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Patient information: Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)

CHRONIC LYMPHOCYTIC LEUKEMIA OVERVIEW

Chronic lymphocytic leukemia, often referred to as CLL, is a type of cancer of the blood. It is one of a group of diseases that affects a type of white blood cell called a lymphocyte. The lymphocytes help the body fight infection.

CLL and small lymphocytic lymphoma are variants of the same disease. If you have been diagnosed with small lymphocytic lymphoma, abbreviated as SLL, the information in this article applies to you, too.

In CLL, abnormally high numbers of ineffective lymphocytes are found in the blood and/or bone marrow (the spongy area in the middle of large bones where blood cells are formed). In SLL, these same cells are commonly found in the lymph nodes. The abnormal cells cannot fight infection as normal lymphocytes do, but instead collect in lymph nodes and other areas, such as the liver and spleen. The accumulation of ineffective lymphocytes can interfere with the production of other blood cells, such as red cells and platelets.

Unlike other types of leukemia, CLL usually progresses slowly. In many cases, it causes the patient little, if any, problems in its early stages. Patients may live with CLL for decades. Some patients, however, live for a shorter period. Many times, it is diagnosed, only incidentally, by blood tests that are performed during a routine physical exam. In other cases, symptoms cause the person to seek medical care.

Careful analysis of the patient's blood and physical condition help to determine the stage of the disease — a crucial first step in deciding on the proper course of treatment. Unlike patients with many other types of cancer, some patients with CLL do not benefit from early, aggressive treatment, but instead do better with careful long-term monitoring of the disease.

STAGING OF CHRONIC LYMPHOCYTIC LEUKEMIA

The natural history of CLL may vary considerably from one person to another. Some people become sick within a short time of diagnosis; others live comfortably for years without problems. Determining which patients are most likely to get sick, and therefore most likely to benefit from treatment, is an important task. (See "Staging and prognosis of chronic lymphocytic leukemia".)

Two systems for staging CLL are now in use. Both systems are based upon results of the physical examination and blood tests.

The Rai system — The Rai system is based on an analysis of how the body is affected by the abnormal lymphocytes [1]. There are five stages. The higher numbers indicate a more advanced stage of disease:

Stage 0 – Increased numbers of abnormal lymphocytes are found in the blood or bone marrow; lymph nodes/organs are not swollen; and production of red cells and platelets is normal.

Stage I – Increased abnormal lymphocytes and enlarged lymph nodes.

Stage II – Increased abnormal lymphocytes with enlarged liver or spleen, with or without enlarged lymph nodes.

Stage III – Increased abnormal lymphocytes with anemia (low red blood cell count), with or without an enlarged spleen, liver, or lymph nodes.

Stage IV – Increased abnormal lymphocytes with a low platelet count, with or without anemia, enlarged liver, spleen, or lymph nodes.

The Binet system — This system considers the five possible sites where lymphocytes can collect (lymph nodes in the neck, armpit, and groin, and lymphocyte-containing channels in the spleen and liver (figure 1)), and also whether anemia or low platelet counts are present [2]. There are three stages:

Stage A: Fewer than three involved sites

Stage B: Three or more involved sites

Stage C: Presence of anemia or low platelet counts

What the CLL stages mean — Staging CLL helps determine how likely it is that you will develop serious problems related to your illness. Patients at Rai stage 0 are considered to be at low risk, those at stages I or II are at intermediate risk, and those at stage III or IV are at high risk. Similarly, patients characterized according to the Binet system have progressively increasing risk, with stage A as the lowest and stage C as the highest risk group.

When is treatment needed? — As noted above, treatment is not always required for CLL. Some studies have shown that patients without symptoms of CLL (also called "smoldering" disease) are no more likely to die than a similar age/sex person who does not have CLL. (See 'Management of asymptomatic chronic lymphocytic leukemia' below.)

However, there are certain groups of patients in whom treatment is generally indicated. This includes patients with:

Symptoms of anemia and/or low platelets (Rai stages III or IV, or Binet stage C)

Disease-related symptoms such as weakness, night sweats, weight loss, painful lymph node swelling, or fever

Autoimmune hemolytic anemia and/or low platelets (when the immune system destroys red blood cells or platelets) that does not respond to treatment with glucocorticoids, such as prednisone

Progressive disease, as demonstrated by rapidly increasing white cells in the blood, and/or rapidly enlarging lymph nodes, spleen, or liver

Repeated infections

MANAGEMENT OF ASYMPTOMATIC CHRONIC LYMPHOCYTIC LEUKEMIA

Although people who do not have symptoms of CLL are not usually treated for their disease, they should be monitored regularly with blood tests and a physical examination. This is usually performed every three months for at least the first year after diagnosis. Depending upon the results of these tests, it may be possible to estimate how aggressive your disease will be in the future.

TREATMENT OF LOCALIZED CHRONIC LYMPHOCYTIC LEUKEMIA

People who have stage I CLL (which causes increased abnormal lymphocytes and enlarged lymph nodes) are sometimes treated with radiation therapy. Radiation therapy (RT) refers to the exposure of tissues to high-energy x-rays in order to slow or stop their growth. Exposure to x-rays damages cells. Unlike normal cells, leukemic cells cannot repair the damage caused by exposure to x-rays, particularly when it is administered over several days. This prevents the leukemic cells from growing further and causes them to eventually die. (See "Overview of the treatment of chronic lymphocytic leukemia".)

TREATMENT OF ADVANCED OR SYMPTOMATIC CHRONIC LYMPHOCYTIC LEUKEMIA

Chemotherapy plus immunotherapy — People with advanced or symptomatic CLL are generally treated first with chemotherapy plus immunotherapy, sometimes called chemoimmunotherapy.

Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide or multiply. Because most of an adult's normal cells are not actively dividing or multiplying, they are not affected by chemotherapy. However, the bone marrow (where the blood cells are produced), the hair follicles, and the lining of the gastrointestinal (GI) tract are all growing. The side effects of chemotherapy drugs are related to effects on these and other normal tissues.

Immunotherapy uses antibodies that target a specific group of cells (usually cancer cells). Rituximab, obinutuzumab, and ofatumumab are antibodies that target B lymphocytes (and CLL cells).

A chemotherapy drug or combination of drugs is referred to as a regimen. Regimens used for the treatment of CLL may include a single agent taken by mouth on a daily basis, while other regimens are given intravenously in treatment cycles.

A cycle of chemotherapy refers to the time it takes to give the drugs and the time required for the body to recover. For example, a typical chemotherapy regimen is at least a one-hour IV infusion of two or more different chemotherapy medications given once every three to four weeks. This three- or four-week period is one cycle of therapy. If this regimen were repeated for a total of three or four cycles, it would take up to four months to complete.

People with advanced or symptomatic CLL are usually treated with a chemotherapy regimen that contains one or more of these agents:

Fludarabine — Fludarabine (brand name: Fludara) is a chemotherapy drug that, when used in combination regimens, can often induce partial or complete remission of CLL. The most common side effects are low blood counts and fever. Older patients seem to be at higher risk of serious side effects from this medicine, including an increased risk of severe infections. (See 'Infection' below.)

Cyclophosphamide — Cyclophosphamide (brand name: Cytoxan) is a chemotherapy drug that may be used in combination with other drugs in people with CLL. It can be given by mouth or through an intravenous (IV) line. Side effects include low blood counts, nausea and vomiting, hair loss, and irritation of the bladder.

Bendamustine — Bendamustine (brand name: Treanda) may be given in combination with rituximab as an initial treatment of advanced or symptomatic CLL, as well as in previously treated patients.

Chlorambucil — Chlorambucil (brand name: Leukeran) may be given in combination with one of the following antibodies: rituximab, obinutuzumab, or ofatumumab as the initial treatment of CLL. The most common side effects are low blood counts.

Rituximab — Rituximab (brand name: Rituxan) is a monoclonal antibody, which means it is a purified protein that targets a specific group of cells, in this case cancer cells. It treats CLL by attacking specific substances (antigens) on the surface of the leukemic cells. This type of treatment has advantages over other cancer treatments, such as chemotherapy, which targets all rapidly growing cells.

Obinutuzumab — Obinutuzumab (brand name: Gazyva) is a monoclonal antibody that targets B lymphocytes. Patients treated with obinutuzumab plus chlorambucil are more likely to respond to therapy than those treated with chlorambucil alone. In addition, initial studies suggest that obinutuzumab helps these patients live longer.  

Ofatumumab — Ofatumumab (brand name: Arzerra) is a monoclonal antibody that targets B lymphocytes. Patients treated with ofatumumab plus chlorambucil are more likely to respond to therapy than those treated with chlorambucil alone.

Ibrutinib — Ibrutinib (brand name: Imbruvica) is a drug that can be given by mouth for patients with relapsed CLL. It may also be used for the initial treatment of patients with certain types of CLL (those with deletion 17p on genetic testing).

Idelalisib — Idelalisib (brand name: Zydelig) is a drug that can be given in combination with rituximab for patients with relapsed CLL.

First line treatment — There is no agreed upon standard treatment regimen for symptomatic CLL. Experts in the field use different treatment approaches. Because experts are not sure which regimen is most effective, all patients with advanced or symptomatic CLL are advised to enroll in a clinical trial, if possible. (See 'Clinical trials' below.)

The combination of fludarabine and rituximab, sometimes with cyclophosphamide, is often used as a first-line treatment of advanced or symptomatic CLL [3]. Overall survival rates appear to be the same with these two regimens, but response rates are higher with the combination of fludarabine, cyclophosphamide, rituximab (FCR) while toxicity (side effects) is lower with fludarabine and rituximab (FR). Complete remission rates of approximately 47 and 70 percent are seen in patients treated with FR or FCR, respectively [4]. Complete remission means that, for at least three months after treatment ends, the person has no signs or symptoms of their disease. Fludarabine is not very effective for older patients with CLL.

The combination of chlorambucil plus immunotherapy (obinutuzumab, ofatumumab, or rituximab) may be preferred for older adults with symptomatic CLL. There is no strict age cutoff used to define older adult in this setting, and an assessment of physiologic age is often more important than chronologic age.

The combination of bendamustine plus rituximab has efficacy and side effects in between those of combinations that use fludarabine and those that use chlorambucil. Bendamustine plus rituximab may be preferred for younger patients who have poor kidney function or other health problems.

Patients with markers of difficult to treat CLL (those with deletion 17p on genetic testing) should be considered for more aggressive treatment, which might include bone marrow transplant or the use of newer drugs such as ibrutinib (brand name: Imbruvica).

The choice between treatment regimens is an individual-based decision made by balancing patient characteristics and drug side effects.

Duration of treatment — Treatment with FCR or FR is usually given every day for either three or five days, followed by no treatment for 23 days. Therefore, one treatment cycle lasts 28 days. Typically, six cycles of this treatment are given. Treatment may be stopped sooner, however, if symptoms do not improve or intolerable side effects develop. More than six cycles is not more effective.

TREATMENT OF RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

Most people with CLL who undergo chemotherapy treatment respond initially, but then develop relapsed disease at some point after treatment ends. A small number of patients do not respond to chemotherapy at all; this is called refractory disease. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

Relapsed — If relapse occurs six or more months after treatment ends, it is often possible to successfully use the same chemotherapy regimen again or use another chemotherapy treatment. (See 'Chemotherapy plus immunotherapy' above.)

Refractory — If a person's disease is refractory or relapses sooner than six months after treatment ends, the options for treatment are limited. Depending upon the individual's situation, the following options should be discussed with a physician:

Participation in a clinical trial

Hematopoietic stem cell (also called bone marrow) transplantation

Treatment with alternate chemotherapy regimens

Treatment to reduce CLL-related symptoms and complications

Importantly, new chemotherapy drugs are in development for patients with CLL that target cellular processes that have not been targeted before. Two of these drugs, ibrutinib (brand name: Imbruvica) and idelalisib (brand name: Zydelig), have been approved for use in the United States for the treatment of patients with recurrent or refractory CLL who have received at least one prior therapy. Responses were seen in the majority of patients treated with these agents in trials, with dramatic responses even in heavily pretreated patients. Other promising drugs are also being evaluated in this setting.

Removal of the spleen — A number of people with CLL will develop a very enlarged spleen. This often responds to treatment with chemotherapy or radiation, so removal of the spleen is rarely done. However, it may provide longer lasting benefits, including increases in red blood cell and platelet counts in some patients [5].

Bone marrow transplantation — Bone marrow transplantation (also called hematopoietic cell transplantation) is being more seriously considered as a therapy for CLL, especially for patients under age 55. If bone marrow transplantation is performed, it is usually done after treatment with chemotherapy. Giving chemotherapy often induces a complete or partial remission. (See "Hematopoietic cell transplantation in chronic lymphocytic leukemia".)

Bone marrow transplantation is a treatment in which the patient is given high doses of chemotherapy or radiation. This kills cancer cells but also destroys all normal cells developing in the bone marrow. After the treatment, the patient needs to have a healthy supply of very young blood cells, called stem cells, reintroduced or transplanted. The transplanted cells then re-establish the blood cell production process in the bone marrow. (See "Patient information: Bone marrow transplantation (stem cell transplantation) (Beyond the Basics)".)

The type of stem cell transplant used for patients with CLL is called an allogeneic transplant. In allogeneic transplant, the patient is given stem cells from a donor, ideally a brother or sister with a similar genetic make-up. If the patient doesn't have a "matched" sibling, an unrelated person with a partially matched genetic makeup may be used.

Patients who are unable to tolerate high dose chemotherapy may be candidates for a reduced intensity transplant (called a mini-transplant or non-myeloablative transplant) from a relative or a matched unrelated donor, and may achieve long term control of their CLL. Studies using non-myeloablative allogeneic transplants have shown significant promise, even in patients with relatively high risk or refractory disease [6].

TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA COMPLICATIONS

The major complications of CLL are caused by the low blood counts and immune system problems that either arise from the disease itself or the treatment.

Infection — Infection is one of the most serious risks of treatment of CLL, accounting for approximately 50 percent of deaths. Although less common, serious infections can also occur in patients who have not yet received any treatment for their underlying leukemia. The most common infections affect the upper respiratory tract (sinuses, bronchi). Smokers are especially vulnerable and should stop smoking. All patients with CLL should make sure their vaccinations are up to date and receive yearly influenza vaccines and pneumococcal vaccination every five years. But they should not get live vaccines such as the shingles vaccine (H. Zoster vaccine). Household contacts of people with CLL should also receive annual influenza vaccination.

Patients with respiratory tract infections sometimes need antibiotic therapy. Infection is often related to low levels of infection fighting proteins called immunoglobulins. For this reason, patients who have repeated infections may be treated with intravenous immune globulin (IGIV, IVIG) to increase their immunoglobulin levels and decrease the chance of infection. Such infusions are usually recommended only for patients with repeated infections and low serum gamma globulins. Infusions of IVIG can decrease the incidence of minor infections, but may not decrease the incidence of serious infections.

Patients treated with certain chemotherapy agents can develop low white blood cell counts, which increases the risk of infections. In some cases, medications that promote the growth of new blood cells may be given to boost the white cell count and decrease the infection risk.

Anemia — Anemia, or low red blood cell counts, is common in CLL. Red blood cells are needed to carry oxygen to all the cells in the body. Patients with anemia may experience fatigue, weakness, and chest pain. Treatment options include blood transfusion and use of a medicine called erythropoietin, which can boost the red cell count in patients with certain types of anemia. Other forms of anemia may be treated with glucocorticoids (also called steroids).

Low platelet counts — Platelets are important components of the blood's clotting mechanism. Without adequate numbers of platelets, internal and external bleeding can occur. Patients with CLL and low platelet counts may see their counts improve with treatment of the CLL. In some cases, platelet transfusions are needed. Removal of the spleen or use of steroids or other treatments that suppress the immune response (as part of the treatment for CLL) usually improves the platelet counts.

Psychological aspects — Patients with CLL are forced to live with the uncertainties associated with a chronic illness. It can be puzzling and frightening to hear that you have leukemia and that no treatment is recommended. You and your healthcare providers must speak frequently and honestly to deal with any fears and clarify any misunderstandings about this sometimes confusing disease. Some patients and families benefit from psychological counseling to help them cope with the strong emotions that can accompany this diagnosis.

CLINICAL TRIALS

Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at:

http://cancernet.nci.nih.gov/clinicaltrials

http://clinicaltrials.gov/

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Leukemia in adults (The Basics)
Patient information: Chronic lymphocytic leukemia (CLL) (The Basics)
Patient information: Neutropenia and fever in people being treated for cancer (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Bone marrow transplantation (stem cell transplantation) (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Classification of the hematopoietic neoplasms
Clinical manifestations, pathologic features, and diagnosis of small lymphocytic lymphoma
Evaluating response to treatment of chronic lymphocytic leukemia
Hematopoietic cell transplantation in chronic lymphocytic leukemia
Overview of the treatment of chronic lymphocytic leukemia
Risk of infections in patients with chronic lymphocytic leukemia
Prevention of infections in patients with chronic lymphocytic leukemia
Overview of the complications of chronic lymphocytic leukemia
Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia
Pathophysiology and genetic features of chronic lymphocytic leukemia
Staging and prognosis of chronic lymphocytic leukemia
Treatment of relapsed or refractory chronic lymphocytic leukemia

The following organizations also provide reliable health information.

National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)

National Cancer Institute

(www.cancer.gov/cancertopics/pdq/treatment/CLL/patient/)

American Cancer Society

(http://www.cancer.org)

The Leukemia & Lymphoma Society

(www.leukemia-lymphoma.org)

The Lymphoma Research Foundation

(www.lymphoma.org)

National Marrow Donor Program

(www.marrow.org)

The American Society of Hematology

(www.hematology.org)

The American Society of Clinical Oncology

(www.cancer.net/portal/site/patient)

The Alliance for Clinical Trials in Oncology

(www.allianceforclinicaltrialsinoncology.org)

Eastern Cooperative Oncology Group

(http://ecog.dfci.harvard.edu/general/intro.html)

Southwest Oncology Group

(www.swog.org/Patients/Index.asp)

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ACKNOWLEDGMENT

UpToDate would like to acknowledge Michael J Keating, MD, who contributed to earlier versions of this topic review.

Literature review current through: Sep 2014. | This topic last updated: Aug 11, 2014.
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