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The Evolving CLL Treatment Paradigm

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Published on October 6, 2015

With a long list of new treatment options, and more on the way, how can a CLL patient work with their doctor to decide which treatments to use and when? Dr. Philip Thompson, a CLL expert from MD Anderson Cancer Center, reviews the key factors that are considered when choosing a treatment path and discusses the evolving role of genetics.

This program was developed in collaboration with and sponsored by CLL Global Research Foundation which received support from AbbVie Inc., Genentech and Biogen Idec. 



CLL Global Research Foundation

Transcript | The Evolving CLL Treatment Paradigm

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, 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: 

Hello and welcome to Patient Power. I’m Andrew Schorr at Stanford University Medical Center in San Francisco. While I’m here, there is a meeting called the iwCLL going on in Sydney, Australia. Our correspondent on the scene is Dr. Philip Thompson, a CLL expert from MD Anderson Cancer Center in Houston. Welcome to Patient Power, Dr. Thompson.  

Dr. Thompson:                  

My pleasure. 

Andrew Schorr:                  

So with all these new options, how will a patient and their doctor know which medicine to use when? 

Dr. Thompson:  

I think the two key pieces of information we need to know to determine how we’re going to treat a patient, the age, fitness and other medical problems that a patient has.  And essentially that determines—the first question we have to answer is, is this patient going to tolerate treatment with chemoimmunotherapy, which is FCR.  The FCR regimen is really still what we would call the gold standard treatment for CLL.

It has the highest proven complete remission rates.  And it has long-term data on follow-up.  But patients need to be physically fit.  They need to really be less than 70 years of age, and they need to have good kidney function and not have other major medical problems in order to be able to tolerate the medication.  So really this hypothetical patient I'm describing doesn’t represent the majority of patients with CLL.  CLL, the average age of diagnosis is 72, and patients often have other medical problems.

And I think this is one of the very reasons that the new medications are so exciting.  Because they’re able to be given to really old patients with CLL, whereas treatment with FCR benefits a smaller group.  The second thing we need to know when we’re determining how to treat a patient is what the genetics of the CLL cells are.

There’s an absolute explosion of information about the genetics of CLL, which is being generated by new technology called next generation sequencing.  So we’re learning more and more about different mutations, which may be responsible in a proportion of cases of CLL for the disease and for the way that the disease behaves.  But at the moment, there are really two particularly important things that we need to know.  The first is does the patient have an abnormality of the protein p53?  So p53 is a protein that is essential for sensing DNA damage in the cell.  And in a normal cell, p53—if there’s DNA damage, p53 will sense that.  It will attempt to then orchestrate repair of the DNA.

And if that fails, it will tell the cell to die in a process called apoptosis.  This is a normal protective mechanism that the human body has to prevent the evolution of cancer.  And so p53 is often either lost or mutated in cancer so that cancer cells can survive.  And if this occurs, if p53 is mutated or lost, so chemotherapy actually works by inducing DNA damage in cells and then via p53-dependent mechanism, the cells will die.

So in CLL, one of the frequent genetic events is deletion of chromosome 17p, which means that you lose the p53 protein.  And also in this situation, about 80 percent of patients will have a mutation in their other TP53 gene, which is the gene that is responsible for producing the p53 protein.

So we now look for both the deletion of the chromosome by a test called FISH, and we also look for mutations in the gene with gene sequencing.  And if we find either of these two things, we know that chemotherapy is not appropriate for such a patient, because they won’t respond well to the treatment, and they won’t respond for a long time.  But what we can do for those patients now is that the new therapies like ibrutinib (Imbruvica) actually have an excellent response in patients with p53 abnormalities.

And so we’re able to actually use ibrutinib in patients with the 17p deletion or a mutation of TP53 as the first treatment for that patient, whereas other patients still have to have received another treatment for their CLL first, before they can access ibrutinib.

Also, some of the newer medications such as idelalisib (Zydelig) combined with rituximab (Rituxan) is also effective in 17p deletion, as are the new medications I mentioned; duvelisib and venetoclax.  The final thing we need to know about a patient is whether they have what we call mutated CLL or unmutated CLL.  This is very important because patients who have mutated CLL, which is approximately half of patients, when they need treatment they have a very, very long response to chemoimmunotherapy with FCR.

And in fact, data was presented by David Rossi from Italy showing that patients without 17p deletion or 11q deletion who have a mutated immunoglobulin heavy chain variable gene will actually have more than 60 percent of them appear to have very long-term survival without disease.

And in addition, our own data suggests that over half of these patients will be alive and with undetectable CLL 12 to 15 years after treatment with FCR.  So this is very exciting.  We think—although everybody hesitates to use the word, we really do think that for all intents and purposes, these patients may be cured of their CLL.  This is a high bar for the new treatments to jump over in terms of beating that.

But there are very important studies that are ongoing at the moment, both in the United States and in the UK that are comparing ibrutinib plus rituximab to FCR for the treatment of CLL.  And I think that these studies will demonstrate superiority of ibrutinib plus rituximab for patients who have unmutated IGHV gene and patients who have 11q deletion.

However, we’ll need to wait a long time, I think, before we know whether ibrutinib plus rituximab is superior to FCR for patients with a mutated CLL.  I think this group is a group that may continue to benefit from chemoimmunotherapy.  But yeah, those are the three things I look at when I'm determining the paradigm of treatment for a patient with CLL. 

Andrew Schorr:              

Dr. Philip Thompson, CLL specialist from MD Anderson Cancer Center, thank you for joining us from the iwCLL meeting in Sydney, Australia to bring us the latest news. For our audience, be sure to join the Patient Power Community so that you can be informed whenever we post something new. 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, contributors, 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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