Advances in Treating High-Risk CLL

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Topics include: Treatments

Chronic lymphocytic leukemia (CLL) patients with certain genetic markers are considered “high risk” and their options for treatment have historically been limited. But research is evolving and offers the promise of more effective options. CLL expert Dr. Jeff Sharman joins Patient Power to discuss emerging approaches to treating high-risk CLL currently being studied in clinical trials. 

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Transcript

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.  Unfortunately, for people with so-called high-risk CLL, options have been more limited. But things may be changing, and there is research underway. One of the leaders in research in CLL is Dr. Jeff Sharman from US Oncology, and he joins us now. Dr. Sharman, thank you for joining us on Patient Power once again. 

Dr. Sharman:        

My pleasure.  Thank you so much for having me.

Andrew Schorr:                                     

Dr. Sharman, let’s start with a basic question: What exactly is high-risk CLL? 

Dr. Sharman:       

So chronic lymphocytic leukemia is a highly varied condition.  There are patients with CLL who are going to get very long durable remissions out of any single treatment, and there are other patients who might get a relatively short benefit out of treatment.  And the way we can oftentimes tell these apart are sometimes clinical features, meaning how long benefit did they get from their last therapy. 

Because in general, if you’re using chemotherapy, the amount of time between cycles diminishes over time.  So if you use the chemotherapy and you get three years of benefit, the next time, if you use another chemotherapy, you often get less.  And so high risk can be defined based on clinical variables such as how long somebody’s responded.  Or what we use frequently now are chromosomes. 

And so there’s testing that can be done called FISH.  FISH stands for fluorescent in situ hybridization.  Essentially, it’s a technique that allows us to measure chromosome changes on a peripheral blood sample.  And there are five main categories of FISH results; normal, missing a copy of chromosome 13, having an additional copy of chromosome 12, missing part of chromosome 11, or missing part of chromosome 17.  And oftentimes there’s a P or a Q associated with that.  And that designates if it’s the long part of the chromosome or the short part of the chromosome. 

And roughly since about 2000, we’ve understood that these different chromosome abnormalities predict oftentimes how a patient is going to do on therapy.  And so those patients with chromosome 11q abnormalities or 17p abnormalities are what we consider high risk from a chromosome perspective.  More often than not those patients are going to get a shorter duration of benefit to any treatment compared to their counterparts who lack those abnormalities. 

Now there’s one other test that can be done called sequencing.  And sequencing is not commonly done.  But sequencing allows you to look at the actual DNA level even at a finer resolution than FISH testing.  And we’ve known that patients who abnormalities in a very specific protein have called TP53 also have high-risk CLL. And it just so happens that TP53 is the same place as 17p.  So you could either be missing 17p, or you could have a mutation in the TP53 gene that’s on 17p.  And either of those confers high risk.  

Andrew Schorr:                  

One of the things we wonder about, Dr. Sharman, is does a patient’s high-risk status change with treatment? 

Dr. Sharman:       

So, when we look at patients with previously untreated chronic lymphocytic leukemia, the presence of high-risk markers is relatively frequent.  We see that about 5 percent of patients will have 17p deletions.  Another maybe 10 percent will have 11q deletions.  And we rarely look for T53 mutations.  But if we do, we might find another three percent of patients who have TP53 mutations.  So all told, you’re dealing with 15 to 20 percent of patients might have high-risk CLL. 

However, when you treat CLL, oftentimes what you’re treating is a mishmash of a variety of different CLL populations in a single patient that have all been trying to evolve.  And so we may not see a high-risk marker in a patient.  It may be a very small amount of the disease.  Say a patient may have only one percent of cells having 17p deletion.  That might not show up on a FISH test.  However, after you treat a patient, oftentimes what you’re doing is you’re eradicating the disease that’s easy to get rid of and you’re left with the disease that is hard to get rid of. 

So when we do those same tests in the relapse setting we see a considerably higher number of patients.  Perhaps over half of patients will have one high risk marker when they’re going into therapy.  The problem is we’re not looking frequently enough.  A lot of doctors think that if you’ve checked a FISH test once, you don’t need to check it again.  But what we know is that these actually evolve.  So, it’s my standard practice, as well as the practice of most docs in academic medicine, to repeat the FISH anytime you’re planning on treating a patient. 

And I think that’s particularly relevant with some of the novel agents because whether or not somebody’s likely to get a durable benefit out of chemotherapy or not is highly dependent upon what sort of molecular markers they have.  And if we’re not testing for them, you could very well miss that a patient has high-risk disease.

Andrew Schorr:

What are the treatment approaches that are currently available in high-risk CLL?

Dr. Sharman:       

So, currently patients with high-risk disease don’t necessarily have a standard algorithm throughout the United States in terms of what are the ways that patients get treated.  Now if a patient has had an early relapse, meaning they only got a few years of benefit out of their front line therapy or they have a high-risk marker, 11q, 17p or TP53, that patient is likely to get the most durable benefit out of some of the novel agents, whether that’s ibrutinib (Imbruvica) or idelalisib (Zydelig). 

And so for patients with high-risk disease, I think even though it’s not totally standardized yet throughout the United States, I think that if you talk with most academic investigators, there would be general consensus that such a patient should be treated with ibrutinib or idelalisib or some of the other experimental novel agents.

Andrew Schorr:                  

So do you feel we can improve upon ibrutinib? 

Dr. Sharman:       

So when we use ibrutinib in CLL patients, we can see a difference depending upon their chromosome abnormalities.  Now for patients with 11q and 17p or TP53 mutations, it’s a virtual certainty that they’re going to get a better effectiveness from ibrutinib than any chemotherapy.  Most patients who get chemotherapy in that setting may only get a short benefit; maybe months, maybe a year.  Whereas on ibrutinib, we think that a lot of those patients are going to get two, three, maybe even more years out of ibrutinib. 

We do know, however, that patients with 11q and 17p don’t do as well on ibrutinib as their counterparts who lack those mutations.  So it kind of almost parallels the story with chemotherapy.  If you have one of these markers, you don’t do as well on ibrutinib as if you don’t have one of them.  That having been said, you’re gonna do better on ibrutinib than just about anything else. 

And so there is a question of can we improve upon the outcome of ibrutinib in those patients who have these markers?  And that’s an area of active research investigation with a variety of clinical trials in that population right now.  In theory, if you perhaps added a second agent or you made a better version of ibrutinib or you fixed—there might be a handful of ways that you could conceive of improving upon things.  Ultimately, nothing has yet been proven to improve upon ibrutinib.  But it is the area subject to a number of ongoing clinical trials.  A number of doctors have wanted to put together antibodies with ibrutinib. 

There’s been some question in the literature whether or not ibrutinib could interfere with drugs like rituximab (Rituxan), or ofatumumab (Arzerra), or even other investigational CD20 antibodies like ublituximab.  There’s been some concern that the way that those drugs kill CLL cells could be interfered with by BTK inhibitors or ibrutinib.  There have been a handful of studies that have reported the combination of the two using rituximab or using ofatumumab or even using ublituximab.  And I think that the early results are encouraging.  What we see is it does appear that the response rates might be higher.  But what we don’t know yet is will they last longer. 

And so that’s the nature of a current study called the GENUINE study, which patients with high-risk CLL receive ibrutinib.  Whether you’re on the control arm of the experimental arm, you receive ibrutinib.  And then half of patients will also receive one of these antibodies called ublituximab with the question being do those patients do better with the addition of a second drug to ibrutinib.  

Andrew Schorr:

For the GENUINE trial, what’s the eligibility criteria?

Dr. Sharman:       

So patients who are going to be eligible for the GENUINE study, the study in which half the patients get ibrutinib, excuse me, everybody gets ibrutinib, and half of patients get the addition of a CD20 antibody have to have high-risk CLL.  And that’s going to be identified by the presence of 11q, 17p by FISH or TP53G mutation by sequencing.  That’s done in the context of this study.  You sign up for the study, and then they measure your blood to see if you have one of these abnormalities.  And if you have one of these abnormalities, then you are eligible for the study.

Other key criteria; that your CLL actually needs treatment.  So just because you have CLL with one of these markers doesn’t necessarily mean that you actually need treatment.  You have to have lymph nodes that can be measured by CAT scan, because we want to be able to measure the disease by pictures to know that we’re getting better.  Other standard things, you have to have enough kidney function, your liver has to be working well, and you’re not taking drugs that interfere with ibrutinib. 

In addition, this is a study opened quite broadly throughout the United States.  It is really in virtually all the major geographies of the United States. And I believe there are some international sites as well. 

Andrew Schorr:                  

So if a patient is interested in participating in a trial, what should be considered?

Dr. Sharman:       

I think any patient who wants to be involved in a research study needs to carefully consider the risks and benefits of any intervention. And that’s probably a discussion best had with their provider.  Antibodies have been commonly used in management of chronic lymphocytic leukemia as well as a variety of other blood cancers.  And so I think there’s a pretty good understanding of the risks.  We always are concerned about what we call infusion reactions where people have almost an allergic reaction as the drug’s being administered.  That appears to be a relatively low frequency but not zero and should be considered. 

We ultimately don’t know that this is going to be an improvement on the status quo.  But that’s certainly the point of doing the study is to find out if it is or not.  I think there’s reason to be optimistic.  But I think we need to be guarded about our confidence in that, that we need to actually see the results before we know that it’s any better.  And I think any good thoughtful discussion with their own physician would be appropriate.

Andrew Schorr:                  

Dr. Jeff Sharman from US Oncology, thank you for joining us once again and keeping us updated as research moves ahead. 

Dr. Sharman:

Thank you for having me.

Andrew Schorr:

Be sure to be signed up for alerts by joining our community for CLL on Patient Power, and you’ll always be in the know.

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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Page last updated on August 2, 2016