Overview of CLL and SLL
If you have been diagnosed with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), you probably have many questions and concerns about your disease and its treatment. This patient treatment summary, which is based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for non-Hodgkin’s lymphoma, will help you understand the best available treatments for CLL and SLL. Talk with your doctor about these therapies so that together you can decide on a treatment plan that is right for you.
Background
Non-Hodgkin’s lymphoma (NHL) is a group of blood cancers that affect the lymphatic system, which is part of the immune system. The immune system defends the body against infections and other diseases. The lymph system is made up of blood, lymph, lymph vessels, lymph nodes, spleen, thymus, tonsils, and bone marrow. NHL originates in lymphocytes, a type of white blood cell in the immune system that make antibodies. There are generally three different types of lymphocytes: T cells, B cells which make antibody, and NK cells. NHL occurs when one of these cells becomes malignant and grows uncontrollably. Therefore, NHL is divided into 3 major types depending on the nature of the lymphocytes from which it originates: T-cell lymphoma, B-cell lymphoma, and NK-cell lymphoma.
CLL and SLL are both indolent, slow-growing subtypes of NHL, caused by the overproduction of abnormal B cells that live much longer than normal B cells. CLL is the second most common type of leukemia next to acute myeloid leukemia. SLL accounts for approximately 5% of NHLs in the United States and is almost identical to CLL. Both diseases are treated in generally the same way. The major difference is that in CLL, a significant number of the abnormal lymphocytes are also found in the bone marrow and blood, while in SLL the abnormal lymphocytes are predominantly found in the lymph nodes.
Lymph nodes are found in the neck, underarms, chest, abdomen, and groin. The lymph nodes trap and remove harmful bacteria and other substances in the lymph. Lymph nodes often become enlarged when the body is fighting infections, such as when you have a cold or sore throat. Most of the time enlarged lymph nodes are not a problem. However, if they stay swollen for more than 2 weeks, a doctor should be consulted, because swollen lymph nodes are one of the common symptoms of SLL and can be found in CLL.
Diagnosing CLL and SLL
The symptoms of CLL and SLL can be very mild, and some patients will have absolutely no symptoms and feel completely normal at the time of diagnosis. Symptoms may include abnormal bruising, enlarged lymph nodes, excessive sweating, night sweats, fatigue, fever, persistent infections, loss of appetite, or unintentional weight loss. Many cases of CLL are found during routine blood tests in people with no symptoms.
With CLL, there is always an elevated white blood cell count, and therefore the diagnosis can be made from a blood sample. The blood is reviewed by a pathologist and also sent to the laboratory for flow cytometry analysis or immunophenotypic analysis (IPA), a specialized test to determine if the white blood cells are cancerous and to characterize what type of cells they are. A bone marrow biopsy or lymph node biopsy are not required to make the diagnosis.
For diagnosing SLL, an incisional or excisional lymph node biopsy will be performed, during which your doctor will remove part or all of the enlarged lymph node to look for NHL. The biopsy sample will be examined using IPA and by a hematopathologist. Once it is confirmed to be lymphoma, more tests will need to be performed on the sample to determine if it is CLL/SLL or another subtype of NHL.
It is of critical importance that your medical team accurately identifies your disease as CLL/SLL, because they are treated differently from other NHLs.
There are several laboratory studies that can be done to determine or predict how aggressive or slow-growing your CLL/SLL may be, the results of which are referred to as prognostic factors. These prognostic factors are not always accurate, but may provide helpful information at least to determine how closely your doctor needs to monitor you. Currently, they are not used to determine when to initiate treatment.
Staging of CLL and SLL
A formal system called staging is used to identify how localized or widespread your cancer is. Staging is an important part of developing the best treatment plan for you.
CLL staging is broken down into five stages:
- Stage 0: Elevated lymphocyte count in blood and bone marrow. The lymph nodes, spleen, and liver are not enlarged and the red blood cell and platelet counts are near normal.
- Stage I: Elevated lymphocyte count in blood and bone marrow, and enlarged lymph nodes. The spleen and liver are not enlarged and the red blood cell and platelet counts are near normal.
- Stage II: Elevated lymphocyte count in blood and bone marrow, and enlarged lymph nodes, spleen and liver. Red blood cell and platelet counts are near normal.
- Stage III: Elevated lymphocyte count in blood and bone marrow, low hemoglobin levels (anemia), and enlarged lymph nodes, spleen, and liver. Platelet counts are near normal.
- Stage IV: Elevated lymphocyte count in blood and bone marrow, low hemoglobin (anemia), low platelet levels (thrombocytopenia), and enlarged lymph nodes, spleen, and liver.
SLL staging is broken down into four stages. They are defined as:
- Stage I: Lymphoma is found in a single lymph node group.
- Stage II: Lymphoma is found in multiple lymph node groups on one side of the diaphragm (the muscle below the lungs and heart that separates the chest from the abdomen).
- Stage III: Lymphoma is found in multiple lymph node groups on both sides of the diaphragm.
- Stage IV: Lymphoma has spread beyond lymph nodes to other organs.
In order to stage your cancer, your doctors may perform several tests. These may include:
- A thorough physical exam, which will include several questions about any symptoms you might have had, your general health, and your medical history
- Blood tests
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Computerized tomography (CT) scan of chest, abdomen, and pelvic region (for SLL; not required for CLL)
- Metabolic panel
- Bone marrow biopsy and aspirate
Treatment of CLL and SLL
Treatment of CLL/SLL involves a number of specialists who plan and work as a team to coordinate a patient’s care, and most often uses a combination of several approaches. Therefore, it is very important that you receive your medical care at a hospital or cancer center where doctors are experienced in treating patients with lymphoma. If the doctors at your hospital do not have a lot of experience treating these illnesses, ask your physician for a referral to a large cancer center where the staff have seen and treated many cases of these diseases. Treatment of CLL/SLL aims to relieve symptoms, slow progression, improve quality of life, and prolong survival.
Before you begin treatment, your doctor may need to perform the following tests:
- MUGA scan or echocardiograms to monitor heart function. One of your treatment options, chemotherapy, may involve a class of drugs called anthracyclines, which can damage your heart. It is important to know the health of your heart before beginning treatment.
- Hepatitis B testing. Your doctor will also need to know if you are a carrier of hepatitis B or if you have recovered from hepatitis B infection. Treatment with chemotherapy and immunotherapy may reactivate hepatitis B, but your doctor can give you antiviral drugs to prevent this from happening.
- Pregnancy testing for women with childbearing potential.
- Some treatment options may affect fertility. Depending on your age and future plans, you may wish to discuss with your doctor how treatment may impact your fertility, and options for preservation.
In general, treatments rely on the following approaches, often in combination:
- Chemotherapy: Drugs are used to kill or slow the growth of cancer cells, including any that have broken away from the original tumor.
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Immunotherapy: Antibodies are used to identify cancerous cells and destroy them. Rituximab, alemtuzumab, and ofatumumab are the monoclonal antibodies used to treat CLL/SLL.
- Chemoimmunotherapy: The combination of chemotherapy and immunotherapy agents is used to treat CLL/SLL.
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Radiation therapy (or radiotherapy): High-energy beams are used to kill tumor cells.
- High-dose chemotherapy or reduced-intensity conditioning with stem cell transplant: Bone marrow cells that have been destroyed by chemotherapy are replaced with healthy cells. This will be done with stem cells from a matched donor (allogeneic transplant). See the section on stem cell transplants for more detailed information.
- Clinical trials: Investigational drugs and protocols will be tried. Despite improvements in outcomes, there is still need for better treatment options. Clinical trials may test novel drugs or alternative ways of giving established drugs that may lead to improved outcomes for all patients.
In about 5% of patients, CLL/SLL will change into an aggressive (fast-growing) form of lymphoma called diffuse large B-cell lymphoma (DLBCL) during the course of the disease. This transformation is known Richter’s syndrome and is more common after patients have received treatment. The treatment options for this group of patients are described in the treatment summary for DLBCL.
Studies have shown that patients do not survive longer by starting treatment earlier if there is no need for treatment. Patients with CLL/SLL may be monitored with observation until they develop an indication for treatment. Indications for treatment generally include advancement to stage III or IV disease or a rapid increase in the number of cancer cells. For patients diagnosed with stage 0 through II, treatment may start if disease-related symptoms develop, such as severe fatigue, night sweats that occur regularly, fever without infection, or unintentional weight loss.
Below you will find more detailed treatment information based on the stage of your CLL/SLL.
Treatment of SLL (Stage I)
If you are diagnosed with stage I SLL your first treatment will be with localized radiation therapy. This may help stop your disease from spreading and no further treatment will be needed until you start experiencing the symptoms detailed below.
Treatment of CLL (Stages I and II) and SLL (Stages II–IV)
If you are diagnosed with CLL (stages I and II) or SLL (stages II-IV), no treatment will be given as long as you
- Are not a candidate for a clinical trial
- Are not experiencing symptoms such as high fever, weight loss, or night sweats
- Do not have signs of lymphoma-related inhibition of organ function, which might be due to compression of organs by nearby enlarged lymph nodes
- Do not have low blood counts
- Do not have bulky disease
- Have no signs of progressive anemia or thrombocytopenia
- Prefer not to undergo treatment
When you start having symptoms, your treatment options will depend on the presence of a certain genetic abnormality. The genetic abnormality is called del(17p), which means that part of chromosome 17 has been deleted. This deletion may lead to cancer cells that divide aggressively and are often resistant to conventional chemotherapy. This del(17p) abnormality is identified by fluorescence in situ hybridization analysis on blood or bone marrow.
Treatment of CLL (All stages) and SLL (Stages II-IV) Without the del(17p) Chromosome Abnormality
Patients without the mutation generally have a good prognosis because this type of CLL/SLL is responsive to conventional treatment options. Treatment is somewhat differentiated by age. For patients younger than 70 years of age and those older than 70 who have no additional health problems, the recommended first-line treatment options include:
- Chemoimmunotherapy, such as FCR (fludarabine, cyclophosphamide, and rituximab) or FR (fludarabine and rituximab). This option is preferred for patients younger than 70 years.
- Monotherapy, such as chlorambucil with or without prednisone, fludarabine, alemtuzumab, or bendamustine.
For patients 70 years or older with health problems, first-line treatment options include:
- Chlorambucil with or without prednisone
- Fludarabine or multiagent chemotherapy with or without rituximab
- Immunotherapy with alemtuzumab or rituximab
- Bendamustine
Relapsed/Refractory Therapy
For patients whose disease does not respond to treatment or who experience relapse, many treatment options are available.
If your lymphoma comes back after treatment (recurrence) or does not respond to initial treatment (refractory), you will be given second-line therapy. Your doctor will also repeat an earlier test to make sure you still do not have the del(17p) chromosome abnormality, which can be acquired in your cells with time and treatment.
If your CLL/SLL returns after 3 years and needs to be retreated, you will most likely be treated with additional cycles of the same chemoimmunotherapy regimens that you previously received. You will keep receiving the same treatment until your remission period is less than 3 years.
If your CLL/SLL returns and needs to be retreated in less than 3 years, you will receive new chemotherapy regimens with or without rituximab. If you are 70 years or older, treatment options may include reduced-dose chemoimmunotherapy, or immunotherapy with ofatumumab or dose-dense rituximab.
If you are younger than 70 years or older than 70 years with no additional health problems, treatment options may include chemoimmunotherapy, immunotherapy with ofatumumab or a combination of alemtuzumab with rituximab, or high-dose methylprednisone with rituximab.
For patients who experience relapse in less than 3 years, another possible treatment option is allogeneic stem cell transplantation. See Stem Cell Transplants below for more information.
Treatment for CLL (All Stages) and SLL (Stages II–IV) With the del(17p) Chromosome Abnormality
Because of the low response rate to standard treatments, patients with the del(17p) mutation are recommended to consider enrollment in a clinical trial. If you do not wish to enroll or are unable to, your options for first-line therapy may include:
- Immunotherapy with alemtuzumab
- Multiagent chemoimmunotherapy, such as FR, FCR, or CFAR (fludarabine, cyclophosphamide, alemtuzumab, and rituximab)
- High-dose methylprednisone and rituximab
- Single-agent chemotherapy with the drug bendamustine
If you experience a complete or partial response to first-line therapy and have no serious heart, lung, liver, or kidney problems, your doctor may recommend an allogeneic stem cell transplant (see later section on Stem Cell Transplants).
If you experience complete or partial response to first-line therapy but are not a candidate for stem cell transplantation, or if you do not experience a response to first-line therapy, you will be given second-line therapy.
Second-line therapy often consists of new immunotherapy or chemoimmunotherapy combinations. Some common treatment regimens are:
- Multiagent chemoimmunotherapy, such as RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), CFAR, or HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high-dose methotrexate and cytarabine)
- Immunotherapy with ofatumumab or a combination of alemtuzumab and rituximab
- High-dose dexamethasone
- Bendamustine
Stem Cell Transplants
Stem cell transplants are rigorous treatments. Sometimes high-dose chemotherapy is used to kill the rapidly dividing cancer cells, but the dose is so high that it kills other rapidly dividing normal cells in your body. This is referred to as myeloablative conditioning. Blood cells that are responsible for your immune responses are destroyed in the process. These blood cells are replaced with an infusion of either your own blood and marrow (autologous) or blood and marrow from a matched donor (allogeneic). These cells then seed your own bone marrow and your body starts making new blood cells. For CLL/SLL patients, only allogeneic transplants are treatment options.
In order to have an allogeneic stem cell transplant, you must have a donor who is a close match to you. Most often, the donated stem cells will come from a close relative, with siblings as common sources. Some centers will also perform stem cell transplants with unrelated donors. This is called a matched unrelated donor (MUD) transplant.
Prior to allogeneic stem cell transplant, you will receive chemotherapy called conditioning. There are two different conditioning regimens: myeloablative and reduced-intensity conditioning. Myeloablative conditioning destroys all bone marrow cells along with any residual lymphoma cells and is harder on the patient, and therefore is often used in younger patients. Reduced-intensity (or non-myeloablative) conditioning uses lower-intensity chemotherapy that suppresses your immune system and allows the transplant to take, but is not strong enough to destroy all bone marrow cells, and is an option for patients who are not considered candidates for myeloablative conditioning, such as those who are older than 55 years.
Once conditioning is complete, new stem cells are infused into your bone marrow. These cells begin to grow and divide in your bone marrow, and grow new blood cells.
A potentially life-threatening long-term side effect of allogeneic stem cell transplant is graft-versus-host disease (GVHD). In GVHD, transplanted donor blood cells attack the patient’s immune system. Acute GVHD occurs immediately after transplant, and chronic GVHD may occur from 3 months to 1 year after transplant.
You will receive immunosuppressive drugs (1 or 2 days prior to transplant) to prevent GVHD and related complications. You may need to take immunosuppressive drugs regularly for many months after transplantation to prevent GVHD.
Because of the risks associated with stem cell transplants and the possibility of rejection of the new stem cells by your immune system, the decision to pursue this option must be made after careful discussion with your doctor.
Side Effects of Treatment
CLL/SLL treatments may result in side effects. Talk to your doctor about what to expect from each treatment and how to manage the possible effects. For example:
- After radiation therapy, people are often fatigued; some may have shortness of breath. Your health care provider can use the NCCN Clinical Practice Guidelines in Oncology™ on cancer-related fatigue to help you reduce fatigue caused by cancer treatments. Also, see Fighting Cancer Fatigue.
- After chemotherapy, people may experience mouth sores, hair loss, fatigue, and/or loss of appetite.
- Your doctor may give you antiemetic (anti-vomiting/anti-nausea) drugs to decrease or prevent nausea and/or vomiting. The
NCCN Clinical Practice Guidelines in Oncology™
on antiemesis can help your doctor determine the most appropriate antiemetic regimen for your situation.
- After chemotherapy, many patients experience constipation. Be sure to report this problem to your doctor so they can prescribe proper medication and diet changes. Constipation can become life-threatening when accompanied by low blood counts, and it is also associated with a higher risk of infection.
- Damage to the heart muscle by chemotherapy drugs is called cardiac toxicity. As a result of this damage, the heart is not able to pump enough blood to supply the body with essential oxygen and nutrients. The most common cause of cardiac toxicity is treatment with chemotherapy drugs called anthracyclines. Doxorubicin is a frequently used anthracycline in chemotherapy. If you have impaired cardiac function, your doctor will monitor your condition and adjust the dose of chemotherapy accordingly. You may also be treated with regimens containing other anthracyclines that cause considerably lower cardiac toxicity.
- Hepatitis B virus reactivation can occur ,mainly in patients who received chemotherapy and rituximab or ofatumumab and who are carriers of hepatitis B or have recovered from hepatitis B infection. Your doctor will give you antiviral drugs, such as lamivudine, to prevent the viral reactivation. Hepatitis B–positive patients may be asked to consult a hepatologist.
- Cytomegalovirus (CMV) reactivation may occur in patients who receive alemtuzumab. CMV is a member of the herpes family that infects most patients at some time during their lives, but rarely causes illness. If your treatment includes alemtuzumab, your doctor will monitor you for the presence of CMV or will give you antiviral drugs to prevent its reactivation.
- CLL can sometimes alter the body’s own immune system in such a way that it attacks its own red blood cells (autoimmune hemolytic anemia [AIHA]) or blood platelets (immune-mediated thrombocytopenia [ITP]). These conditions may be treated with drugs such as intravenous immunoglobulin, steroids, or rituximab. You may be treated with newer drugs, such as romiplostim or eltrombopag, if you develop ITP that does not respond to conventional therapies. AIHA may develop during treatment with fludarabine. If it does, your doctor will stop treatment. Subsequent treatment with fludarabine should be avoided.
- Tumor lysis syndrome (TLS) is a side effect of chemotherapy associated with rapid and massive breakdown of tumor cells, resulting in serious complications such as kidney failure, irregular heartbeat, and seizures. You will be given drugs such as rasburicase or allopurinol to prevent TLS.
Talk to your doctor or oncology nurse about the best ways to manage side effects. It is important for you to discuss any possible side effects as soon as they appear.
Prognosis
In determining a prognosis—the likely course or outcome of a disease and its treatment—a doctor may look at survival statistics taken from studies of large groups of patients with CLL or SLL. However, such statistics:
- Are estimates only
- Can vary widely with each cancer stage
- Are sometimes based on older data that do not reflect recent advances in treatment options
- Cannot be used to precisely predict your survival
Your individual prognosis will be affected by many factors, including:
- Your age
- Your overall health, including other diseases you may have
- The risk category of your cancer
- Your response to the treatment(s) being used
New therapies and combinations of therapies are enabling people with cancer to live longer, better quality lives than ever before. You may want to find out whether you are eligible to participate in a clinical trial, in which new and experimental therapies are used and may be compared to standard treatments.
Life After Treatment
Once your treatment is completed, you will need to see your doctor for follow-up visits at regular intervals to make sure that you remain healthy and that any long-term effects of cancer or its treatment can be attended to.