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Treatment OptionsTreatment Options for Newly Diagnosed Patients Treatment Options for Newly Diagnosed PatientsIndividuals diagnosed with CLL can have very different experiences and rates of disease progression. For many, the disease may progress slowly, while others will have a more aggressive course. There is also the possibility of developing complications related to autoimmunity or immunodeficiency, which are not related to disease progress. The current strategy involves deferring therapy until it is required. Thus, treatment often does not always immediately follow diagnosis. A strategy known as ‘watch and wait' is an option when managing the disease. The reason a doctor may advise observation or ‘watch and wait’ is that, while the disease is progressing slowly, there are no studies that have shown that treatment administered early, while the patient is without symptoms, provides a benefit for the patient or an increased survival. Some people with CLL remain without symptoms for many years. This strategy might seem counterintuitive. One might wonder why it is not better to treat when there are fewer sick cells around. The thing to remember is that treatment affects normal cells as well as cancer cells. Thus, there are advantages to limiting how much treatment a patient receives, especially early on. The monitoring of a person’s blood counts and routine physical examinations are very important elements of disease management during the watch and wait period. Treatment is usually recommended when a person:
People with CLL is advised to talk with a doctor about whether their symptoms require treatment, balancing the benefits of treatment with side effects associated with the available treatments. Recent advances in the understanding of certain genetic mutations and expressions and status of certain genes have some of the medical community (physicians and researchers) re-evaluating the ‘watch and wait’ policy. The healthcare community needs to determine whether earlier treatment would be of benefit to those patients with poor prognostic markers. Someone with poor chromosomal and genetic prognostic indicators may wish to discuss their options for the early treatment of their disease with their doctor. It is important to remember that even when comparing the survival curves for a bad prognostic marker versus a good one, the curves always overlap, and physicians do not know where an individual will be on the curve.
Types of Active Treatments for CLL The treatment options available to a person diagnosed with CLL include: chemotherapy, biologic therapy, radiation, stem cell transplantation, and most recently, vaccination. Chemotherapy is the treatment of cancer with medication that circulates throughout the body. This treatment is especially helpful when the cancer in question is not localized to one organ of the body, as is the case with CLL. Two types of chemotherapy are most used in the treatment of CLL. These can be separated into two chemical groups known as nucleoside analogues and alkylating agents. The terms nucleoside and alkylating refer to the chemical structure of the compounds being used as chemotherapy. Both nucleoside analogues and alkylating agents attack cancerous cells, but are only partially selective in the process. They also attack other types of cells in the body and cause side effects. Side effects could be damage to the bone marrow, which produces normal cells, and as a result may include low white counts, decreased red blood cell counts, or also reduced platelet counts. These side effects are all called 'penias', referring to "low." These "penias" include:
You may hear your physician refer to these "penias" when you have a "complete blood count." Looking at these "penias" will help to carefully monitor the side effects of chemotherapy. Many medications exist to help you with these side effects (see "side effects of treatment" below). The different chemotherapies used in the treatment of CLL are listed below. Nucleoside (Purine) Analogues One of the first drugs a person with CLL may receive is called fludarabine. Other nucleoside analogues, including pentostatin and cladribine are also sometimes used, although fludarabine is used more commonly. These are administered through an intravenous injection. They are listed below including their other common names:
Alkylating Agents Some alkylating agents available for the treatment of CLL can be given orally, while cyclophosphamide may also be administered intravenously. Other agents are occasionally tried. Prednisone (available under many brand names) is a type of oral corticosteroid (a potent hormone) that is often given together with chlorambucil or cyclophosphamide. They are listed below including their other common names:
Combination Therapy In the past, patients were initially treated with either fludarabine alone or chlorambucil/prednisone and later switched to an alternative regimen if the initial treatment did not produce sufficient benefit. Current studies are showing that using several drugs together (combining fludarabine and cyclophosphamide) might be more effective. Biologic therapy is the use of substances (made by the body or created in a laboratory) that are part of or stimulate the body's immune system to fight the cancer. This may be called immunotherapy. Monoclonal antibodies (MoABs) are produced to target certain receptors on the cancerous cells (antigens), and to destroy the cell. When a Y-shaped antibody attaches to such a target, it either alerts other cells of the immune system to destroy the cell, or its presence prompts the cell to die. In the 1980's it became possible to genetically engineer antibodies to target a specific antigen and this eventually lead to the development of a new class of therapies. Two monoclonal antibody therapies are currently available for the treatment of CLL: Alemtuzumab (Campath-1H, MabCampath) Alemtuzumab (Campath-1H) is a monoclonal antibody that has been approved by the U.S. Food and Drug Administration (FDA) for use in patients with advanced CLL who are no longer responding to other treatments. The antibody can be given either intravenously (through the vein) or subcutaneously (under the skin). It targets the antigen known as CD52. (CDs, ‘clusters of differentiation’, are antigens on the surface of cells.) Every lymphoma (leukemia) cell has different sets of these CD antigens, and therefore targeted therapies can be developed. Clinical researchers are investigating whether there is a therapeutic benefit to using alemtuzumab following fludarabine as a first line therapy. Rituximab (Rituxan®) Rituximab is a monoclonal antibody that is administered intravenously and binds to a protein known as the CD20 found on the surface of B-cells. Rituximab has been found to be useful as a first line treatment for CLL in combination with chemotherapy, including F(fludara) C(cytoxan) R(rituxan), FR and P(pentostatin)CR. (There is now even an investigative protocol that uses rituximab in combination and follow up with alemtuzumab.) Radiation therapy is the use of high-energy x-rays or other particles to kill cancer cells. Radiation therapy is not used frequently in patients with CLL because the disease is spread throughout the body. Radiation therapy can, however, be very helpful in shrinking an enlarged spleen or swollen lymph nodes and eliminating symptoms that may be associated with such growths. Radiation also has side effects previously quoted, such as immune suppression and ‘penias.’ Too new to be of any value for CLL patients now, vaccines are in development which will take some material from the patient and develop a specific (to that patient) vaccination. The vaccine is then re-introduced into the patient, assisted by other chemical factors, in the hope of alerting and making the patient’s own immune system aggressive. This technique has been used to date with some success in other lymphomas, but CLL has unique problems that make using vaccines more difficult. Transplantation (the patient is the actual donor) has not been routinely used with CLL patients. It does have some possible merit with patients who have transformed into a more aggressive disease. A typical transplant procedure uses processes (chemotherapy and/or radiation) to ‘wipe out’ the cell system in a patient. In autologous transplant, the patient’s own cells are cleaned and re-introduced into the body. In allogeneic transplants, the patient receives a healthy product from a relative or a non-related matched donor. Both procedures carry considerable risk. In the allogeneic situation, there is the danger of rejection and associated disease. Chemotherapy for CLL can cause nausea and vomiting, although these symptoms can generally be prevented with appropriate use of anti-emetic drugs. Talk to your doctor about these drugs. The more serious side effects involve decreases in normal blood counts which lead to an increased risk of infection, bleeding (due to decreased platelets), and fatigue. To manage these side effects, some patients need transfusions of red blood cells and platelets, or antibiotics to treat infections. Monoclonal antibodies are generally less toxic to the body than some of the other chemotherapies mentioned. This is because, as mentioned earlier, they target the leukemia cells as “guided missiles” and not the cells of the hair, skin, and stomach in the same way chemotherapy does. Decreases in blood counts following chemotherapy are sometimes more severe in patients with CLL than in other types of cancer because of the presence of CLL cells in the bone marrow, the place where new B-cells are made, may have already compromised normal cell production. Sometimes subcutaneous injections of white blood cell growth factors such as filgrastim (Neupogen), sargramostim (Leukine), or pegylated filgrastim (Neulasta) are used to increase the bone marrow production of normal white blood cells. Injections of epoetin (Procrit or Epogen) or darbepoetin (Aranesp) can be given to increase red blood cell production. The first administration of rituximab or alemtuzumab is sometimes accompanied by flu-like symptoms (e.g., chills, muscle aches). However, these side effects usually become less severe after the first treatment. Most side effects associated with the therapies can be effectively managed with medication. Rituxan maintenance may be associated with decreased immunoglobulin, often already reduced in CLL patients. Radiation treatment may cause fatigue, mild skin reactions, nausea, diarrhea, or constipation. Most side effects go away soon after treatment is finished. Treatment Options for Previously Treated CLL PatientsOverview of Treatment Options After being first treated for CLL, a majority of patients have a favorable response. Some have what is called a complete remission (CR) and others have a partial remission (PR). The standards for defining a CR or a PR are not totally clear, and are liable to subjective interpretation. No matter what the level of success of the initial treatment is, it is important for a person to attend routine follow up examinations. These visits enable the treating physician to monitor the level to which the may or may not be progressing. Of course, the length of time or duration of a response to therapy, the remission, can vary widely. In the interim the patient is generally placed back on “watch and wait.” Most hematologists will request follow up approximately every three months; some more, some less. If the disease is indolent (slow-growing) as much as a year can pass between visits. The re-visit will definitely include blood tests, a physical exam for swollen lymph nodes (lymphadenopathy) and enlarged liver and spleen. On occasion a scan may be requested. A CT (computer tomography) scan is most often used, although there is some radiation connected with it. An MRI (magnetic resonance imaging) scan can be used, but physicians claim less information can be obtained with this type of scan. These days the most popular is a combination PET (positron emission)/CT scan, which sometimes carries less radiation than a full CT scan, and is believed to be the most informative in identifying what is happening in the patient’s body. The persistence of obvious CLL following treatment is known as refractory (a cancer that is resistant to treatment) disease. In other words, the patient has shown to be “refractory” to the particular treatment just completed. A relapse is a more general term, meaning the return of the disease after some time. From a treatment perspective the difference between refractory disease and relapse is that refractory disease prompts the immediate consideration of a more aggressive treatment approach, while detection of relapse does not always mean that treatment is needed immediately. Also, in the event of a relapse, the doctor may try the original treatment a second time. A period of observation is usually advisable when disease has relapsed. Eventually, more of the same, another, or a more aggressive treatment may be required. A patient may wish to consider several factors with their physician such, as the level of relapse, the rate at which sick cells are increasing and the presence of symptoms, before deciding on a second line treatment strategy.
Second-line treatment options, or the second strategy employed to reduce the number of leukemic lymphocytes, may be more aggressive than first line. For example, if chemotherapy alone was used as a first line therapy, a combination chemotherapy and immunotherapy may constitute a more effective approach. The optimal application of monoclonal antibody therapies in previously untreated CLL is still under investigation. However, the FDA has approved two immunotherapies (rituximab and alemtuzumab) for relapsed or refractory CLL. Also, as described earlier, a procedure called bone marrow (stem cell) transplantation is another second line treatment for CLL, depending on the patient’s age and condition. Specific Treatments Options R-CHOP R-CHOP is the combination of the monoclonal antibody known as Rituximab, administered with the combination chemotherapy known as CHOP. CHOP is an acronym for the following:
This therapy (CHOP) has been used since the 1970’s on many lymphomas. It is still a reliable work horse. Sometimes COP is used, without doxorubicin. CHOP is often used for CLL patients who have transformed to a more aggressive lymph malignancy. Cyclophosphamide is an alkylating agent. Alkylating agents work directly on DNA to prevent the cancer cell from reproducing. Vincristine is a drug agent that interferes with the growth of cancer cells and can eventually destroy them. Doxorubicin is an antibiotic that can, however, cause a decrease in the number of blood cells in the bone marrow. Finally, Prednisone is a steroid and steroids are effective immune system suppressors. The monoclonal antibody therapy known as rituximab targets the CD-20 antigen (see earlier section), or a molecule that can be found on the surface of B-cells. When an antibody binds to an antigen it prompts destruction of the cell through a variety of mechanisms such as alerting the immune system to the presence of a diseased cell or setting in motion the diseased cell’s own process known as apoptosis or cell death. Rituximab can clear away additional diseased cells not eliminated by CHOP, and aid in the identification of sick cells. Alemtuzumab (Campath)
Alemtuzumab is a therapeutic monoclonal antibody that targets the CD52 antigen which is found on the surface of both malignant and non-malignant B and T-lymphocytes. Once the antibody binds to the CD52 antigen, it prompts destruction of the cell through a variety of immune system mechanisms. Alemtuzumab can prompt the elimination or death of malignant lymphocytes from the blood, spleen, and, most importantly, the bone marrow. Although it has some effect in removing malignant lymphocytes that have accumulated in the lymph nodes and extra nodal masses, its most important action is clearing the bone marrow of diseased cells, thus allowing the body to replenish the blood cell supply.
Occasionally different nucleosides may be tried, as some cross resistance may have developed.
Other Useful Approaches
It is also important to check whether additional genetic or chromosomal transformations have occurred, such as the p17 transformation mentioned earlier.
The ever expanding field of knowledge regarding treatment of relapsed CLL offers much hope. One strong possibility is to become enrolled in a clinical trial. These are ongoing, and can be found by going to www.clinicaltrials.gov where most trials are listed and described. Technology and knowledge are advancing so rapidly that this might be the best approach for a patient in trouble.
Secondly, depending on the cancer center with which you are working, new approaches, beyond clinical trials, may already be available. Sometimes a doctor may favor a particular approach and, although the FDA may not have approved the special drug for treatment of relapsed CLL, it may be obtainable on the basis of what is called “compassionate use.”
The CIG website also provides information about CLL/SLL and upcoming educational programs. |
