Frequently Asked Questions
What is a cord blood transplant?
What is leukapheresis?
What about alternative/complementary therapies?
Is additional vitamin C recommended for people with CLL?
What is a neutropenic diet?
What medical centers specialize in treating CLL?
What are clinical trials?
What constitutes a remission in CLL?
What is minimal residual disease (MRD)?
What constitutes a relapse in CLL?
The reason for the watch and wait approach is that CLL is generally thought to be incurable. Treatments are usually aimed at controlling the disease and managing its symptoms (palliative) not at curing the disease (curative). Over time, most treatments lose their efficacy, and for this reason, it is generally agreed that treatment should not begin until it is necessary to control the symptoms of the disease. Even escalating lymphocyte counts often do not mandate treatment.
The decision to begin treatment is an important juncture in the CLL journey. As a general rule, one doesn’t want to start treatment too early or wait too long. Selecting the right time to begin treatment and the type of treatment are very important decisions. Some patients prefer to leave these decisions entirely in the hands of their physicians, while others prefer to take an active role in determining both the timing and the selection of their treatments.
Following is a general outline of the types of treatments used in the various stages of CLL (see also: What are the stages of CLL?): Stage 0 (elevated lymphocyte counts only) – Treatment is generally not needed.
Stage 1 (elevated lymphocyte counts and enlarged lymph nodes) – If the patient is without symptoms, treatment may still not be required. External radiation therapy to swollen lymph nodes and chemotherapy may also be considered.
Stage 2 (elevated lymphocytes, enlarged nodes, and liver or spleen enlargement) – If there are few or no symptoms, treatment may still not be required. Other possibilities at this stage include chemotherapy, external radiation to the spleen and/or lymph nodes, and clinical trials. (see also: What are clinical trials?)
Stage 3 (elevated lymphocytes and too few red blood cells; lymph nodes and liver or spleen may be enlarged) – Treatment at this stage may include any of the following: chemotherapy, external radiation to the spleen, surgery to remove the spleen (splenectomy), external radiation to the whole body (total body radiation), clinical trials of bone marrow transplantation, and clinical trials of biological therapy.
Stage 4 (elevated lymphocytes and too few platelets; lymph nodes, liver, or spleen may be enlarged, and there may be too few red blood cells) – The treatment options in stage 4 are much the same as stage 3.
Refractory CLL – Refractory means that the CLL initially or no longer responds favorably to treatment. The CLL may become refractory to a particular course of therapy in which case other therapies are used. If the CLL becomes refractory to all standard treatments, the patient’s treatment options will depend on many factors. Two options that may be available to consider include entering a clinical trial of new chemotherapy, biological response modifier, or monoclonal antibody drugs and bone marrow transplantation.
Chemotherapy – drugs, taken either orally or intravenously, are used to kill cancer cells. Chemotherapy is called a systemic treatment because it enters the bloodstream and travels throughout the body.
Radiation therapy – x-rays or other high-energy rays are used to kill cancer cells and shrink tumors.
Biological therapy – a type of therapy that tries to get the body to fight CLL. It uses substances made by the body or made in a laboratory to boost, direct, or restore the body’s natural defences against the disease. Biological therapy is also called biological response modifier (BRM) therapy or immunotherapy.
Surgery – in some cases, if the spleen is severely swollen and causing symptoms, it may be removed in an operation called a splenectomy.
Bone Marrow Transplantation (BMT) – there are two main types of bone marrow transplants: allogeneic and autologous. An allogeneic transplant uses healthy marrow taken from a donor whose tissue is the same as, or almost the same as, the patient’s. Donors are classified as matched related donors or matched unrelated donors (MUD). An autologous transplant uses marrow from the patient, which has been treated with drugs to destroy any cancer cells. The treated marrow is then frozen and stored until the patient is ready for transplantation.
In bone marrow transplantation, all of the bone marrow in the body is destroyed with high doses of chemotherapy and radiation therapy. An exception is the non-myeloablative or mini-transplant (see also: What is a mini-transplant?). Healthy marrow, either from a donor (allogeneic) or from the patient (autologous) is then given to the patient intravenously to replace the marrow that was destroyed. Transplantation of bone marrow involves potentially serious risks, and patients require the care of skilled medical staff and state-of-the-art support services. For this reason, BMT should be performed at established transplant centers wherever possible.
Supportive treatment – includes transfusion of packed red blood cells for anemia, platelet transfusions for bleeding associated with thrombocytopenia, and antibiotics for bacterial infections.
Drugs used in treating CLL are administered either as single agent therapies or as combination therapies. Most physicians agree that complete remissions are more likely with combination therapies than with single agents. The rationale to combination therapy is to use drugs that work at different parts of the cell’s metabolic processes, thereby increasing the likelihood that more cancer cells will be killed. In addition, the toxic side effects of chemotherapy may be reduced when drugs with different toxicities are combined; each at a lower dose than would be needed if one drug were used alone.
A number of drugs are used in the treatment of CLL. Following are examples of these drugs and the categories to which they belong. Where possible, the generic name is shown first followed, in parenthesis, by the trade name (capitalized) and any common names.
Alkylating agents – For many years, the standard first-line chemotherapy treatment for CLL has been the use of alkylating agents such as chlorambucil (Leukeran), cyclophosphamide (Cytoxan), and busulfan (Myleran).
Corticosteroids – Corticosteroids, such as prednisone (Deltasone), are generally used in conjunction with other drugs such as chlorambucil. They have also been evaluated as single agent therapies. When used as single agents, decreases in node, liver, and spleen enlargement commonly occur, but complete responses are rare.
Purine analogues – Perhaps best known in this category is the drug fludarabine phosphate (Fludara, FAMP). Historically, fludarabine has been used primarily as a second-line therapy, after the initially used alkylating agent (chlorambucil or cyclophosphamide) stopped showing a satisfactory response. More recently, based on impressive test results, fludarabine has gained significant ground as a first line therapy, particularly in the US. Examples of other purine analogues used in the treatment of CLL are cladribine (Leustatin, 2-chlorodeoxyadenosine, 2CdA), pentostatin (Nipent, 2-deoxycoformycin), and compound 506U78 (AraG).
Antitumor antibiotics – These drugs are antibiotic chemotherapy agents, as opposed to antibiotics that work against bacteria. Antiluekemic chemotherapy agents in this category include drugs such as doxorubicin (Adriamycin) and mitoxantrone (Novantrone).
Monoclonal antibodies (Mab or MoAb) – Monoclonal antibodies are another method of treatment that, on theoretical grounds, promises to improve our ability to control CLL. One example is alemtuzumab (Campath-1H), an anti-CD52 monoclonal antibody that is toxic to all lymphocytes and which may be effective in producing remissions in patients who have failed prior therapies, including fludarabine. Another monoclonal antibody is rituximab (Rituxan, IDEC-C2B8), which is active against cells expressing CD20. Rituximab is also in clinical studies currently in conjunction with fludarabine and cyclophosphamide. Zevalin, a 90Y labelled anti-CD20 monoclonal antibody, is the radioactive form of rituximab. Tositumomabiodine (Bexxar) is another radioactive anti-CD20 monoclonal antibody. It is combined with radioactive iodine 131, which delivers lethal radioactivity to cancer cells and also flags them for destruction by the immune system.
Growth Factors and Cytokines – Growth factors are used to stimulate the production of different types of blood cells. Filgrastim (Neupogen, G-CSF), a granulocyte stimulating factor, epoitin alfa (Epogen, Procrit), a red cell stimulating factor, and thrombopoeitin, a platelet stimulating factor are examples of growth factors.
The following table summarizes many of the drugs that are used in the treatment of CLL, some of which are still in clinical trials and not yet approved for general use:
|Generic Name||Trade Name||Also Called||Type of Drug|
|aldesleukin||Proleukin||Interleukin 2||biological response modifier|
|epoitin alfa||Epogen, Procrit||erythropoitin||growth factor|
|fludarabine phosphate||Fludara||FAMP||purine antimetabolite|
|oblimersen||Genasense||bcl-2 antisense||bcl-2 inhibitor|
|tositumomab||Bexxar||Iodine 131||investigational radioimmunotherapy|
|vincristine sulfate||Oncovin||vincristine||plant alkaloid|
- What drugs will be used?
- What are the goals of this treatment?
- When will treatments begin? How often will they be administered? When will they end?
- Will they be administered on an outpatient basis?
- How will we know if the drugs are working?
- What side effects should I expect during treatment? How long do the side effects last? What can be done to manage them?
- Can these drugs cause side effects later on?
- Will they in any way affect or limit future treatment options?
Anticancer drugs generally affect dividing cells. Because cancer cells divide more often than healthy cells, they are more likely to be affected by chemotherapy. However, healthy cells that divide often may also be damaged by chemotherapy. Cells in this category include blood cells, cells in hair roots, and cells in the digestive tract.
When chemotherapy affects healthy cells, side effects may include, lowered resistance to infection, a tendency to bleed more easily, fatigue, nausea, loss of hair, vomiting, and mouth sores. Most side effects disappear gradually during the recovery periods between treatments or after treatment stops. Some anticancer drugs can also affect fertility, and these changes may be permanent. Patients are advised to ask about side effects prior to treatment. (see also: What questions should I ask prior to chemotherapy?)
There are two main types of transplants. Autologous transplantation uses the patient's own bone marrow or stem cells. After the cells are removed from the patient, they may be treated in an attempt to remove leukemic cells—a process called purging—and are then given back to the patient. Allogeneic transplantation uses bone marrow or stem cells collected from a matched donor who may be related or unrelated to the patient.
The advantage of autologous transplantation is the opportunity to achieve remission without the risk of graft-versus-host disease (GVHD). Approximately eighty percent of autologous transplant patients achieve complete remissions. The disadvantage centers on the possibility that leukemic cells will be given back to the patient. The relapse rate with autologous transplantation is approximately 50 percent four years after transplant, and overall survival at the four year mark is between 50 and 80 percent. Unfortunately, there is no plateau in disease-free survival curves which, coupled with the high relapse rate, suggests that autologous transplantation does not cure CLL. Patients with disease that is sensitive to treatment and who are transplanted while in complete remission usually achieve the best outcomes.
Allogeneic transplantation offers the possibility of long-term control and perhaps even cure. Two types of allogeneic transplants are used in CLL: standard and non-myeloablative. The latter is the so-called mini transplant procedure. In both procedures, the donor cells given to the patient are totally free of leukemia. The disadvantage of allogeneic transplantation is that the donated cells may attack the patient's body, which is called graft-versus-host disease (GVHD). Ideally, the donor cells will come from a matched related donor—usually a sibling. If this is not possible, cells from a matched unrelated donor (MUD) can be used. Standard MUD transplants carry the greatest risk of all the transplant procedures with a three in ten chance the patient will die from the procedure itself. Treatment related mortality (TRM) in non-myeloablative transplants is somewhat lower. With allogeneic transplants the relapse rate ranges from 10 to 25 percent, and there is a plateau in disease-free survival curves, which suggests that a fraction of patients is cured with this procedure.
Transplant is usually considered only for patients with progressive disease who are running out of other treatment options and therefore have a poor prognosis. When the risk of CLL becomes greater than that of transplantation, the transplant option comes into consideration.
Age is also a factor when considering transplant. Younger patients tend to want, and are often able to better withstand, aggressive treatment. In some cases, aggressive treatment also seems to be more effective in younger patients. Older patients frequently don't want aggressive therapy, because they don't want to go through all of the potential side effects. The ability to rebound from high dosage chemotherapy also diminishes with age, and the risk of graft-versus-host disease is well established to increase with advancing years. As a rule of thumb, allogeneic transplantation becomes less of an option after a patient reaches 60 years of age, and autologous transplantation is usually ruled out after 65 years of age. However, it is important to note that there are some 65 year olds who are otherwise very fit and healthy and could be candidates for transplant, while there are some 45 year olds who would not survive the procedure. The overall fitness of the patient is therefore somewhat of an overriding factor in determining the age-limit for transplant.
Transplant should not be considered or undertaken too early in the disease when the patient may have many more quality years of life with or without treatment. Similarly, it is important not to wait until the patient has already failed all other forms of treatment. In the latter situation, it is very difficult to perform a bone marrow transplant and achieve a good result. In summary, there is a window of time during the course of CLL when transplant makes the most sense to consider.
Patients who are considering transplant are encouraged to seek institutions and physicians that are performing this procedure in conjunction with CLL research. If this is not possible, patients are urged to find facilities that are experienced in transplants and have the skilled staff and state-of-the-art support services required to undertake this procedure.
For autologous transplantation to be successful, the patient’s marrow must be relatively free of disease when it is harvested. By the time CLL is diagnosed, the percentage of leukemic cells in the marrow is generally higher than is acceptable for the harvest procedure. For this reason stem cells are usually not harvested until after treatment begins and a remission is achieved. Some treatment centers feel that the best time to perform the harvest is at the first or second treatment induced remission.
The decision on whether or not to harvest and store cells will depend on several factors including the overall treatment strategy that has been agreed to with the patient and the ability to achieve a treatment induced remission that eliminates sufficient disease to perform the harvest procedure.
Another consideration is that most institutions doing bone marrow transplants do not have sufficient storage facilities for long-term cell storage, and that overrides all other considerations at many cancer centers.
In a standard allogeneic transplant, the patient is given high-dose chemotherapy or radiotherapy or a combination of the two. The goal of this preparative regimen is to totally destroy the patient’s bone marrow in an attempt to eliminate all leukemic cells and to suppress the patient’s immune system sufficiently to allow engraftment.
In a mini-transplant, however, the patient is given just enough chemotherapy to allow the donor's bone marrow or stem cells to engraft in the patient. If all goes as planned the T-cells from the donor will then recognize the patient’s leukemic cells as foreign, and they will mount a response against the leukemic cells. This is called the graft-versus-leukemia effect.
The risks in a mini-transplant are certainly less than in a standard allogeneic transplant; however, the risk of developing chronic graft-versus-host disease is still very significant. For this reason, the mini-transplant is certainly not a minor undertaking as its name might suggest. Indeed, it should be viewed as potentially having the same frequency of long-term complications as a standard allogeneic transplant.
Umbilical cord blood transplantation (UCBT) has several potential advantages. Perhaps the main advantage is decreased incidence of graft-versus-host disease (GVHD), which is attributable to decreased functionality of fetal lymphocytes. This decreased functionality also enables transplants to be undertaken with a lesser degree of HLA matching. The use of cord blood also expands the size of the potential donor pool and enhances the speed of finding suitable matches. The potential for viral contamination such as cytomegalovirus is also sharply reduced, and the limitations of cross-racial matching can be largely overcome with UCBT. Potential disadvantages of UCBT include possible transmission of genetic diseases that are clinically unapparent at birth. Maternal contamination of umbilical cord blood, while unlikely, is also a potential risk that could cause severe and even fatal graft-versus-host disease.
The availability of umbilical cord blood transplantation has raised many ethical questions that revolve around issues such as ownership, privacy, and allocation of limited resources. Patients who wish to learn more about the status and availability of umbilical cord blood transplantation are encouraged to discuss this possibility with their hematologists.
Leukapheresis can reduce the circulating white count rapidly, efficiently, and safely, in CLL patients. The question is whether such a procedure will provide the patient with short-term and/or long-term benefits. In a study of 59 CLL patients treated with therapeutic leukapheresis, reduction in elevated lymphocyte counts (lymphocytosis), swollen lymph nodes (lymphadenopathy), and swelling of the liver and spleen (hepatosplenomegaly) was noted in 50-60% of the patients studied.
Despite its ability to reduce circulating white counts, leukapheresis is not standard therapy for CLL. It is very expensive, and it usually has to be repeated every one to three weeks, or longer. Patients seeking additional information on the use of leukapheresis in the treatment of CLL should consult their hematologists.
We all need vitamin C to live. The question then is, what amount of vitamin C is appropriate for people with CLL? The consensus seems to be, stick with recommended daily allowances, and do not go too high above that.
If neutrophil counts drop to near or below 1000, patients should be on a neutropenic diet and should be in close touch with their hematologists. Following are examples of foods that must be avoided when on a neutropenic diet:
- Raw nuts, vegetables, and salads
- Apples, peaches, grapes, plums, nectarines, kiwi, strawberries, and other uncooked thin-skinned fruits
- Self-serve buffets, salad bars, and deli foods
- Cheeses such as feta, brie, camembert, blue, etc.
- Raw or rare meats, fish, and poultry
- Commercially prepared potato or macaroni salad
- Raw, un-pasteurized milk and eggnog or milkshakes made with raw eggs
- Bakery breads, muffins, cakes donuts, and cream or custard filled cakes
In addition to the selection of appropriate foods, extra care is important in food preparation. Food preparers must wash their hands frequently in warm soapy water, especially if handling raw meat, chicken, eggs, and fish. Counter tops, cutting boards, and cooking utensils should also be washed with hot soapy water after they have come in contact with food.
Additional information on food preparation and foods that are safe for patients with neutropenia can be found on-line at www.acor.org/leukemia/neutro.html.
- Dana Farber Cancer Institute – Boston, Massachusetts (DFCI)
- Fred Hutchinson Cancer Research Center – Seattle, Washington (The Hutch)
- Johns Hopkins Medical Center – Baltimore, Maryland (JH)
- Long Island Jewish Hospital – New Hyde Park, New York
- Mayo Clinic – Rochester, Minnesota
- Memorial Sloan Kettering Cancer Center – New York, New York (MSKCC)
- M. D. Anderson Cancer Center – Houston, Texas (MDACC)
- Ohio State University Cancer Center – Columbus, Ohio
- Royal Marsden – London, England
- Stanford Medical Center – Stanford, California
- The Burnham Institute – La Jolla, California
- Thomas Jefferson University – Kimmel Cancer Institute – Philadelphia, PA
- University of California, San Diego – UCSD Cancer Center – La Jolla, California
- University of Michigan Cancer Center – Ann Arbor, Michigan
- Walter Reed Army Medical Center – Hematology/Oncology Service – Washington D.C.
A more complete list of cancer centers can be found at www.acor.org/leukemia.
Patients who are considering participation in a clinical trial are encouraged to ask for a copy of the full protocol—the document that describes the clinical trial in detail. Consent to participate in a trial should only be given after reviewing the full protocol and considering all other relevant clinical trials for which the patient might by eligible.
Most clinical research that involves the testing of new drugs progresses in an orderly series of steps. Cancer clinical trials generally follow three phases:
Phase I Trials - evaluate how a new drug should be administered (orally, intravenously, or by injection), how often, and in what dosage. A Phase I trial usually only enrolls a small number of patients.
Phase II Trails - provide preliminary information about how well the new drug works and generate more information about safety and benefit. Each Phase II study usually focuses on a particular type of cancer.
Phase III Trials - compare a promising new drug, combination of drugs, or procedure with the current standard. Phase III trials typically involve large numbers of people nation-wide. If you participate in a Phase III treatment trial, you are likely to be randomized (assigned by chance) to a group receiving either the new treatment or the standard treatment. The reason the clinical trial has been initiated is that the superiority of one treatment over the other has not yet been firmly established.
In the United States, one way to learn more about clinical trials is through PDQ, a computerized resource developed by the National Cancer Institute. PDQ contains information about cancer treatment and about clinical trials throughout the US. Cancer Information Service offices (1-800-4-CANCER) provide PDQ searches to callers and can tell physicians how to obtain regular access to the database. Information can also be found at www.cancer.gov/clinicaltrials. Another way to find out about clinical trials is to ask your hematologist how you can obtain information on trials in your area.
According to the National Cancer Institute-sponsored Working Group (NCI-WG) on Chronic Lymphocytic Leukemia, complete remission requires all of the following criteria as assessed at least 2 months after completion of therapy:
- Absence of enlarged lymph nodes.
- Absence of enlarged spleen and liver.
- Absence of constitutional symptoms
- A normal complete blood count (CBC) as exhibited by:
- lymphocytes less than 4,000 per microliter of blood
- neutrophils greater than or equal to 1,500 per microliter of blood
- platelets greater than 100,000 per microliter of blood
- hemoglobin greater than 11 grams per 100 milliliters of blood (untransfused).
- A bone marrow aspirate and biopsy should be performed at least 2 months after the last treatment and after all of the above requirements have been met. The marrow sample must be at least normocellular for age with less than 30% of nucleated cells that are lymphocytes, and lymphoid nodules should be absent.
Partial Remission (PR)
A partial remission requires that the patient exhibit the following features for a period of at least two months:
- A fifty percent or greater decrease in the peripheral lymphocyte count from the value before therapy.
- A fifty percent or greater reduction in lymphadenopathy and/or
- A fifty percent or greater reduction in the size of the liver and/or spleen (if abnormal prior to therapy).
In addition to the factors outlined above, the patient must also exhibit one or more of the following:
- Neutrophils greater than or equal to 1,500 per microliter of blood or a fifty percent improvement over the pre-treatment baseline without need for external growth factors.
- Platelets greater than 100,000 per microliter of blood or a fifty percent improvement over baseline without need for external growth factors.
- Hemoglobin greater than 11 grams per 100 milliliters of blood or a fifty percent improvement over baseline without transfusions or erythropoietin.
When complete remissions are achieved, physicians can order tests for MRD using two techniques: polymerase chain reaction (PCR) or flow cytometry. Each of these techniques offers low-sensitivity tests, which are capable of detecting the presence of one CLL cell in 200 to 500 cells and high sensitivity tests, which are capable of detecting as little as one CLL cell in 100,000 cells. The low-sensitivity tests are called consensus primer PCR and CD5/CD19 flow cytometry while the high-sensitivity tests are called allele-specific PCR (ASO PCR) and MRD flow cytometry.
When minimal residual disease is present, it is predictive of a shorter event-free period of remission. For this reason, some physicians will attempt to intensify complete remissions by treating residual disease with drugs like rituximab (Rituxan) and alemtuzumab (Campath-1H).
Patients are defined as having complete remissions without minimal residual disease when they have less than one CLL cell per 10,000 white blood cells. Complete remissions without the presence of minimal residual disease—sometimes called molecular remissions—are thought to be the most durable remissions.
- Appearance of new or enlarged lymph nodes.
- A 50 % increase in previously noted liver or spleen enlargement or enlargement where there was none previously present.
- A 50% increase in absolute lymphocyte count with at least 5,000 lymphocytes per microliter of blood.
- Transformation to a more aggressive situation such as Richter’s Syndrome.
- Occurrence of low levels (cytopenia) of neutrophils, platelets, and/or red blood cells which are attributable to CLL.
Patients who have relapsed are considered to have progressive disease.