All About Chronic Lymphocytic Leukemia (CLL)

OncoLink Team
Last Reviewed: May 21, 2018

This article is a more specific discussion of CML. Please be sure to read Leukemia: The Basics first, so you have a basic understanding of leukemia.

What is CLL?

CLL is a chronic blood cancer that affects the lymphocytes which are white blood cells. There are two types of lymphocytes, B and T lymphocytes. These white blood cells are an important component of the immune system-they help 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. Another cancer, small lymphocytic lymphoma (SLL), behaves similarly to CLL however in SLL there are few abnormal lymphocytes circulating in the blood. SLL primarily impacts lymph nodes, bone marrow and lymphoid tissues. SLL is treated in a very similar way to CLL and the treatment sections in this article apply to both CLL and SLL.

There are two other types of B cell leukemias.  They are 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 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 60,000 new cases of leukemia in the United States annually, it is estimated that 20,900 of those will be new cases of CLL. This accounts for about 25% of the new cases of leukemia. The average age at diagnosis is 70. 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.

How can I prevent CLL?

Because there are very few risk factors for CLL, none of which are things you can easily change, CLL is not thought of as a preventable cancer.

What screening tests are used for CLL?

Because CLL is so rare, screening isn’t typically performed. Regular physicals by your healthcare provider are your best method of screening. To determine if a person has CLL, a blood count would be drawn by the provider. This blood count shows an abnormally high number of white blood cells in a person with the disease.

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 there are symptoms they may 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.

Your healthcare provider may also order additional blood tests to assist in staging as well as to identify any potential chromosomal changes that may impact treatment decisions.  These tests may include include immunoglobulin tests, fluorescence in situ hybridization (FISH), and G-banding karyotyping.  These tests can help identify chromosomal abnormalities that may be present in patients with CLL including deletion of chromosome 13 (13q-), trisomy 12 (an extra copy of chromosome 12), deletion of chromosome 11 (11q-), structural abnormalities in chromosome 14 or 6 and/or deletion of chromosome 17 (17p-). These chromosomal changes may indicate if the CLL is considered high risk (faster growing) disease and can influence treatment decisions.

How is CLL staged?

Some patients with CLL will have aggressive disease, which requires treatment, while others have a very slow progressing disease. About half of all patients are in between these two extremes. There are two staging systems for CLL, the Rai system and the Binet System. The Rai system categorizes patients into three risk groups that take into account blood counts, enlarged lymph nodes and splenomegaly and/or hepatomegaly in assigning a stage. Risk status refers to the potential of the disease to progress more rapidly and overall length of survival after diagnosis. The Binet system looks at the number of involved areas and hemoglobin/platelets levels in assessing a disease stage. SLL is staged differently focusing on nodal status and extranodal involvement. SLL staging uses the Lugano Modification of the Ann Arbor Staging System.

Rai Classification System

Modified Risk Status

Stage

Description

Low

0

Lymphocytosis, lymphocytes in blood >5 x 109/L clonal B-cells and >40% lymphocytes in the bone marrow

Intermediate

I

II

Stage 0 with enlarged node(s)

Stage 0-1 with splenomegaly, hepatomegaly, or both

High

III*

IV*

Stage 0-II with hemoglobin <11.0g/dL or hematocrit <33%

Stage 0-III with platelets <100,000/mcL

Binet Staging System

Stage

Description

Stage A

Hemoglobin >10 d/dL and Platelets >100,000/mm3 and <3 enlarged areas

Stage B

Hemoglobin >10 d/dL and Platelets >100,000/mm3 and >3 enlarged areas

Stage C*

Hemoglobin <10 g/dL and/or Platelets <100,000 and any number of enlarged areas

* Immune mediated changes to blood counts are not the basis for these stage definitions.

 

SLL Stage System/Lugano Modification of the Ann Arbor Staging System (primary nodal lymphomas)

Stage

Involvement

Extranodal (E) Status

Stage I

One node or a group of adjacent nodes

Single extranodal lesions without nodal involvement

Stage II

Two or more nodal groups on the same side of the diaphragm

Stage I or II by nodal extent with limited contiguous extranodal involvement

Stage II bulky

II as above with “bulky” disease

N/A

Advanced

 

 

Stage III

Nodes on both sides of the diaphragm

Modes above the diaphragm with spleen involvement

N/A

Stage IV

Additional non- continguous extralymphatic involvement

N/A

 

There are a few other features that help clinicians determine prognosis and the need for treatment.

  • The presence of CD38 on the surface of CLL cells is a predictor of poorer prognosis.
  • 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.
  • Extent to which the bone marrow is involved can be prognostic and can help to determine treatment.

How is CLL treated?

The decision to treat or not to treat is an important, individualized 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. Historically, clinicians feared that patients would experience significant psychological distress from "watching and waiting", however 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 aware of while living with CLL. 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. Avoid 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.

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 (using an 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. Individuals with CLL are also at risk for tumor lysis syndrome (TLS) which is the rapid breakdown of cells which causes an imbalance of chemicals and electrolytes in the body.  TLS impacts levels of uric acid, potassium, phosphate and calcium and can cause kidney failure, seizures, and heart rhythm changes.

Chemotherapy

The type of treatment you receive will depend upon your age, the type and stage of your leukemia as well as the presence of any genetic mutations.

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 of killing them. You will be prescribed a regimen that lasts from days to weeks that will include a variety of chemotherapeutic medications. Examples of chemotherapy medications used to treat CLL include bendamustine, chlorambucil, pentostation, cyclophosphamide, fludarabinedoxorubicincytarabinecladribine, 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 alemtuzumabobinutuzumabofatumumab and rituximab. They are all given intravenously. Kinase inhibitors block growth signals within cancer cells reducing the production of new cancer cells. Examples of kinase inhibitors include acalabrutinibibrutinib and idelalisib. Another targeted therapy that may be used in the treatment of CLL is venetoclax. Individualized immune therapy called CD19 Chimeric Antigen Therapy (CAR-T) is currently being studied in CLL patients.

Surgery

People with CLL may be treated with a surgical procedure, called a splenectomy. In this procedure, the spleen is removed. This procedure is not without risk, as the spleen helps to filter old, unneeded cells from the blood. People without a spleen are at a higher risk of infection. Splenectomy is only helpful in patients who are experiencing splenomegaly (enlarged spleen).

Bone Marrow Transplant

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). Typically, allogenic transplants are used in patients with CLL. Giving the patient a donor's marrow after this marrow-killing (marrow-ablating) chemotherapy serves to "rescue" the patient with healthy bone marrow. One effect that doctors see as a very important part of all allogeneic transplants is called the "graft versus tumor effect". Basically, this is the effect that the donor's immune system (which is part of the marrow that the donor donated) has on the recipient patient's cancer cells. The hope is that the healthy donor immune system can attack any stray cancer cells in the patient that survived the preparative regimen.

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. 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 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 a chronic cancer. It 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 as because CLL can progress rapidly 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
Information on all types of cancer, living with cancer and information on support for patients and advocates.

References

NCCN Clinical Practice Guildlines: CLL/SLL (log in required). https://www.smith.edu/ssw/eol https://www.smith.edu/ssw/eol

SEER Statistics: CLL, https://seer.cancer.gov/statfacts/html/clyl.html

Conte, M. J., Parikh, S. A., Bowen, D. A., Call, T. G., Kabat, B. F., Chaffee, K. G., ... & Shanafelt, T. D. (2016). The Role of Splenectomy in the Care and Treatment of the CLL Patient.

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.

Gaidano, G., & Rossi, D. (2017). The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. ASH Education Program Book2017(1), 329-337. 

Hallek, M., Cheson, B. D., Catovsky, D., Caligaris-Cappio, F., Dighiero, G., Döhner, H., ... & Stilgenbauer, S. (2018). Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood, blood-2017.

Lucas, F. M., & Gribben, J. (2017). Chronic lymphocytic leukemia. Clinical Manual of Blood and Bone Marrow Transplantation, 123-130. 

Magalhaes, I., Kalland, I., Kochenderfer, J. N., Österborg, A., Uhlin, M., & Mattsson, J. (2018). CD19 Chimeric Antigen Receptor T Cells From Patients With Chronic Lymphocytic Leukemia Display an Elevated IFN-γ Production Profile. Journal of Immunotherapy41(2), 73-83.

Randhawa, J. K., & Ferrajoli, A. (2016). A review of supportive care and recommended preventive approaches for patients with chronic lymphocytic leukemia. Expert review of hematology9(3), 235-244.

Roberts, A. W., Davids, M. S., Pagel, J. M., Kahl, B. S., Puvvada, S. D., Gerecitano, J. F., ... & Wong, S. (2016). Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. New England Journal of Medicine374(4), 311-322. 

Thompson, P. A., Tam, C. S., O’Brien, S. M., Wierda, W. G., Stingo, F., Plunkett, W., ... & Keating, M. J. (2016). Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood127(3), 303-309.

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