Clinical Research Updates on CLL Frontline Therapies

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Andrew Schorr:

Here's another question from Bob.  Bob wants to know, will approaches likely change for first?line treatment, for instance venetoclax, or Venclexta, within the next two years?  You have ibrutinib (Imbruvica) first line.   

Dr. Sharman:

Yeah.  

Andrew Schorr:

You have FCR that's been around.  You have idelalisib (Zydelig) I think could be used first line.  

Dr. Sharman:

Actually, idelalisib is specifically contraindicated for first?line therapy, because of side effects.  

Andrew Schorr:

Okay.  So what about first?line therapies, Jeff?  Where are we there and what's coming?  

Dr. Sharman:

Yeah, so you're kind of in this bind currently where your choices are chemoimmunotherapy or targeted therapy, and both of them have strengths and weaknesses.  The strength of chemoimmunotherapy is that you give treatment for a fixed duration of time, and then you get treatment?free interval that in properly selected patients should be measured in multiple years.  

Andrew Schorr:

I went 17 years.  

Dr. Sharman:

Yeah, absolutely.  So effective therapy in appropriately selected patients.  Now, when I say appropriately selected patients, that does get into some of the nuance about FISH changes and IGHV mutation, and I will tell you even amongst thought leaders in the field there's some debate as to where you draw the line.  Some patients are more suitable for ibrutinib either because of co?morbidities or wish to avoid chemotherapy, but at least as of today ibrutinib is something you start and then stay on indefinitely.   

And per the prior question, some patients have difficulties with that, whether it's arthralgias or bruising bleeding and so forth.  The medication you made mention of I think is the frontline therapy that may have the most profound impact on treatment selection in the next two years.   

Andrew Schorr:

Venetoclax.

Dr. Sharman:

So the German Research Group, which is really just absolutely one of the best out there, have fully enrolled a clinical trial of obinutuzumab (Gazyva) venetoclax versus chlorambucil and obinutuzumab, and I have to believe that that is going to result in a superior outcome for the venetoclax arm and that we will have the combination of obinutuzumab venetoclax for front?line setting.

And what's really appealing about that is that is one year of treatment and then treatment is suspended and stopped.  And though we haven't compared that to more traditional BR or FCR, I think it would be a highly effective regimen.  We are currently conducting a study in the United States in our research network looking at the combination of obinutuzumab and venetoclax, and what I like about our study is we give—for the listeners who might not be familiar with venetoclax, starting venetoclax is a little bit clunky because it works so quickly we have to be careful about a condition called tumor lysis syndrome, which is if you kill too much cancer cells too quickly that can cause some dangerous conditions, and venetoclax does do that.  

And so what we're doing is we're giving two months of obinutuzumab and sort of getting rid of the bulk of the CLL and then starting the venetoclax hopefully under much safer conditions, because, you know, in the Pacific Northwest we would say you can't have forest fires if you don't have any trees.  So if we get rid of all the CLL or a substantial fraction of it somebody is less likely to have tumor lysis.  So I think that's the approach that is probably the next up in frontline.  

The one other thing that could potentially change is acalabrutinib has conducted a three?arm study??excuse me, Acerta with acalabrutinib (Calquence), where they give—it's a three?arm study with either chlorambucil Gazyva, acalabrutinib or acalabrutinib with Gazyva.  And so does the addition of a C?20 antibody make BTK work better, remains the question outstanding.  

Andrew Schorr:

All right.  Let me just explain things to people.  I've been around this for a long time and Jeff deals with these acronyms all the time.  So, first of all, Gazyva is the same as obinutuzumab.

Dr. Sharman:

Thank you, yes.  

Andrew Schorr:

It's an infused CD20 that's targeting the CD protein on the B cell, the bad guy, and it is sort of I don't know if you'd describe it as a more powerful version but it followed from Rituxan or rituximab that many of us had.  So the idea is you have an infused therapy for some length of time, and then you may have an acalabrutinib with it or you may have a venetoclax or Venclexta with it.  Get I get it right, Jeff?  

Dr. Sharman:

Yes.  And if I just had one other comment.  I think there are a lot of questions and certainly some very compelling data about the combination of a BTK inhibitor such as ibrutinib with a Bcl?2 inhibitor such as venetoclax.  

Andrew Schorr:

Two pills.  

Dr. Sharman:

Two pills, yes.  And I think the preliminary data really looks extremely encouraging.   

The challenge with that approach is it's not approved in that combination and probably not going to be approved in the next two years unless the FDA does something that maybe I'm not anticipating at this point.  That clinical trial that compares that to an existing standard is really only just getting off the ground now.  

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.