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Latest Research and Promising DevelopmentsPrognostic Indicators Although this section may be slightly repetitive with other material posted on this site, it warrants special attention. The course of CLL can vary to a great degree, with survival ranging from months to decades for different individuals. Methods that can help to predict the potential aggressiveness of CLL are sometimes influencing the standard approach to therapy. Prognostic IndicatorsUsing the growing number of biomarkers (prognostics) that can help to predict for aggressive forms of CLL, hematologists are now better able to gauge what clinical course the disease will take. The information can then be applied to treatment decisions. A risk-stratified approach to selecting from the available treatment options (e.g., higher risk disease may benefit from earlier and more aggressive treatment) may now be applied, even occasionally through entrance into clinical trials. Many clinical trials are exploring the potential benefit of using aggressive treatment strategies for when biomarkers indicate the presence of a potentially aggressive form of CLL. However, it is important to state that it is still not known whether there is any benefit to initiating treatment before the onset of symptoms or the classical indicators, according to the NCI working group guidelines. The Rai classification system is still very much used in determining the need for treatment. The survival curves generated by prognostic indicators are still only useful for describing how a population of patients will do, not how one individual will do. Some patients with good prognostic markers will progress before many of those with poor prognostic markers. The prognostic markers, however, appear to have an increasing place in determining the timing of treatment. The most significant will be a forthcoming clinical trial attempting to determine whether there is a benefit of immediate treatment instead of deferred treatment in patients with undulated immunoglobulin genes. One might ask, however, what the purpose is of knowing one's prognostic indicators, with the exception of helping in making early treatment decisions at diagnosis. Consider the impact that some of this questionably useful knowledge might have on a patient's state of mind. Or, consider the effect on a patient's thinking if he/she is told that, after finishing a treatment, he/she has not reached what is known as "molecular remission". This is determined by a so-called PCR (polymerase chain reaction) test. Since this knowledge would change nothing, some would rather not know, assume the treatment was successful, and wait and see. Nevertheless, for the sake of completeness, let us continue with a review of genetic abnormalities that warn of a poorer outcome in CLL. The prognostic markers of greatest importance are: Rai stage, IgVH (immunoglobulin gene heavy chain) mutation status, interphase FISH (iFISH), ZAP-70 status, and CD38 status. The hierarchy of prognosis indicated by each factor is as follows:
One of the above consists of a deletion of 17p13, which corresponds to loss of the p53 tumor suppressor gene, and another of deletion of 11q22-23, which results in loss of the so-called ATM tumor suppressor gene. The prognosis associated with an un-mutated immunoglobulin variable heavy chain (IgVH) region is poorer than the prognosis for a mutated IgVH. As described in another section, determining IgVH mutational status is difficult, if not impossible, for the practicing community oncologist. Surrogate markers of IgVH mutational status, such as CD38 and ZAP-70, have made it easier to test for the mutated status and tailor treatment according to the absence or presence of the mutation. Monoclonal TherapyWith the introduction of monoclonal antibody therapies, such as rituximab (Rituxan®) and alemtuzumab (Campath®), therapy for patients with previously treated and relapsed CLL has undergone a revolutionary transformation over the past decade. While these antibodies have activity as single agents, additional therapeutic benefit has been observed when they are used in combination with chemotherapeutic agents such as fludarabine. Combination therapies such as FR (fludarabine/rituximab), FR followed by alemtuzumab, FA (fludarabine/alemtuzumab), FCR (fludarabine/cyclophosphamide/rituximab) and FCA (fludarabine/cyclophosphamide/alemtuzumab) are all the subject of investigations because of the potential for extending survival. New monoclonal antibodies being developed include HuMax-CD20, Hu1D10, and hLL1 among others. HuMax-CD20 is the furthest along in development. HuMax-CD20 binds to the CD20 protein like rituximab, but at a different site. HuMax-CD20 is thought to possibly be able to more actively recruit the immune system to attack the CLL cells as well as induce CLL cell death. HuMax-CD20 is also a human antibody (generated in a mouse with a human immune system), whereas rituximab is a chimeric (half mouse-half human). TransplantationStem cell transplantation is another therapy being investigated for CLL. Traditional conditioning regimens (e.g., high-dose chemotherapy or radiation) - used to clear the bone marrow of all blood cells (myeoloablation) so that new healthy cells can be implanted - are toxic. The elimination of all immune system cells places the transplant recipient at a risk for infection. These factors limit the ability to perform stem cell transplantation in many people, especially the elderly. Stem cells transplants may be a treatment option when an aggressive form of the disease occurs in a young person. Two types of stem cells transplants are performed. An autologous stem cell transplant uses a person’s own blood stem cells, collected from the bloodstream or bone marrow. Once the stem cells are collected, the patient receives high doses to treatment that will hopefully eliminate all of the CLL cells. This amount of treatment will also eliminate the normal bone marrow cells. This is why normal blood stem cells are collected before hand. They are re-infused and repopulate the bone marrow. The problem with autologous transplants is that the disease cells may not be completely killed by the treatment, or even re-infused with the blood stem cells, keeping the treatment from being curative. Autologous transplantation has not been used with much success in CLL/SLL. Allogeneic stem cell transplantation is still the only potentially curative therapy for CLL. Allogeneic transplants use blood stem cells from another person. This could be a sibling or an unrelated person whose cells match the recipient. Ten different proteins (HLA proteins) are typically matched between donors. The safety of the transplant is in part determined by the number of proteins that match. Usually only when nine or ten proteins match is a transplant performed. The allogeneic transplant relies more on the donor’s immune system to attack the CLL than the preparative regimen to kill off the CLL cells. This process is not without risk. The toxicities of the allogeneic transplant are primarily seen as infection and graft versus host disease (GVHD). The infection risk is related to having low blood counts while the immune system is being regenerated and from the immunosuppressive medication that patients need to stay on to prevent GVHD. GVHD results from the donor immune cells attacking the patients cells because they are seen as foreign by the donated cells. A little GVHD is good as it can help control the CLL. Too much could result in severe damage to other organs, including liver, lung, skin, and GI tract. A major advance in reducing the risks associated with stem cell transplantation has been the introduction of non-myeloablative, or reduced intensity conditioning, prior to transplant, regimens. Reduced intensity conditioning regimens appear to be associated with a decreased mortality after allogeneic transplantation, and allow transplantation in those who are older, making this approach applicable to an increased number of CLL cases. Reduced intensity conditioning regimens, called mini-transplants, sometimes include fludarabine to exploit the immunosuppressive as well as anti-leukemic properties of this agent. Stem cell transplantation using reduced-intensity conditioning also has potential to be a promising treatment for aggressive CLL. VaccinesVaccination has been an area of investigation in lymphomas for a while. An idiotypic vaccine was developed for follicular lymphoma some time ago. What this means is that, after chemotherapy to decrease the degree of illness in a patient, material is taken from a tumor of the patient (hence “idiotypic”), and a vaccine responding specifically to the antigens in that tumor is developed. The process takes several months, and the patient is then injected with this vaccine in the hope that the immune system will react strongly and mount a strong immune response, killing diseased cells. One pharmaceutical company has started a trial in an effort to develop such a procedure for CLL/SLL patients. There are no results available yet, the trial is underway. Further research is needed to determine the effectiveness of this treatment for CLL. Other vaccine developments are underway, particularly not “idiotypic” vaccines, which could be developed for the CLL population at large. AntisenseAntisense is a potentially very interesting therapy. The beginnings occurred in England well over a decade ago. The idea is to identify some component in the genome responsible for, or for making worse, a patient’s illness. Once one of these “bad guys”, usually a particular gene, is identified, antisense therapy attempts to introduce into the patient’s system, particularly into his RNA (called “messenger DNA”, i.e. into his genetic system) a protein molecule which gives a message to the particular “culprit” to stand down. A drug call Genasense is currently in trial. This drug targets the bcl-2 gene, which plays a role in cell death. Too much of the bcl-2 gene prevents cell death of cancerous cells, and so this therapy attempts to down-regulate the effects of bcl-2. Although some success has been achieved, further research is needed. Antisense is the first approach attempting to treat lymphomas by adjusting genetic components causing the illness, a potentially powerful approach. back to top |
