Chronic lymphocytic leukemia (CLL)
INTRODUCTION — 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.
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). They cannot fight infection as normal lymphocytes do, and collect in increased numbers in lymph nodes and other areas, such as the liver and spleen. Their high numbers can cause them to interfere with the proper production of other blood cells, such as red cells and platelets.
Unlike acute lymphoblastic leukemia, which is fatal if left untreated, CLL is usually characterized by a slow progression of the disease and related symptoms. In many cases, it causes the patient little, if any, problems in its early stages. Patients may live with CLL for decades. Many times, it is diagnosed by blood tests that are performed during a routine physical exam. In other cases, symptoms may bring the patient to the doctor.
Careful analysis of the patient’s blood and physical condition help the doctor 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 may not benefit from early, aggressive treatment, but rather, may do better with careful long-term monitoring of the disease without treatment.
STAGING OF CLL — The natural history of CLL may vary considerably from person to person. Some patients may 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 are most likely to benefit from treatment of the disease, has been a challenge for doctors.
Two systems for staging CLL are now in use. They are used as a way to help identify patients with more serious versus “smoldering” disease, and as a way to help identify which patients are most likely to develop serious problems in the near term.
The Rai system — The Rai system is based on an analysis of how the body is affected by the abnormal lymphocytes. 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), and also on whether or not anemia or low platelet counts are present. 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
Experts have recommended that these two systems be used together to define the stage of leukemia, for example, stage A0, A1, AII, BI, and so on. However, many clinicians still use either the Rai or Binet method.
What the stages mean — Staging helps doctors decide how likely it is that the person is soon to develop serious problems related to the CLL. 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. Average survivals for these three risk categories are: Low risk — 12 years Intermediate risk — 7.5 years High risk — 1.5 years
In general, doctors are more certain about expected disease progression in the higher versus the lower risk groups. That is, it is more difficult to tell which patients in the lower risk groups are most likely to go on to develop more serious disease. Research is underway to identify factors associated with a more aggressive course. For example, analysis of certain aspects of bone marrow cells and comparison of the patient’s blood test results over time may prove helpful in identifying which patients in the lower risk groups are more likely to become ill with CLL.
Indications for treatment — As noted above, treatment is not always required for CLL. Some studies have shown that patients with so-called “smoldering” CLL are no more likely to die than a normal person of similar age and sex. Although treatment can be effective in controlling progression of the disease and alleviating symptoms, it usually does not produce a cure. This means that doctors and patients must carefully weigh the risks and discomforts of treatment against expected benefits to be gained.
However, there are certain groups of patients in whom some type of treatment is generally indicated. This includes patients with: 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 Progressive disease, as demonstrated by rapidly increasing white cells in the blood, and/or rapidly enlarging lymph nodes, spleen, or liver Repeated infections
In some cases, especially in younger patients, doctors may recommend treating patients who do not have symptoms and/or those with low risk disease. Patients and doctors may choose to aggressively treat these milder forms of the disease in the hopes of obtaining long-term benefits and possibly a cure. Such aggressive treatments, such as bone marrow transplantation, may have serious side effects, and are generally part of a formal research study.
In other cases, detailed examination of the leukemic cells may be able to determine the future clinical course of the disease (ie, the prognosis), as well as the suitability of one or more treatment options. Such studies are the subject of a large number of ongoing research trials.
A number of different forms of treatment may be proposed. These are outlined in the following sections.
CHEMOTHERAPY — Chemotherapy, or the use of medications to kill cancer cells, can be effective in treating CLL. Depending on factors such as the stage of illness, the patient’s age, and symptoms, the goals of chemotherapy may vary. For example, in some cases the goal is to halt the progression of the disease and relieve symptoms. In other cases, medicines will be chosen that are designed to help induce a remission of the disease. A patient undergoing chemotherapy for CLL should talk with the doctor about the goals for treatment.
Some of the medicines that may be used are listed here. Ask your doctor for complete information about the specific medicines you will receive, whether or not you will need to be admitted to the hospital for therapy, and what side effects you should watch for.
Historical agents — The following three agents were among the first to be successfully used for the treatment of CLL:
Chlorambucil (Leukeran) — This is taken by mouth either daily or in a single dose given every three to four weeks. The most common side effects are anemia, low white blood cell counts (leading to risk for infection), and low platelet counts (increasing the risk for bleeding).
Cyclophosphamide (Cytoxan) — This medicine 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 urinary bladder.
Steroids — Some treatment programs call for the use of steroids such as prednisone to treat CLL. Side effects include increased susceptibility to infections, high blood glucose, gastrointestinal problems, muscle weakness, and psychiatric symptoms.
Newer agents — The following two agents have been shown to be clearly superior to the historical agents noted above. Fludarabine, in combination with cyclophosphamide, is the most potent combination regimen developed to date.
Fludarabine — This medicine is showing promise as a way to induce a partial or complete remission of the disease. It must be given intravenously. Major side effects are low blood counts and fever. Older patients seem to be more prone to serious side effects from this medicine, including an increased risk of severe infections.
Cladribine (2-CdA) — This is a medicine similar to fludarabine, with similar side effects.
BIOLOGIC THERAPIES
Monoclonal antibodies — Medicines called monoclonal antibodies may help treat CLL by attacking specific substances (antigens) on the surface of the leukemic cells. Examples include rituximab and alemtuzumab. Combinations of antibodies with such chemotherapeutic agents as prednisone, cytoxan, and/or fludarabine are achieving very high complete remission rates of long duration.
Immunotherapy — The availability of agents known as biologic response modifiers has led to investigation of these agents in the treatment of CLL. Examples include recombinant interferon alfa or interleukin-2. These medicines may boost the patient’s immune response so that it can more effectively fight the cancer.
RADIATION THERAPY — Radiation therapy may be used to shrink large, bulky masses of lymphoid tissue that occur because of accumulation of leukemic cells. These cells are very responsive to radiation and usually shrink considerably, although the swelling may return. The spleen or other areas of the body may be treated.
REMOVAL OF THE SPLEEN — Patients with CLL who have significant enlargement of the spleen often respond well to chemotherapy. In patients with persistent enlargement of the spleen, radiation therapy may be prescribed, but removal of the spleen is more likely to provide longer lasting benefits, including improvement in low red cell and platelet counts. If the patient is well enough to withstand surgery, removal of the spleen may be recommended.
BONE MARROW TRANSPLANTATION — Bone marrow transplantation (also called hematopoietic stem cell transplantation) is being more seriously considered as a therapy for CLL, especially for patients below the age of 55. Bone marrow transplant is a treatment in which the patient is given very high doses of chemotherapy or radiation, which kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body’s normal pipeline for replenishing critical blood components, the bone marrow, is no longer functional. 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: Overview of bone marrow transplantation”).
There are two main types of stem cell transplant: allogeneic and autologous.
Allogeneic transplant — In allogeneic transplant, the healthy cells that the patient receives following the high dose chemotherapy or radiation come 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 similar genetic makeup may be used.
Patients whose disease has become life-threatening but who are unable to tolerate high dose chemotherapy may be candidates for a reduced intensity transplant (called a mini-transplant or non-ablative transplant) from a relative or a matched unrelated donor, and may achieve long term control of their CLL.
Autologous transplant — In autologous transplant, the patient’s own stem cells are removed before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemic cells that may be present, then they are frozen for storage. After the patient’s chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient.
POSTPONING TREATMENT — As noted above, treatment of CLL is not appropriate for all patients. In a patient whose disease is not progressing rapidly, or in whom there are no troubling symptoms, the risks and discomforts of treatment may be greater than any possible benefit. In these cases, doctors will advise the patient to return for blood tests and a physical exam every three months. At the end of a year, it should be clear whether or not the patient has an aggressive form of the disease that requires treatment.
TREATMENT OF 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. They include infection, anemia, and low platelets.
Infection — Episodes of infection are major complications that occur during the treatment of CLL. Infection is often related to low levels of important infection fighting proteins called gamma globulins. For this reason, patients who have repeated infections may be treated with intravenous immune globulin (IGIV, IVIG) to decrease the chance of infection. Infections of the upper respiratory tract are common, but usually respond to antibiotics. Some patients may develop chronic sinusitis.
Patients treated with certain chemotherapy agents may develop low white blood cells counts, and an increased risk of other infections. Early treatment with antibiotics is recommended, and, 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 includes blood transfusion and, in some cases, administration 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 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, use of steroids, or agents which suppress the immune response as part of the treatment for CLL usually results in improved platelet counts.
Psychological aspects — Patients with CLL are forced to live with the uncertainties associated with a chronic illness. In some cases, it is puzzling and frightening to hear that there is a diagnosis of leukemia and that no treatment is recommended. Patients and their healthcare providers must speak frequently and honestly to deal with 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.
THE ROLE OF 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
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
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8. Johnson, S, Smith, AG, Loffler, H, et al. Multicenter prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 1996; 347:1432.
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