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What Gene Mutations Matter in CLL?

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Published on October 2, 2012

Researchers are discovering new genetic mutations in cancer cells at an ever more rapid pace. Some of these discoveries have immediate significance for a CLL patient's prognosis and treatment strategy while the significance of some other mutations is less clear. Renowned CLL expert, Dr. Stephan Stilgenbauer explains which of these genetic mutations are significant now and discusses why. He also explains how exciting, investigational treatments could vastly improve outcomes and reduce side effects for a broad group of CLL patients.

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Transcript | What Gene Mutations Matter in CLL?

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

Andrew Schorr on location in Barcelona, Spain, where there are hematology experts from around the world gathered, and of course one of the conditions they’re discussing is chronic lymphocytic leukemia, CLL.  A leader in the field from Germany is Dr. Stephan Stilgenbauer, who we’ve interviewed many times.  He has been among the doctors who have identified many genetic mutations for CLL.  We wanted to know what mutations are significant to patients and their doctors at this time.

Dr. Stilgenbauer, there are so many mutations that can be identify in CLL, but what would you say to patients about what is clinically significant and ones that they and their doctors should pay attention to? 

Dr. Stilgenbauer:

Clearly, mutations or genomic abnormalities are really relevant for the pathogenesis of the disease but also for the outcome of the patient.  We know that there’s a wide range, and it’s actually a growing number of mutations that has been identified currently, but we know that only a limited number of them are relevant for the real clinical course. 

For instance, among early-stage patients probably the mutation status of the IgVH gene is important because that determines the pace of disease progression.  However, it should not determine if a patient is treated or not.  There we should wait for the usual criteria for treatment indication to be met, such as low hemoglobin levels, low platelet count, or symptomatic disease. 

Now, when treatment is required the abnormality that is really important is the 17p deletion or the TP53 mutation.  Both of those have been shown in prospective multicenter trials to impact on treatment outcome with conventional therapy.  So those patients, if they’re young, should be considered for an allogeneic stem cell transplantation, or at least this option should be discussed with them.  And fortunately we have new agents that are on the horizon that are in clinical trials that may overcome the adverse impact of the 17p deletion or TP53 mutation. 

 

Andrew Schorr:

Could you mention a couple of those that you think might have promise? 

Dr. Stilgenbauer:

Well, the new agents can be kind of categorized into large groups.  There are antibodies, there are small molecules available, and there are immunomodulatory agents.  So for instance Revlimid (lenalidomide) belongs to the latter group and has shown promise in the treatment of CLL.  There are new antibodies against CD20 but also targets such as CD37 that become available or are in clinical trials and may become available in the future. 

And last but not least, and probably most promising, are the small molecules that target B cell receptor and other signaling pathways in CLL.  Those are targeting, in particular, the BTK molecule, the PI3-kinase molecule, but also apoptosis molecules, such as the Bcl-2 family members.  And for all these agents there is evidence from early clinical trials that in patients who failed conventional chemotherapy those agents are very efficacious, and very importantly, they are very well tolerated, which obviously is of prime importance in our patients. 

Andrew Schorr:

Is it possible that there could be a pill, an oral agent that someone could take even with more aggressive CLL, and that could take the place of the need for a transplant? 

Dr. Stilgenbauer:

That is indeed a possible dilemma that we may face in the future.  However, I think it is kind of a fortunate dilemma that we may face because an allogeneic stem cell transplantation, as we all know, is not the most easy thing to do and not the thing that you as a patient want to have because it’s obviously associated with severe side effects and even a risk to die from the procedure. 

So even if it’s the only chance of cure that we have currently available in the long-term, the future may offer other promises, as you say, pills, oral drugs that can control the disease or maybe even put the disease into very deep remission for a long time.  Having said that, one has to be a bit cautious because the data that we have available from clinical trials is based on limited numbers of patients and on limited follow-up, so with regard to long-term outcome the jury is still out there. 

However, these agents certainly will come into play in particular in refractory relapsed high-risk patients but probably also in the frontline treatment, and maybe in the somewhat more distant future for those patients who we don’t consider for treatment today, so the early-stage asymptomatic patients who early on control the disease, prevent progression of the disease and prevent the patient from getting problems from the disease to begin with. 

Andrew Schorr:

Are you saying that there could be pills that CLL patients could take where a broad range of CLL patients would get effectiveness, and they could just go on with their life? 

Dr. Stilgenbauer:

I think so.  I mean, a similar thing to antibiotics is that these pills or new agents really specifically target that is wrong in the cell, like antibiotics target the bacteria that caused the disease.  So although you consider it kind of a broad-spectrum treatment, it’s still much more specific than the classical chemotherapy that we have available that obviously harms all cells in the body while these new agents target specific disease aspects such as signaling molecules, as we discussed. 

Andrew Schorr:

So are you encouraged about where we are now and where we are headed in CLL? 

Dr. Stilgenbauer:

The range of treatments that now appear on the horizon and are actively being investigated in clinical trials to me look really promising, and I think the future for our patients holds really great promises when we get these agents into our hands and for the benefit of our patients. 

Andrew Schorr:

Positive news for patients with CLL, even if it may be more aggressive, the real prospect of living a longer and full life. 

On location in Barcelona, Spain, I’m Andrew Schorr.  Remember, knowledge can be the best medicine of all.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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