Treatment Options
What You Should Know Before Starting Treatment
Treatment Options for Newly Diagnosed Patients
Treatment Options for Previously Treated CLL Patients
Prognostic Factors
Glossary of Medical Terms and Acronyms
What You Should Know Before Starting Treatment
Getting a CLL diagnosis is frightening and patients are naturally concerned about what their future may hold. Oftentimes, patients will ask their physician about their outlook or prognosis, the medical term used to describe how the disease will progress and the likelihood of recovery. To be an educated healthcare consumer, it is important to understand the nature of CLL and what to expect from treatments, including any possible effects on quality of life, such as lifestyle, emotions and financial issues.
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Treatment Options for Newly Diagnosed Patients
Individuals 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.
Watch and Wait
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:
- is classified as Stage III or IV in the Rai classification system
- develops symptomatic lymphadenopathy (swollen nodes)
- develops so called B-symptoms (night sweats, low grade fevers, extreme fatigue)
- has a doubling time of white count of less than six months
- develops autoimmune findings (anemia – low red counts; thrombocytopenia – low platelets)
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
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:
Alkylating Agents:
- Chlorambucil (Leukeran)
- Cyclophosphamide (Cytoxan, Neosar)
- Bendamustine (Treanda) - Bendamustine (Treanda) is a novel alkylating agent that damages the DNA in tumor cells, thereby disrupting the cell cycle and causing cell death. Approved originally for clinical use in Germany for cancer, the US FDA approved bendamustine in 2008 for the treatment of indolent B-cell NHL that has progressed during or within six months of receiving rituximab (Rituxan) or a rituximab-containing regimen. It has also been approved to treat CLL.
Cortisteroids:
- prednisone
- solumedrole
- dexamethasone
View Common Types of Drugs Currently Available for the Treatment of CLL
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.
View Common Combination Drug Regimens Used to Treat CLL
Biologic or Immunotherapy
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.
Ofatumumab (Arzerra)
Ofatumumab (Arzerra) is another monoclonal antibody that targets the CD20 antigen, which is found on the surface of CLL cells. The FDA granted the accelerated approval of ofatumumab (Arzerra) for the treatment of patients with CLL whose disease is refractory to fludarabine (Fludara) and alemtuzumab (Campath) in fall 2009. Unlike other monoclonal antibodies, ofatumumab (Arzerra) binds to a specific part of the CD20 protein on the surface of cells called the small loop epitope. This drug kills cells by recruiting proteins called “complement,” that lead to cell death. It also induces antibody dependent cellular cytoxicity by recruiting the body’s natural killing cells to kill CLL cells. As this drug was just recently approved by the FDA, future editions of this book will provide more detail.
Rituximab (Rituxan)
Rituximab (Rituxan) is a monoclonal antibody that targets a protein called CD20, which is found on the surface of cancerous and normal B-cells. The drug has already received approval (as a single agent or in combination with specific chemotherapies) for certain people with follicular lymphoma, diffuse large B-cell lymphoma or slow-growing B-cell NHL. Rituximab (Rituxan) has already been approved in Europe for the frontline treatment of CLL. Rituximab (Rituxan) was approved by the FDA in combination with fludarabine and cyclophosphamide for patients with untreated or previously treated CD20-positive chronic lymphocytic leukemia on February 18, 2010. This treatment combination is referred to as FCR (fludarabine-cyclophosphamide-rituximab).
Radiation Therapy
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.’
Vaccine Therapy
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
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.
Side Effects of Treatment
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.
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Treatment Options for Previously Treated CLL Patients
Overview 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:
Cyclophosphamide(cytoxan),
Adriamycin (doxorubicin),
Vincristine (oncovin), and
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.”
Some common single-agent therapies currently used in the relapsed setting include:
- Alemtuzumab (Campath)
- Fludarabine (Fludara)
- Chlorambucil (Leukeran)
- Rituximab (Rituxan)
- Ofatumumab (Arzerra)
- Bendamustine (Treanda)
Some common combination treatment regimens used in the relapsed or refractory setting include:
- CVP (Cytoxan, Vincristine, Prednisone)
- FR (Fludarabine, rituximab)
- FCR (Fludarabine, Cytoxan, rituximab)
- R-CHOP (Rituximab, Cytoxan, Adriamycin, Vincristine, Prednisone)
- BR (Bendamustine and rituximab)
There are many novel therapies currently under clinical trial investigation in the relapsed/refractory setting and include:
- ABT-263 (an inhibitor of the Bcl-2 protein)
- Flavopiridol (a cyclin-dependent kinase inhibitor)
- Oblimersen sodium (Genasense)
- Lumiliximab (anti-CD23 antibody)
- Lenalidomide (Revlimid)
- TRU-016 (anti-CD37 protein)
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Prognostic Factors
The Role of Classical Predictive Factors in Deciding When to Treat
We will speak a great deal about the newly developing thinking utilizing “predictive factors.” However, doctors consulted in the writing of this report were unanimous in stating that, although they are aware of the new molecular prognostic factors, their decision to treat is still based on the clinical manifestations of the Rai Staging System, a classification developed decades ago.
Stage 0 Low Risk Lymphocytosis in blood and marrow only
Stage 1, 2 Intermediate Risk Lymphadenopahty (swollen nodes or spleen/liver)
Stage 3, 4 High Risk Anemia (low red counts), thrombocytopenia (low platelets)
Other classification methods take into account whether there is lymphadenopathy above and below the diaphragm, and which body organs may be involved. To arrive at proper staging, the doctor should consider blood results, biopsies, and body scans.
An important method of analysis, flow cytometry, is the measurement of so-called “clusters of differentiation,” antigens/proteins, called CDs. Cells carry these markers on their outer surface, and the type and strength of expression of these markers help doctors determine whether the disease is CLL. The markers classically characteristic of CLL are CD5, CD20, and CD23.
The Role of Novel/Molecular Diagnostics in Prognosis
Patients with CLL can have very different experiences before and after diagnosis. Some people may live for a long time without ever requiring therapy, while others may experience a rapid progression of their disease. The healthcare and research communities do not completely understand all the genetic changes present in cancerous cells. However, researchers have been able to identify and link the presence or absence of certain mutations (changes) to how the disease will behave. Techniques have been developed to examine the genes of cells and their possible mutational status.
In the last decade, impressive progress has been made in understanding the genetics of CLL through the development of new diagnostic tests for CLL. Investigators have identified mutations or measurable factors in the bloodstream thought to be of value in predicting how the disease will behave. Having found the same abnormalities in many CLL patients, and observing the course of their disease, scientists establish "prognostic factors." The ultimate value of new prognostic tests for determining treatment is not yet clear. Future and ongoing clinical trials are being conducted to determine whether patients at high risk for disease progression actually benefit from early treatment intervention. A person, for example, with early stage CLL that is demonstrating several unfavorable risk factors may wish to participate in clinical trials designed to measure the benefit of early treatment with chemotherapy in combination with immunotherapy.
FISH (fluorescent in-situ hybridization) is a new and useful technique for looking at chromosomal abnormalities, which reflect gene abnormalities. Chromosomes 11, 12, 13 and 17 are of particular interest. Of importance is the presence of the p53 gene, which has an effect on regulating cell death (apoptosis). Hematologists pay particular attention to aberrations (variations from the norm) in the 17th chromosome where the p53 gene is located, since the normal function of p53 is important for the response to chemotherapy.
IgVH
The mutational status of a gene known as IgVH helps predict how quickly a person with CLL might progress. Every B-cell rearranges its genes to make specific antibodies to a particular target (antigen) which, for instance, may be on a bacteria. When CLL is derived from cells that undergo the change to make antibodies (mutated genes), an individual will have a more indolent (slow-growing) course of disease. A person with un-mutated (unchanged) IgVH will likely have a more progressive and/or aggressive disease than those with the mutated gene.
ZAP-70
ZAP-70 is a substance involved with cell activation. Researchers have found that the leukemic cells that have ZAP-70 seem to progress faster than those leukemic cells that do not have ZAP-70.
CD-38
CD-38 is a protein antigen attached on the outside of leukemia cells. The presence of CD-38 suggests a faster progression, but scientists still do not completely understand why CD-38 plays a role in CLL.
Summary
As scientists continue to research how CLL occurs and progresses, they will continue to develop a better understanding of these factors. Many patients get very anxious about their “progression status” and worry about what this will mean and how long it will be before they need treatment. It is important to remember that at this time most hematologists/oncologists decide when to start treatment for CLL patients based on the clinical (classical) Rai staging, not novel/molecular prognostic factors. Treatment initiation is thus never based on these markers/factors, although they may impact how patients are ultimately treated.
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The CIG website also provides information about CLL/SLL and upcoming educational programs.
Subscribe to the related discussion group where frequent and interesting discussions do take place. Richard Furman, MD, a CLL expert from Weill Medical College of Cornell University and New York-Presbyterian, is active on this discussion group, so we have an important medical advisor on board.
