Exploring the Link Between Genetics and CLL Drug Resistance

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Topics include: Treatments

Research is ongoing into the potential for patients to become resistant to new and emerging inhibitor chronic lymphocytic leukemia (CLL) treatments, and recent study results into the link between genetics and resistance could help to identify a patient's susceptibility. To learn more, Dr. Brian Koffman, a Patient Power host and CLL advocate, met with Dr. Richard Furman, a leading CLL expert, at the 2014 American Society of Clinical Oncology (ASCO) meeting in Chicago. Dr. Furman explores how this new research could lead to improvements in early detection as well as the development of combination therapy approaches to help combat resistance.

 

This activity was made possible by Pharmacyclics, Inc. and Janssen Biotech, Inc.

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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.

Brian Koffman:

I'm Dr. Brian Koffman, a family doctor turned patient with CLL and reporting from ASCO 2014 with my friend Dr. Richard Furman.  Dr. Furman, you want to introduce yourself? 

Dr. Furman:

Hi.  I'm Dr. Richard Furman from Weill Cornell Medical College in New York.

Brian Koffman:

So we were talking a little bit about some of these trials, and I know that there's recently published a very small number of resistance—we're trying to tease out the resistance, so give us not just what the resistance information is but the perspective on how big of a problem this is or isn't in terms of resistance to ibrutinib.

Dr. Furman:

So it’s important to remember that the data is specific to ibrutinib (Imbruvica), and we've been working very carefully on it.  I do have to commend Pharmacyclics has been very helpful in pulling together this information.  So as best we can tell, we looked at the first 246 patients treated with ibrutinib, and we found out of about 20 cases who progressed 13 who had CLL responded and then had CLL afterwards.  So it excludes those patients who had a Richter's transformation.

Brian Koffman:

So, just doing the math, 11, so it was almost a 50/50 split between the progression with CLL versus the progression with Richter's.  And before you go on, I've heard of something called this aggressive CLL or something that's sometimes in people that's sort of an intermediate—do you know what I'm talking about here?

Dr. Furman:

Yes.

Brian Koffman:

So explain what that is, and did any people fit into that category.

Dr. Furman:

Well, I think that that's sort of, you know, the correct answer is we don't have information on that.

Brian Koffman:

Okay.

Dr. Furman:

Because it's not a formally recognized category.

Brian Koffman:

Okay.

Dr. Furman:

So it's hard to really make that distinction.  I think that most clinicians have ideas that when patients progress they progress with a much more aggressive phenotype, that it's still a little bit of hearsay.

Brian Koffman:

Okay.

Dr. Furman:

I think's it's important to remember that. 

Brian Koffman:

Okay.

Dr. Furman:

So I don't want people to be fearful that when they progress it's going to be bad.  But what I really think is important to recognize, so out of 20 people who progressed seven had Richter's, and we don't expect ibrutinib to hold Richter's.

Brian Koffman:

Right.

Dr. Furman:

So we have no expectation that they should have responded.  So out of the 13 who had CLL responded in CLL, in six of them—we sequenced 10 of them and in six of them we found single-based paramutations that could explain the resistance.  So two genes seem to be affected.  One was actually the BTK gene itself.

Brian Koffman:

Where the ibrutinib binds.

Dr. Furman:

Right.  And it was actually specific to the amino acid that ibrutinib binds to renders—it changes the amino acid from assisting to a searing, and so ibrutinib no longer binds, or it binds but not irreversibly.  So it changes ibrutinib from an irreversible inhibitor to a reversible inhibitor.  And because of the half-life of ibrutinib, as a reversible inhibitor it's really not effective.  So that sort of explains why those patients progress.

Brian Koffman:

So let me stop you there.  Would it make sense to take it as a BID or TID drug?  Would that be a simple answer?

Dr. Furman:

That would be a simple answer if it's tolerated.  We don't have data at this time that that would actually work.

Brian Koffman:

Okay.

Dr. Furman:

Now, in the two other patients, we actually found the mutation in what's—in another enzyme called PLC gamma, which is sort of an enzyme that can bypass the BTK.

Brian Koffman:

Right.  It's further down the path.

Dr. Furman:

Right.  So these—actually, it was six mutations in five patients.  So these five patients all developed resistance to ibrutinib and progressed, and many of them were treated with other things.  Now, the thing I think is really important to understand is that all of these patients had evidence of what we call genomic instability.

So they had either a 17p deletion, they had an 11q deletion, both of which impact upon DNA repair, or they had very complex chromosomal abnormalities that really indicate that their cells weren't able to sort of maintain normal chromosomal instability—normal chromosomal stability.  So in essence, they had mutator phenotypes.

Brian Koffman:

Okay.

Dr. Furman:

And the reason why I think that's so important is that when we look at the treatment naive patients treated with ibrutinib and the 31 patients that we treated there, we've actually not seen any progression with CLL. And we've not seen the developments of any resistance.

So the resistance happens in a very small number of patients.  So remember the vast majority of 17p deleted patients haven't developed resistance and are still responding to the drug.

Brian Koffman:

And is that also true for the complex karyotypes and the 11qs?

Dr. Furman:

Yes.

Brian Koffman:

Okay.

Dr. Furman:

In that the—you know, we're talking about just a small handful of patients and it also really seems to be in these heavily, heavily treated patients, not the

treatment naive, less heavily treated patients.

Brian Koffman:

Okay.  All right.  And I know—again, this may be a little controversial that there's been some studies at MD Anderson that found some different resistance

pathways.  Do you know anything about that, or can you comment on that?

Dr. Furman:

Well, I'm not so sure resistance pathways, but there was just more, additional…

Brian Koffman:

Okay.

Dr. Furman:

…information regarding the same pathways.

Brian Koffman:

Okay.

Dr. Furman:

So they were really all the same pathway.

Brian Koffman:

All right.  So let me follow-up on this, so what it seems to me that there's a couple lessons to take from that.  Let's deal with the first.  It seems to me it would make sense then to be looking to moving these treatments earlier up the line.

Dr. Furman:

Absolutely.

Brian Koffman:

Right now these are approved as second-line therapies. I don't know what the idelalisib label will say.  None of us know until we actually see it, but I would be surprised if it would be a first-line treatment, but maybe it will be.

Dr. Furman:

So ibrutinib is approved for relapsed CLL.

Brian Koffman:

Right.  But not for first-line, treatment-naïve patients.

Dr. Furman:

And idelalisib, the assumption is that the approval is going to be the same for what the population was studied on the trial, so you're talking relapsed CLL patients who were considered to be unfit for chemotherapy.  And these patients were unfit for chemotherapy because they either had a lot of co-morbidities, and we use a CIRS score, or a cumulative illness rating scale score, to assess that, or they had some, you know, poor kidney function and we—creatinine clearance was somewhere between 30 and 70, or they had persistent myelosuppression from chemotherapy.

Brian Koffman:

Right.  So they had low counts.

Dr. Furman:

But not low counts due to CLL.

Brian Koffman:

Right.

Dr. Furman:

So if you did a bone marrow biopsy and it showed CLL, that doesn't qualify.

Brian Koffman:

Right.

Dr. Furman:

So the assumption is that the approval for idelalisib will be in that patient population.

Brian Koffman:

Right.

Dr. Furman:

Now once a drug is approved it's important to recognize that a physician can prescribe it for anything.  And so I certainly would prefer to see these agents used up front, in first relapses and in young patients, in all patients in the place of chemotherapy.  And that I think is very important because we know the toxicities of chemotherapy, and while we only have four-year up

follow-up data for these new agents what we've seen in the first four years is remarkable, and the hope is if you really need to make CLL a truly chronic disease, we need to sort of do away with the toxicities that chemotherapy that causes that really impair people's ability to live long term.

Brian Koffman:

So I hear that the doctor can prescribe it, but whether the insurance will cover it is a whole other issue.

Dr. Furman:

That is a very 'nother issue.

Brian Koffman:

All right.  So this moves me to the second concern, and although the numbers are small they're there are people who do relapse…

Dr. Furman:

Let me just say one thing to what you had just commented on.  Is that both Pharmacylics, Janssen and Gilead have very, very…

Brian Koffman:

And those are the manufacturers…

Dr. Furman:

…those are the manufacturers.

Brian Koffman:

…of ibrutinib and idelalisib, yeah.

Dr. Furman:

They have very extensive patient assistance programs. And so out of all the prescriptions I've written for ibrutinib, so far I've actually only had one patient that I couldn't obtain it for.

Brian Koffman:

Okay.  So the other question I want to go to is the patients who are on the medication, have been on it for three years.  There's more of this population.  Some of—many of whom are your patients.  So the patients are taking the meds, but they're not in a complete remission.  And as a patient on ibrutinib, I'm worrying am I going to be one of that few percent that's going to mutate?  Doesn't it make sense to try to get me off of third base and home?  Doesn't it make sense to be looking at combination therapies or something to get this disease down to a lower level so that one cell doesn't mutate and turn into a resistance problem? Doesn't it make sense to treat it before I relapse?

Dr. Furman:

It makes perfect sense, and I absolutely understand that.  The big caveat is that you have to knock out that additional disease without causing any additional toxicities.

Brian Koffman:

Right.

Dr. Furman:

So if you're going to add anti-CD 20 antibody as long as you don't create worsening infections or other problems…

Brian Koffman:

Right.

Dr. Furman:

…then it's no problem. The second caveat you have to remember is that, you know, in these treatment-naive patients for the vast majority of relapse/refractory patients who have achieved excellent responses but still have levels of persistent disease, we've not seen any them do poorly because of that.  So we're also making an assumption that is something that we need to act on.

So those are two big caveats to the whole process.  Now, I to believe personally that a treatment strategy of, you know, six to 12 months of ibrutinib or idelalisib followed by obinutuzumab (Gazyva), which would sort of knock out that persistent disease may actually be a home run, and that may be what gets you to home base—to home plate, excuse me.

Brian Koffman:

Right.

Dr. Furman:

But the, you know—but that's still—I can't tell you that it's absolutely necessary and that I'm not putting my patients in harm's way by doing that.

Brian Koffman:

And would you consider ABT as a follow-up drug in those circumstances, ABT-199?

Dr. Furman:

So absolutely.  So ABT-199 is an excellent drug.  Its really only limitation is tumor lysis syndrome.

Brian Koffman:

Right.

Dr. Furman:

And what I—actually a trial that we're now currently proposed and waiting to hear back from is actually using the ABT-199 in patients who have been debulked by ibrutinib and idelalisib.

Brian Koffman:

I love it.

Dr. Furman:

So you would take the ibrutinib and idelalisib on day one and then on day 365 start taking the ABT-199, and there you won't have any tumor lysis to worry about because the tumor con itself will have been reduced 99 percent.

Brian Koffman:

I love it, and I actually blog on exactly that idea. Any final thoughts or anything you want to share from ASCO 2014?

Dr. Furman:

So I think these are—this has been a remarkable year for CLL.  We've actually seen the development of two new agents to fruition, so, and that's, you know these are agents that started their development pathway four to five years ago.  They're now here.  They're near a reality, and the truth is is five years from now we'll be talking about versions 3.0 and 4.0 of these agents.

Brian Koffman:

All right.

Dr. Furman:

We already have a new BTK inhibitor.  There's actually two new BTK inhibitors that look very exciting as well.

One is called ACP-196.  The other one is the ONO-4059. And, you know, one could only assume in another five years we'll have a huge array of these agents.  So I think we're at the time, point in time where CLL can truly become a chronic disease, and you can take your pill just like your high blood pressure and not have to worry about the CLL.

Brian Koffman:

Dr. Furman, thanks.  Always great to see you.

Dr. Furman:

Thank you.

Brian Koffman:

Dr. Brian Koffman at ASCO 2014 with some pretty good news about CLL and the changing therapeutic landscape.

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 July 21, 2014