All About Chronic Lymphocytic Leukemia (CLL)

Carolyn Vachani, RN, MSN, AOCN
Modified by: Lara Bonner Millar, MD
Updated by: Karen Arnold-Korzeniowski
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 16, 2016

What is CLL?

CLL is a chronic blood cancer that affects the lymphocytes, of which there are two types, B and T lymphocytes. These white blood cells are an important component of the immune system, helping to fight infection. More than 90% of CLL cases affect the B cells. In acute leukemia, one cell begins rapidly reproducing, leaving little room for healthy cells, eventually causing symptoms. In CLL, the abnormal B cells accumulate over time, but the rate they are reproducing is not abnormal. Rather than overgrowth, CLL is caused by a loss of apoptosis, or programmed cell death. The B cells should die once they reach a certain number, but cancerous B cells have lost the ability to self destruct in this situation.

There are two other types of B cell leukemias called prolymphocytic leukemia and hairy cell leukemia. T cell leukemias are quite rare, accounting for only 2% of all CLL cases. These include: mycosis fungoides, T-PLL, adult T-cell leukemia, NK (natural killer) cell leukemia (NK cells are a part of the immune system) and large granular lymphocytosis. In 3-15% of patients, CLL "transforms" into an aggressive form of lymphoma, which is called Richter's syndrome. There is no way to predict which patients this will occur in, but the prognosis with transformation is very poor. Patients with Richter's syndrome will have increasing swelling of the lymph nodes, spleen and liver; develop fever, abdominal pain and weight loss. Blood counts typically worsen, with anemia (low red blood cell count), thrombocytopenia (low platelet count) and a rapid increase in the lymphocyte count. A lymph node biopsy can diagnose the lymphoma.

What causes CLL and am I at risk?

No one really knows what causes CLL. Exposure to radiation and a chemical called benzene can lead to other types of leukemia, but this is not a cause of CLL. Exposure to Agent Orange, an herbicide used during the Vietnam War, is associated with CLL. In rare cases, more than one person in a family may have CLL, but in the large majority of cases it is not familial in nature.

Of the estimated 60,140 new cases of leukemia in the United States in 2016, it is estimated that 18, 960 of those will be new cases of CLL accounting for about 25% of the new cases of leukemia. The average age at diagnosis is 71 and it is rarely seen in people under the age of 40 and very rare in children. It is more common in men and much less common in Asian populations, compared with U.S. or European populations. Prolymphocytic leukemia (PLL) tends to occur in older persons and most are diagnosed with advanced stage disease. While PLL also affects B cells, they are less mature than those affected in CLL. Hairy cell leukemia (HCL) occurs in about 600-800 people each year in the United States and is more common in men, by a rate of 4 to 1.

How can I prevent CLL?

Because there are very few risk factors for CLL, none of which are modifiable, it is not thought of as a preventable type of cancer.

What screening tests are available?

CLL is not a cancer that we screen for because it is rather rare. To determine if a person has CLL, a blood count would be drawn by the provider, which would show an abnormally high number of white blood cells in a person with the disease. Regular physicals by your healthcare provider are your best method of screening.

What are the signs of CLL?

The majority of people will not have any symptoms of the disease, and are diagnosed after a routine blood test shows an abnormally high white blood cell count. If present, symptoms can include: fever, night sweats, repeated infections, fatigue (due to anemia or low red blood count), bleeding or bruising (due to low platelet count), and enlarged lymph nodes. As the disease progresses, healthcare practitioners may find enlargement of the spleen (splenomegaly) or liver (hepatomegaly) and/or enlarged lymph nodes.

How is CLL diagnosed?

Once suspected, a blood sample will be sent for a test called "flow cytometry," which detects "markers" on the surface of the cancer cells, confirming the diagnosis. Markers seen on CLL cells include: CD5, CD19, CD23 and CD20. The presence or absence of a marker called ZAP-70 (zeta chain associated protein kinase) can provide information on prognosis.

Blood tests are usually enough to diagnose CLL. However, a bone marrow aspiration and biopsy may be performed to determine how advanced the disease is. Bone marrow testing may be done prior to starting treatment and then again during or after treatment to determine if the treatment used was successful.

How is CLL staged?

Some patients with CLL will have aggressive disease, which requires treatment, while others have a very slow growing disease. About half of all patients are in between these two extremes. Researchers have developed the Rai system to stage the disease, assess prognosis and the need for treatment. Originally Rai assigned stages of 0-IV, but it was determined that there were only three groups for the purposes of prognosis, so the system was modified to include low, intermediate and high risk. (See table below)

 Rai Classification System

Simplified System

Stage

Clinical Features

Median survival in years

Low risk

0

Elevated lymphocyte count (lymphocytosis) greater than 5000/mm 3 (in blood and bone marrow)

>10

Intermediate risk

I

II

Lymphocytosis with enlarged lymph nodes

Lymphocytosis with enlarged spleen and/or liver (may or may not have enlarged lymph nodes)

7

High risk

III

IV

Lymphocytosis with anemia (hemoglobin<11G/dl)

Lymphocytosis with low platelet count (platelets<100,000)

(Both stage III & IV may or may not have enlarged lymph nodes, spleen and/or liver)

1.5-4

In Europe, the Binet staging system is more widely used. This system is classified by the number of lymphoid tissue groups affected by the disease and by whether or not the patient has anemia or thrombocytopenia. (see below)

Binet Staging System

Binet Stage A

Fewer than 3 areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia

Binet Stage B

3 or more areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia

Binet Stage C

Anemia and/or thrombocytopenia are present

There are a few other features that help clinicians determine poorer prognosis and the need for treatment. The presence of CD38 on the surface of CLL cells is a predictor of poorer prognosis. Following the lymphocyte count over time determines the lymphocyte doubling time, which is the time it takes for the count to double. Taking longer than 12 months to double is considered lower risk, faster than this is considered higher risk disease. The extent to which the bone marrow is involved can be prognostic, and while bone marrow biopsy is not a necessary test to evaluate disease, many practitioners use it to decide on treatment. CT scans, or other radiology tests, are not routinely done in CLL unless progressive disease (called Richter's syndrome) is suspected.

How is CLL treated?

The decision to treat or not is an important one. People with early stage or less aggressive disease can actually have better outcomes if treatment is not started until disease related symptoms or rapid doubling time occur. For years, clinicians thought that patients would experience significant psychological distress from "watching and waiting", but this did not prove true in studies, therefore the standard approach for a stage 0 CLL is observation.

Supportive Care

Even if CLL is not being treated, there are certain precautions that patients should be mindful of. CLL affects a person's ability to fight infection and precautions must be taken to prevent infection. The number one way to prevent infection is through hand washing; both the patient and those they come into contact with. Avoiding large crowds, like a shopping mall on the busiest shopping day of the year! The lack of a properly functioning immune system means that the common cold, flu or pneumonia can spell real trouble, and can even be life threatening, for a person with CLL. Unfortunately, the same dysfunction in the immune system makes vaccines, such as the flu vaccine, much less effective in people with CLL. Patients should discuss the need for vaccines and when to receive them (in relation to treatments) with their healthcare team. Some studies have shown that giving the pneumococcal vaccine (protects against the most common type of pneumonia) early in CLL may improve its effectiveness.

People with low hemoglobin counts (also called anemia) can experience fatigue, shortness of breath or appear pale. Talk with your healthcare team about ways to treat anemia. Low platelet count (also called thrombocytopenia) can lead to bleeding. This can be as small as gums bleeding when brushing the teeth or a nosebleed to dangerous bleeding, such as a stroke. Patients should avoid contact sports, shaving (electric razor is okay), or any activities that increase the risk of bleeding or bruising. Patients should always inform their healthcare team if they have symptoms of anemia or thrombocytopenia.

If the decision to treat has been reached, there are no set in stone regimens. There are a number of different treatment options including chemotherapy, monoclonal antibodies, targeted therapy, supportive care and stem cell transplant. The type of treatment depends upon the type and stage of your leukemia and what you and your provider decide together is best to treat your CLL.

Chemotherapy

Chemotherapy refers to medications that are usually given intravenously or in pill form. Chemotherapy travels throughout the bloodstream and throughout the body to kill cancer cells. This is one of the big advantages of chemotherapy. If cancer cells have broken off from the tumor and are somewhere else inside the body, chemotherapy has the chance killing them. You will be prescribed a regimen that lasts from days to weeks that will include a variety of chemotherapy medications. Examples of chemotherapy medications used to treat CLL include fludarabine, doxorubicin, cytarabine, cladribine, and vincristine. Steroids may be given with chemotherapy or alone to treat CLL. Examples of steroids used to treat CLL are prednisone and methylprednisolone.

Targeted Therapy

Targeted therapy is a general term that refers to a medication or drug that targets a specific pathway in the growth and development of a tumor cell. The targets themselves are typically various molecules (or small particles) in the body that are known or suspected to play a role in cancer formation. The two types of targeted therapy used in the treatment of CLL are monoclonal antibodies and kinase inhibitors.

Monoclonal antibodies are man made antibodies that attach to a cancer cell. The body starts an immune response and the cells are destroyed by your immune system. Examples of monoclonal antibodies are alemtuzumab, obinutuzumab, ofatumumab and rituximab. They are both given intravenously. Kinase inhibitors block growth signals within cancer cells reducing the production of new cancer cells. Examples of kinase inhibitors include ibrutinib and idelalisib.

Bone Marrow and Stem Cell Transplants

Transplants can be done using a donor's bone marrow or stem cells (allogeneic) or a patient's own bone marrow or stem cells (autologous). Autologous transplants are used to maximize the amount of chemotherapy that a patient can safely receive. The problem with giving large doses of chemotherapy is that this can kill the patient's bone marrow, which would lead to death. However, a patient can tolerate this high dose of chemotherapy if the bone marrow (or stem cells) is replaced soon after the chemotherapy, using cells that have been stored ahead of time. In an allogeneic transplant this is also true, but in leukemia and lymphoma the role of graft-versus-tumor effect is the key to its efficacy. This is the ability of the donor's cells and immune system to attack any remaining cancer cells in the recipient.

Other medications used to treat CLL include: cladribine (2-CDA), pentostatin, and prednisone.

More recently, a trial involving the infusion of autologous T cells genetically modified (the patient’s own T cell that have been modified in the laboratory) with a "chimeric antigen receptor" (or CAR) targeting a CD19 protein that is found on most B-cell CLL cells. This treatment takes the patient's own T cells and modifies them to include an antibody that recognizes CD 19. Once these cells are given back to the patient, they are able to seek out the CLL cells, which have the CD19 protein on their surface, and stimulate the immune system to attack and kill these cells. Although only a handful of patients with CLL have been treated, the results are promising and these T cells were able to kill off large quantities of the leukemia cells. Research continues into this treatment.

PLL tends to respond poorly to chemotherapy. Many patients with hairy cell leukemia (HCL) will not require treatment, which is only initiated if the disease progresses. When treatment is necessary, cladribine and pentostatin are chemotherapy agents, which can achieve remission in 90% of patients, though the treatment is not curative. Other medications used to treat HCL include interferon alpha and Rituxan. Patients with HCL were often treated by removal of the spleen (splenectomy) until the early 1980's, when it was determined that this did not change the course of the disease. Splenectomy may still be performed in patients who do not respond to other therapy.

Clinical Trials

There are clinical research trials for most types of cancer, and every stage of the disease. Clinical trials are designed to determine the value of specific treatments. There are clinical trials being studied for the use of targeted therapies, antibiotics, and vaccines for leukemia and lymphoma. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered, or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help manage side effects. Clinical trials are extremely important in furthering our knowledge of this disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.

Follow-up Care and Survivorship

Once you are diagnosed with CLL, whether or not it is treated, you will be followed closely by your provider to monitor the progression of the disease. CLL is rarely cured and most people will need treatment on and off for years. Checkups may include physical exams, blood draws to monitor your blood counts, and imaging if needed. It is important to notify your provider of any new health concerns, side effects or symptoms you are experiencing. This is important because CLL can progress and people with CLL have a higher risk of developing a second cancer.

Fear of recurrence, financial impact of cancer treatment, employment issues and coping strategies are common emotional and practical issues experienced by people with CLL. Your healthcare team can identify resources for support and management of these practical and emotional challenges faced during and after cancer. 

Cancer survivorship is a relatively new focus of oncology care. With some 15 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.

Resources for More Information

Leukemia and Lymphoma Society
www.lls.org
Information on CLL, phone based support and educational materials.

National Cancer Institute
www.cancer.gov
Infomration on all types of cancer, living with cancer and information on support for patients and advocates.

References

Abeloff, M., Armitage, J., Niederhuber, J., Kastan, M. & McKenna, G. (Eds.): Clinical Oncology (2004). Elsevier, Philadelphia, PA.

Chiorazzi N, Rai KR, Ferrarini M (2005). "Chronic lymphocytic leukemia". NEJM. 352 (8): 804–15

Eichhorst, B et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol (2010)21(suppl 5):v162-v164.

Eichhorst B et al. Initial therapy of chronic lymphocytic leukemia. Seminars in Oncology. 2016. 43:241-250.

Hoffman, R et al. (Eds): Hematology Basic Principles and Practice (2005). Elsevier, Philadelphia, PA.

National Comprehensive Cancer Network. NCCN Guidelines for Patients. Chronic Lymphocytic Leukemia. 2016. Found at: https://www.nccn.org/patients/guidelines/cll/index.html#2

Palma, M et al. The biology and treatment of chronic lymphocytic leukemia. Annals of Oncology 17 (Supplement 10): x144–x154, 2006.

Porter D, Levine B, Kalos M, et al (2011). Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia. NEJM. 365(8): 725-733.

Robak T et al. Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia. Semina

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