Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)

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

Authors Kanti R Rai, MD Michael J Keating, MD

CHRONIC LYMPHOCYTIC LEUKEMIA OVERVEIW

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 chronic lymphocytic leukemia, 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 chronic lymphocytic leukemia 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 rather, 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 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 chronic lymphocytic leukemia. 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 chronic lymphocytic leukemia. (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 chronic lymphocytic leukemia 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 chronic lymphocytic leukemia (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 "Initial treatment of chronic lymphocytic leukemia".)

TREATMENT OF ADVANCED OR SYMPTOMATIC CHRONIC LYMPHOCYTIC LEUKEMIA

Chemotherapy — People with advanced or symptomatic chronic lymphocytic leukemia are generally treated first with chemotherapy. 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.

A chemotherapy drug or combination of drugs is referred to as a regimen. Regimens used for the treatment of follicular lymphoma 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 chronic lymphocytic leukemia are usually treated with a chemotherapy regimen that contains one or more of these agents:

Fludarabine — Fludarabine is a chemotherapy drug that, when used in combination regimens, can often induce partial or complete remission of chronic lymphocytic leukemia. 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.)
Rituximab — Rituximab is a monoclonal antibody that treats chronic lymphocytic leukemia 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.
Cyclophosphamide (Cytoxan) — Cyclophosphamide is a chemotherapy drug that may be used in combination with other drugs in people with chronic lymphocytic leukemia. 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.
Alemtuzumab — Alemtuzumab is a monoclonal antibody that can be used to treat CLL by attacking specific substances (antigens) on the surface of leukemic cells. The antigens targeted by alemtuzumab are different from those targeted by rituximab.
Bendamustine — Bendamustine may be given by itself or in combination with rituximab as an initial treatment of advanced or symptomatic CLL, as well as in previously treated CLL patients.
Chlorambucil — Chlorambucil was the primary agent used to treat CLL for decades prior to studies that demonstrated greater tumor shrinkage yet similar survival rates with fludarabine treatment. Chlorambucil may still be an appropriate initial treatment for some patients.
First line treatment — There is no agreed upon standard treatment regimen for symptomatic chronic lymphocytic leukemia. Experts in the field use different treatment approaches. Because experts are not sure which regimen is most effective, all patients with advanced or symptomatic chronic lymphocytic leukemia 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 chronic lymphocytic leukemia [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 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 three months after treatment ends, the person has no signs or symptoms of their disease.

Other physicians may recommend treatment with alemtuzumab, bendamustine, or chlorambucil. Neither alemtuzumab nor bendamustine have been directly compared to fludarabine in trials therefore it is difficult to know which may be more effective. 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 five days, followed by no treatment for 23 days. Typically, six cycles of this treatment are given. However, treatment may be stopped sooner if:

Symptoms do not improve
Intolerable side effects develop

TREATMENT OF RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

Most people with chronic lymphocytic leukemia 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' 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 chronic lymphocytic leukemia-related symptoms and complications

Removal of the spleen — A number of people with chronic lymphocytic leukemia will develop a very enlarged spleen. While this often responds to treatment with chemotherapy or radiation, removal of the spleen is more likely to provide longer lasting benefits, including increases in red blood cell and platelet counts [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 reestablish the blood cell production process in the bone marrow. (See "Patient information: Bone marrow transplantation (stem cell transplantation) (Beyond the Basics)".)

There are two main types of stem cell transplant: allogeneic and autologous.

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].

Autologous transplant — In autologous transplantation, the patient's own stem cells are removed before the high dose chemotherapy or radiation is given. Because the potential for cure with autologous transplantation is low for people with CLL, it is not usually recommended.

TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA COMPLICATIONS

The major complications of chronic lymphocytic leukemia 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 chronic lymphocytic leukemia, accounting for approximately 50 percent of deaths. The most common infections affect the upper respiratory tract (sinuses, bronchi).

Infection is often related to low levels of infection fighting proteins called gamma globulins. For this reason, patients who have repeated infections may be treated with intravenous immune globulin (IGIV, IVIG) every three to four weeks to decrease the chance of infection.

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 chronic lymphocytic leukemia. 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 chronic lymphocytic leukemia 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 chronic lymphocytic leukemia 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:

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 (The Basics)

Patient information: Chronic lymphocytic leukemia (CLL) (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

Epidemiology and clinical manifestations of chronic lymphocytic leukemia

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

Initial treatment of chronic lymphocytic leukemia

Overview of infectious complications following purine analog therapy

Overview of the complications of chronic lymphocytic leukemia

Pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia

Pathophysiology and genetic features of chronic lymphocytic leukemia

Randomized clinical trials of chemotherapy in 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)

National Marrow Donor Program

(www.marrow.org)

The American Society of Clinical Oncology

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

Eastern Cooperative Oncology Group

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

Southwest Oncology Group

(www.swog.org/Patients/Index.asp)
[1-6]

Literature review current through: 20.3: ene 2012

This topic last updated: nov 30, 2011

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