the average age of presentation is 60 years
  • Even though both males and females are affected, the male-female ratio is 2:1
  • It can occur worldwide and all racial and ethnic groups may be affected

What are the Risk Factors for Chronic Lymphocytic Leukemia? (Predisposing Factors)

No specific risk factors have been identified for Chronic Lymphocytic Leukemia. However, the following general factors may contribute towards leukemia formation and development:

  • Advanced age; older individuals commonly have a higher risk
  • Individuals with weak immune system (due to various health conditions)
  • Family history of immune disease
  • The presence of any systemic disease
  • Smoking
  • Exposure to radiation and industrial chemicals
  • Chemotherapy
  • Viruses (in some rare cases); Epstein-Barr virus infection
  • X-ray, CT scan exposure
  • Profession involving radiation exposure, which may include nuclear plant workers, pilots, astronauts, etc.
  • Certain medications and drugs

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Chronic Lymphocytic Leukemia? (Etiology)

Lymphocytes are a type of white blood cells that are responsible for providing immunity in the human body. B-cells and T-cells are the two different types of lymphocytes. When under certain circumstances, the lymphocytes grow and multiply abnormally, it can result in a form of blood cancer.

The causative factors of Chronic Lymphocytic Leukemia are unknown. It may be caused by genetic mutations. Also, there may be certain genetic defects, such as translocation, which is a juxtaposition of regions of chromosomes resulting in:

  • Change of regulatory elements of certain cancer-causing genes called as oncogenes, which can lead to increased production of their mRNA (overexpression), thus increasing their protein levels
  • Exchange of protein coding regions of gene, giving rise to new proteins that can stimulate the inappropriate growth of cells

It is believed that the abnormal development of lymphocytes gives rise to cancerous cells leading to the formation of this condition. Nevertheless, how this occurs and the factors that cause it remain under investigation.

What are the Signs and Symptoms of Chronic Lymphocytic Leukemia?

Chronic Lymphocytic Leukemia is a systemic condition that involves the blood and bone marrow. The signs and symptoms of CLL may include:

  • Anemia causing pale skin, due to lower levels of red blood cells
  • Thrombocytopenia due to decreased platelets, which can cause bleeding disorders
  • Increased infections due to poorly functioning white blood cells
  • Easy bruising
  • Unintentional weight loss; changes in appetite
  • Fatigue and weakness, headache
  • High temperatures and excessive night sweats (may be recurrent)
  • Frequent infections
  • Trouble breathing
  • Low blood pressure
  • Back pain
  • Swelling of the legs
  • Abdominal pain and swelling; constipation
  • Frequent urination 
  • Many individuals may not have significant signs and symptoms early in the disease

When there is the involvement of certain organs and body parts, there may be specific signs and symptoms related to the involved organs. This may include:

  • The presence of enlarged lymph nodes in the neck, armpits, or groin, (and other locations) which may be painless
  • Associated autoimmune disorders, which can cause joint and muscle pain, heat intolerance, recurrent rashes, abdominal pain, and a general feeling of illness
  • If the brain is involved, then neurological symptoms such as the following may be observed:
    • Confusion
    • Tinnitus (ringing in the ears)
    • Hearing and visual impairment
  • If the gastrointestinal (GI) tract is involved, then GI tract symptoms such as the following may be observed:
    • Ulcers
    • Diarrhea
    • Inflammation
    • GI bleeding
  • Joint inflammation and fluid accumulation (edema) can occur, if the joints are affected

How is Chronic Lymphocytic Leukemia Diagnosed?

A diagnosis of Chronic Lymphocytic Leukemia is performed by obtaining biopsy samples from the affected region and examining them under a microscope to detect the cancerous cells. Other methods to aid in the study-diagnosis may include:

  • A thorough physical examination and a complete medical history, which is very important
  • Blood tests that may include:
    • Complete blood cell count (CBC) blood test
    • Absolute lymphocyte count on peripheral blood
    • Liver function blood test (LFT)
    • Lactate dehydrogenase (LDH) blood test
    • Chemistry panel
    • Serum calcium levels
    • Serum albumin levels
    • HIV testing
  • Biopsy from the affected area:
    • A biopsy of the tumor is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
    • Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
    • Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, molecular testing, flow cytometric analysis and very rarely, electron microscopic studies, to assist in the diagnosis
  • Radiological imaging may be performed to determine the extent of cancer in the body including:
    • X-ray of the affected region
    • Ultrasound scan of the affected region
    • Computerized tomography (CT) scan of the affected region
    • Vascular radiological studies
    • Whole body bone scan
    • Whole body CT-PET scans to determine how far the cancer has spread, by checking the size and metabolic rate (a reflection of uncontrolled growth) of lymph nodes, throughout the body. This can also help determine, if the cancer has spread to other organ systems
    • Brain MRIs are used if neurological symptoms are present, which can help determine if the cancer has spread to the brain, or to tissues that cover the brain
  • Bone marrow aspiration and biopsy is performed and sent to a laboratory for a pathological examination, to determine if the bone marrow is involved. Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, histochemical stains, molecular testing, and very rarely electron microscopic studies. However, a bone marrow biopsy is not needed in the early stages of the condition
  • In case the cancer involves the lymph nodes, then biopsies of the enlarged lymph nodes are taken and examined in a lab to determine if the cells are malignant or benign. The biopsies may be performed under general or local anesthesia. Normally, the entire lymph node is removed to help determine the subtype of the condition
  • Flow cytometry to identify cells as they flow through an instrument, called a flow cytometer. Flow cytometry measures the number and percentage of cells in a blood sample, and cell characteristics such as size, shape, and the presence of biomarkers on the cell surface. This method helps to sub-classify the condition and also to detect residual levels of disease after treatment. This tool can help in diagnosing relapse and restart treatment as needed
  • Fluorescence in situ hybridization (FISH): It is a test performed on the blood or bone marrow cells to detect chromosome changes (cytogenetic analysis) in blood cancer cells. The test helps in identifying genetic abnormalities that may not be evident with an examination of cells under a microscope
  • Immunophenotyping to identify a specific type of cell in a sample, which can help determine the best treatment course to be followed
  • Polymerase chain reaction (PCR): It is used to measure the presence of certain biomarkers in blood or bone marrow cells. The test is ultrasensitive and detects extremely low amounts of biomarkers remaining in blood, which can be missed by cytogenetic methods, such as FISH, karyotype, or flow cytometry. PCR allows a more sensitive follow-up of patients in remission and can help determine whether additional treatment is necessary
  • Testing for genetic mutations: The presence of certain mutations affects the severity of CLL. Some genetic mutations generally make the condition better, while others make it worse. Hence, usually lab testing for the presence of such mutations is performed
  • GI endoscopy: It may be performed to assess the extent of tumor spread
  • Multigated acquisition (MUGA) scan or echocardiography to identify cardiotoxicity as a result of chemotherapy
  • Lumbar puncture to determine if the brain is involved
  • In addition, the cerebrospinal spinal fluid (CSF) may be collected by inserting a needle in the spine and subjected to microscopic, flow cytometric, PCR, and biochemical analysis, to diagnose central nervous system (CNS) involvement, if any
  • Exploratory laparoscopy (diagnostic laparoscopy) may be required, if gastrointestinal symptoms are present. In this procedure, the abdomen is examined using a minimally-invasive technique, and a tissue biopsy and tissue for culture obtained. Minimally-invasive approaches help decrease complications and the length of stay at the hospital. A diagnostic laparoscopy is also helpful in staging of the tumor. Nevertheless, this procedure is not very much used

Note: Differential diagnoses, to eliminate other tumor types are often considered, before arriving at a definitive diagnosis.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Chronic Lymphocytic Leukemia?

The complications due to Chronic Lymphocytic Leukemia may include:

  • Involvement to local and distant organs: It can spread from the lymph nodes to other parts of the body, resulting in loss of function of the organ/area to which the cancer has spread
  • Hemolytic anemia
  • Heavy bleeding due to severe thrombocytopenia
  • Weakened immune system (or immunosuppression) can be a complication, which can become more severe during treatment. Due to this, individuals are more vulnerable to infections; there is an increased risk of developing serious complications from such infections
  • If the condition spreads to the brain and central nervous system, it can give rise to:
    • Inflammation of the meninges or brain (that can be lethal)
    • Vision changes
    • Facial numbness
  • If the abdomen is affected, it can cause intestinal obstruction that results in urine outflow obstruction and kidney damage
  • The leukemic cells can overgrow and cause clogging of vessels resulting in stroke, or blurring of vision

There may be complications related to chemotherapy used in treating the condition, which may include:

  • Side effects such as dizziness, vomiting, appetite loss, mouth ulcers, and hair loss
  • By damaging healthy cells, the individual is more open or vulnerable to secondary infections
  • The treatment can also cause infertility in men and women. Hence, measures to protect the individual’s fertility must be considered, before starting chemotherapy
  • Tumor lysis syndrome: This can occur due to chemotherapy treatment and can result in kidney failure, if not recognized promptly

How is Chronic Lymphocytic Leukemia Treated?

During the initial stages of Chronic Lymphocytic Leukemia, it may be indolent and slow-growing; the condition may be asymptomatic. In such cases, the healthcare provider may adopt a ‘watchful wait’ approach.

In individuals with significant signs and symptoms a combination of treatment measures may be effectively used to treat the condition. The treatment also depends upon the stage, overall health, age, and type of blood cancer. The treatment may involve the following procedures:

  • Chemotherapy: This approach uses a combination of drugs to kill the cancerous cells and can be used in patients, for all stages of the cancer
    • There can be severe side effects including fatigue, nausea, hair loss, anemia, high risk of infection, and drug-specific reactions
    • Many cancers can be resistant to chemotherapy. It can also damage healthy cells
    • Chemotherapy can be administered as a pill, liquid, shot, or intravenously

Note: Men and women in child-bearing age would greatly benefit from counseling regarding fertility issues. Some chemotherapy agents can cause infertility in both men and women. There can be permanent damage to the testicles and ovaries, harming their ability to produce sperms or ova. In men, sperm banking can be considered before initiating therapy. In women, in many cases, due to urgency of starting chemotherapy, it is often difficult to perform ovum banking. However, if there is sufficient time prior to chemotherapy, ovum banking may be performed. The healthcare provider may help assess the risk-benefit analysis, depending upon each individual’s specific circumstances.

  • Radiation: Radiation therapy is the use of high-energy radiation waves to kill cancer cells, by destroying their DNA
    • This treatment modality is generally used for early stage cancers. It is most commonly used in combination with chemotherapy
    • The radiation may be administered by a machine placed outside the body, or by placing a radioactive material inside the body
    • The side effects of radiation therapy include nausea, vomiting, fatigue, pain, risk of cancer later in life, and risk of heart disease
    • Radiation can damage healthy cells in addition to cancer cells, causing further complications
  • Surgery: If the spleen is involved, then a splenectomy (removal of spleen) may be considered
  • Intrathecal chemotherapy, if there is an involvement of the brain
  • Supportive treatment: Steroids, blood transfusions, anti-nausea medications, and antibiotics, may be used as supportive therapy. In combination with other treatment measures, these can help combat the symptoms of immunodeficiency, on a case-by-case basis

If Chronic Lymphocytic Leukemia is not fully responsive to treatment, or if the chance of recurrence is high, then bone marrow transplantation or stem cell transplantation can be considered.

  • Bone marrow transplantation: Typically systemic cases may be treated by administering high doses of chemotherapy or radiotherapy. But, high doses of chemotherapy drugs will also damage the bone marrow, preventing it from making any blood cells. Hence, before starting high-dose chemotherapy, the physicians may take out some of the patient’s bone marrow and freeze/preserve it. Collecting the bone marrow is called a bone marrow harvest. The bone marrow is then stored. After high dose chemotherapy or radiation, the bone marrow is thawed and injected back into patient through a drip (transfusion). This is called an autologous bone marrow transplant. Sometimes bone marrow donated by another matching person (usually a brother or sister) is used, if the condition recurs following transplant using one’s own cell. This is called as allogeneic bone marrow transplant
  • Stem cell transplantation: This procedure is similar to bone marrow transplantation and involves the transplantation of healthy blood-forming stem cells into the body. The procedure is also called hematopoietic progenitor cell transplantation. Stem cells can be collected from the bone marrow, circulating (peripheral) blood, and umbilical cord blood. It may either involve an autologous stem cell transplantation, where stem cells are harvested from individuals before treatment and transplanted back into the patient after treatment, or involve an allogeneic stem cell transplantation, where stem cells donated by another matching person (usually a brother or sister) is used, if the condition recurs after stem cell transplant using one’s own cell. This is called as allogeneic stem cell transplant

Note: Allogeneic bone marrow and allogeneic stem cell transplants may have more side effects and complications, and this treatment may not be suitable for every individual. If allogeneic transplants come from a healthy donor with no malignant cells, then the chances of recurrence of the condition may be reduced.

  • In order to prevent infections because the immune system is weakened by CLL or by its treatment, the patient is kept in an isolated ward and treated with appropriate antibiotics
  • Nowadays, targeted therapies are being developed, that can selectively kill the leukemia cells. Many of them are in the stage of clinical trials
  • Clinical trials: There may be some newer treatment options, currently on clinical trials, which can be considered for some patients depending on their respective risk factors

Your healthcare provider will determine the best course of treatment depending on your individual circumstances. Also, follow-up care with regular screening and check-ups are important post-treatment.

How can Chronic Lymphocytic Leukemia be Prevented?

Presently, the cause of Chronic Lymphocytic Leukemia is unknown and there are no known methods to prevent its formation. Eliminating certain risk factors may help in avoiding the condition.

  • Healthy diet and exercise, as well as avoidance of unnecessary exposure to chemicals, may help decrease its risk
  • Avoidance or cessation of smoking
  • Undertaking appropriate and prompt treatment of any viral infection or other disorders
  • Promptly addressing the cause of concern of immunodeficiency
  • Using appropriate protective gear while working with x-rays and other radioactive source
  • In order to avoid a relapse, or be prepared for a recurrence, the entire diagnosis, treatment process, drugs administered, etc. should be well-documented and follow-up measures initiated

Regular medical screening at periodic intervals with blood tests, scans, and physical examinations, are mandatory. Often several years of active vigilance are crucial and necessary.

What is the Prognosis of Chronic Lymphocytic Leukemia? (Outcomes/Resolutions)

  • Chronic Lymphocytic Leukemia is a slow-growing cancer that affects the bone marrow and blood. The prognosis of the condition is guarded; it is evaluated on a case-by-case basis
  • The prognosis depends upon a set of several factors, which include:
    • Stage of tumor: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
    • Genetic mutations: Some mutations are known to make the outcome much worse and the prognosis is dependent on the presence of such mutations
    • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
    • Age of the individual: Older individuals generally have poorer prognosis than younger individuals
    • The size of the tumor: Individuals with small-sized tumors fare better than those with large-sized tumors
    • Individuals with bulky disease have a poorer prognosis
    • Involvement of vital organs may complicate the condition
    • Whether the tumor is occurring for the first time, or is a recurrent tumor. Recurring tumors have worse prognosis compared to tumors that do not recur
    • Response to treatment: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment
    • Progression of the condition makes the outcome worse (progressive CLL)
  • An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and delayed treatment
  • The combination chemotherapy drugs used, may have some severe side effects (such as cardio-toxicity). This chiefly impacts the elderly adults, or those who are already affected by other medical conditions. Tolerance to the chemotherapy sessions is a positive influencing factor

Additional and Relevant Useful Information for Chronic Lymphocytic Leukemia:

  • Treatment for Chronic Lymphocytic Leukemia can cause physical and emotional distress; supportive care and encouragement, help positively and can bring a measure of relief to the patients

The following article link will help you understand leukemia and lymphoma (blood cancer):

http://www.dovemed.com/diseases-conditions/leukemia-and-lymphoma/

What are some Useful Resources for Additional Information?


References and Information Sources used for the Article:


Helpful Peer-Reviewed Medical Articles:


Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: March 18, 2016
Last updated: May 18, 2018