Therapeutic Management of CLL - Episode 1
Thomas J. Kipps, MD, PhD: There’s a great importance to try and identify factors that can help to predict outcome. Having treatment is never easy, and it’s nice to be able to identify features that could predict how you’re going to do. Given the fact that we have now, today, some treatment options other than just one-size-fits-all, having these factors around really helps you to try and decide what therapy is best for a patient. We like to say that the prognostic factors should not be disease or treatment-related, but it’s actually related to how the patient’s going to fare overall. We have predictive factors and prognostic factors.
Predictive factors are giving us a prediction of how well a patient is going to do with this therapy versus this therapy versus this therapy. If there’s only 1 type of therapy, a predicative factor becomes a prognostic factor. But a prognostic factor should be independent of therapy. Now, with more therapies, we are actually seeing a breaking up of the issue of prognostic factors versus predictive factors. What I mean is that you can look at a therapy and ask, “Given the features of my disease, what is the particular chance I’ll have a favorable outcome with this treatment versus this other treatment?”
We have now identified features that are associated with outcome, and some of these are identified with a test called FISH, which is a test that’s usually done on your leukemia cells. What it does is paint the chromosomes and try to identify common genetic lesions that are found in many patients. We can see changes in chromosome 11, chromosome 13, and chromosome 17, and some of these have very strong prognostic and predictive value.
Some time ago, in the year 2000, it was first shown that patients who have deletion in chromosome 17 actually have an inferior prognosis compared to patients who do not. As a prognostic category, those patients who had deletions in chromosome 11 fell into an intermediate category. Patients who had deletions in chromosome 13 or had an extra copy of chromosome 12 tended to fare better, and it was not really certain as to why that was. With the research that has gone on, we now clearly know what the molecular changes associated with these FISH abnormalities are that are useful for predicting outcome.
For example, patients who have deletions in chromosome 17 typically have an inactive protein called p53. And this protein’s very important in defining the ability to respond to chemotherapy. So, patients with leukemia cells that don’t have a functional p53 typically don’t respond as well as patients who do have functional p53. And so right now, we know that patients, because of newer treatment options, might want to steer away from chemotherapy, particularly if it’s not going to be able to affect a favorable response in the patient and only cause toxicity.
I think the other prognostic factors that we have are related to a patient’s age. The older we get, the less we can tolerate very intensive therapy, or even less intensive therapy. Comorbidities also influence the treatment decision. If I have a lot of other medical diseases or other conditions, they can influence how well I tolerate one therapy versus another.
There are also some other factors too, which include prior history of treatment. It has to be factored in: What type of treatment? What was the response to treatment? So, all these things together should be assimilated by your doctor to try and define, what is the likely outcome you would have if you were to engage in, say, chemotherapy versus some of the newer targeted therapies?
A very important predictive marker is called the mutation status of antibody genes. These leukemia cells are of a type of cell called B cells, and they make antibodies—that’s their job. That could come in 2 flavors: making antibodies that do not have any mutations versus making antibodies that do have mutations. Now, we typically equate mutations as being a variant that might give rise to a more adverse disease or a more serious disease. However, it’s just the opposite. Those patients who have leukemia cells that make antibodies without any mutations typically have a more aggressive clinical course. They may actually respond to therapy but have a shorter duration of remission after therapy. And it really goes to the fact that patients with leukemia cells that make unmutated antibody genes probably have a leukemia that’s derived from an earlier B cell, as opposed to a later B cell that’s more mature through the process of immune differentiation.
It’s a very important factor because, by-and-large, if you take patients who have unmutated antibody genes expressed by their leukemia cells, they typically have a shorter time from diagnosis to requiring treatment, and they also have a shorter period of time when they’re in remission after treatment with chemoimmunotherapy. There are some other associated markers, quite a few—a litany of these. For example, the expression of CD38 or CD49b. These are useful in segregating patients. If you have them, then you are in a more adverse subcategory. We’ve also defined work with ZAP70, which is present in patients who have more aggressive disease. These are factors that weigh on the leukemia, and they make it more likely for it to progress. And so, anything that fuels the leukemia and makes it progress more rapidly is typically associated with a shorter time from diagnosis to therapy.
More recently, we’ve identified another protein called WAR1 that seems to be associated with a much shorter, certainly, time between diagnosis and initiation of therapy if it’s expressed at a high level in the leukemic cell. But we have so many markers that I think it’s very important to try and use them carefully in defining what type of treatment you would like to take, and some of these are clearly defined by what we can find with the FISH test and the mutation status. For that, we have a lot of data.
Transcript Edited for Clarity