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Risk-adapted strategy shows promise in CLL

Posted Mar 24 2009 3:39pm

Mayo Clinic researchers have published a paper outlining a risk-adapted strategy to treating CLL. This is the first trial asking whether some patients with the disease are better served by taking chemotherapy soon after diagnosis, or waiting.

CLL is an abbreviation of Chronic Lymphocytic Leukemia. This illness is characterized by an overproduction of white blood cells, known as lymphocytes. The disease probably starts out as an abnormal activation of the immune system by some stimulus, probably infectious agents. Usually, the immune system shuts down after an infection, but in some cases, for unknown reasons, the immune system can stay activated over a period of several years.

The threshold of "clonality" is how doctors define whether the immune system overactivation fulfills the definition of cancer or leukemia. In most immune responses, the immune system produces a broad spectrum of antibodies, targeted at a very wide range of disease-causing organisms.

In the case of leukemia, the immune system devotes most of its resources into the production of immune cells or antibodies targeted against one particular target. This phenomenon can be detected using advanced technology, and is taken as evidence that one group of cells is growing outside of the usual checks and balances of the immune system.

CLL, then, is the measurement of a clonal population of lymphoid cells in the circulation or bone marrow. Doctors have long known that many patients can have persistent CLL clones in the circulation without developing progressive problems like anemia, bulky adenopathy (gland enlargement), or bleeding. If these problems are absent upon diagnosis, the usual strategy is to observe the patient until problems develop. This strategy is "watchful waiting," and many patients are satisfied not to have to take chemotherapy.

Some patients, though, ask me, "If I have a leukemia now, and it is not causing advanced problems, wouldn't it be easier to treat it now with chemotherapy to prevent problems from cropping up down the road?" I have not had a good answer to this question, and it is a vexing one, since there are probably some patients who would benefit more from treatment immediately than later.

Mayo Clinic appears to be answering this question with a clinical trial approach. Clincian-scientists there published a paper last month describing a group of 30 newly-diagnosed CLL patients who were given chemotherapy based on a set of high-risk features of their disease. In other words, patients with higher risk disease were treated immediately with therapy.

The researchers used CD38 and ZAP-70, or chromosomal mutations, as markers for high-risk disease. Patients were treated with an all-monoclonal antibody therapy consisting of Campath (alemtuzumab) and Rituximab (rituxan).

The followup was 17.6 months, not long enough to say whether this approach is superior to the current approach. The response rate was 90%, which is in the realm of what's expected with conventional CLL treatments. The median progression-free interval with FCR treatment for CLL these days is six years, so it will take a long time to see whether the Mayo Clinic strategy is superior to the treatments already available for the disease.

The study authors conclude that they have justified opening a randomized clinical trial, but I would argue that if there is such a trial, it should only ask one question at a time. That is, they should either look at whether Campath/Rituxan is better than FCR in high-risk disease, or whether early treatment versus watchful waiting is better in high-risk disease. I doubt we will get such clarity here, though I will solicit comment from the lead author, Clive Zent, M.D.

Right now, Campath is only FDA approved for the treatment of CLL as a single agent, so this clinical trial asks two questions: can we improve CLL treatment by treating the "bad risk" patients with "up front" therapy, and is a combined "antibody cocktail" a good approach to therapy?
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