After being first treated for chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma(SLL), 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 computer tomography (CT) 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/SLL 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 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/SLL is still under investigation. However, the FDA has approved three immunotherapies (rituximab, ofatumumab and alemtuzumab) for relapsed or refractory CLL/SLL.
Also, as described earlier, a procedure called bone marrow (stem cell) transplantation is another second line treatment for CLL/SLL, depending on the patient’s age and condition.
Specific Treatments Options
R-CHOP is the combination of the monoclonal antibody known as rituximab, administered with the combination chemotherapy known as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone); CHOP has been used since the 1970’s to treat many forms of lymphoma. Sometimes COP is used, without doxorubicin. CHOP is often used for CLL/SLL 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, 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 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/SLL 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/SLL, 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)