Mechanisms of Ibrutinib Resistance in CLL

Transcript:William G. Wierda, MD, PhD: So we're here in Orlando at ASH 2015 and one of our colleagues has departed, Dr. Susan O'Brien, but we're continuing our discussion and I'm grateful for those of you who've been able to stay with us for the discussion to continue. Let's continue on with a little bit more about ibrutinib. And we know it's a very, very effective active agent. Resistance or progression on ibrutinib is a rare event, but I wonder, Tom, if you can give us a little bit of insight into maybe mechanisms of resistance and what that looks like clinically.

Thomas J. Kipps, MD, PhD: I think it's important to follow your patients who are on ibrutinib because they can display signs of having disease progression on this drug. For example, a reversal in the reduction of lymphadenopathy or increasing lymphocyte count that occurs months, if not years, after starting therapy. We do run into a problem of disease resistance based upon evidence that shows that the leukemia can acquire or be selected to have mutations, some of which may confer a change in the BTK enzyme that precludes the BTK enzyme from forming a covalent bond with ibrutinib. And, therefore, ibrutinib, which has a very short half-life after a patient takes it, no longer can stay with the BTK. The BTK will be active for just a few hours after taking the medication. And this could give rise to a leukemia that is not responsive to the drug, and that accounts for resistance.

There are other mutations that might occur, too, that sometimes fuel a B-cell that is less sensitive to deprivation of some of the survival signals. So this represents a problem. I know that many have looked at patients who've developed resistance to ibrutinib. And it can be quite dramatic in that patients may develop rapidly progressive disease, and it does represent a medical problem that we have to face. So it's really I think important to recognize. But then the question comes is, what do you do about it?

Oftentimes there can be some consideration for using other medications such as idelalisib, which inhibits another enzyme in this pathway. And you might have some success with those measures. Although it's not guaranteed that it will be entirely successful, because the pathway that's dysregulated may be downstream of even the PI3 kinase, which is the enzyme that's inhibited by idelalisib. So newer therapies coming online, for example, venetoclax, which is the BCL-2 inhibitor, may prove to be effective. And other agents and new antibodies might be necessary for this patient population.

William G. Wierda, MD, PhD: Do you think monitoring patients like we do for CML in looking at mutations in ABL, do you think in CLL we'll see an era in the near future where we're looking for BTK mutations or PLC gamma 2 mutations? And are there trials now that are looking at whether or not that's a clinically relevant issue?

Thomas J. Kipps, MD, PhD: I know this is being done at several centers to monitor for BTK mutations. Unfortunately, the BTK mutations may not represent the sole basis for resistance. And I, again, apply for community physicians it's very important to follow your patient and be sensitive to changes in their clinical behavior on this drug. Obviously, if you have evidence for a BTK mutation, it does raise some concern that either you're about to develop resistance or you're at risk for developing resistance.

And I think that it may be useful if we have other agents that can be applied at that point. In that absence of that right now, it's difficult to know what to do in the community if you have that information. So, I wouldn't perhaps advocate getting that information currently in clinical practice. It may create anxiety and develop a false sense of things without having a means to remedy the situation.

Richard R. Furman, MD: One of the things that's important to keep in mind as we have newer BTK inhibitors coming through clinical studies, and I'm thinking primarily about ONO4059 and ACP196, is that those are very dependent upon the same cysteine that ibrutinib binds to. And so these mutations that lead to resistance with ibrutinib will also lead to resistance to the other BTK inhibitors. It doesn't look like necessarily cross-resistance between B-cell receptor antagonists if you go from a BTK-directed to a PI3-kinase directed inhibitor. But, going from one BTK to another will likely be ineffective.

Alessandra Ferrajoli, MD: Maybe another consideration that we should discuss for our colleagues in practices, when is the time to discontinue therapy with a BCR receptor antagonist and move to another modality that we have such as a stem cell transplant or CAR T-cell? Because, we need to keep in mind that at least for the patient with high-risk feature such as deletion 17p or multiple chromosomal abnormalities, we know that those agents are great, they are very effective. But we are starting to see the median response duration.

William G. Wierda, MD, PhD: I would agree.

Shuo Ma, MD, PhD: Another important point is that, once patients progress on ibrutinib, their disease tends to accelerate. So, it's very important that, before you stop ibrutinib, you have to have your next line of therapy lined up. And most of the current clinical trials for a patient who progress after ibrutinib has a very short washout window of only about two to three days. Because I have learned that even once a patient is progressing on ibrutinib, ibrutinib is still having some anti-leukemia effect. So once you take the patient off therapy, they can really have an accelerated case.

William G. Wierda, MD, PhD: So you've got to have a plan.

Richard R. Furman, MD: I'm going to actually disagree with you, though. And I think certainly it's important to keep in mind that you know with the specific mutation in the Cys41, in BTK you do lose the irreversibility of BTK inhibition with ibrutinib, and so it still functions as a partial inhibitor, but only reversible. But I think that there are many, many patients who do progress on ibrutinib who don't have their disease explode. And the same thought also occurred in mantle cell lymphoma where the patients who progress on ibrutinib did exceedingly poorly. And we have data from mantle cell now—and of course there's a lot of issues with this analysis—that really shows that their survival after ibrutinib was longer than the time interval between their last therapy and ibrutinib. Richter's syndrome has an escape mechanism for ibrutinib that's certainly real and important to recognize. But if you're talking about a patient who has CLL, responds, and then progresses and still is CLL, then a lot of these patients still will be just like they were beforehand. And it's probably more an effect of the genomic instability that's required to develop the BTK mutation that is causing other changes to make the disease more aggressive than it is the actual BTK mutation itself. So, I think it's really more of a characteristic of the disease than it is of the therapy we're using.

Shuo Ma, MD, PhD: Right. It's very interesting that The Ohio State series showed that patients who progress after ibrutinib due to CLL progression mostly have the BTK mutation or the PLC gamma mutation. Whereas, patients who progress by transforming to Richter’s actually don't have those mutations. So they're transforming through a different mechanism.

William G. Wierda, MD, PhD: Tom, what's your thoughts on Richter's transformation in the era of the small molecular inhibitors? Do you think that's an event that is driven or in some way related to the small molecular inhibitors, or do you think the chemoimmunotherapy that they got before that, and the extended survival for these patients, is a factor?

Thomas J. Kipps, MD, PhD: Obviously Richter's transformation is a serious turn for the patient and has great prognostic implications. It always has. Unfortunately, Richter's transformation is probably several different types of diseases. We've known this even prior to the advent of these small molecule inhibitors. And there may even be a lack of a relationship between the clone of CLL and the clone of Richter's by looking at the so-called signature, the VDJ rearrangement. There also could be different histologies, and in some patients, particularly with the advent of therapy that's very immunosuppressive, it may be more like post-transplant lymphomas with EBV transformation.

So, we do have a broad category here. And the question is, are the patients with Richter's increasing with the advent of these newer agents? My impression is that it’s not. I think that patients are living longer and doing better. And, in the earlier trials when patients were going on to these studies, some of whom had many different treatments and actually might have succumbed to their disease had they not had these agents available. So, I think that keeping them surviving the CLL has allowed them potentially to experience Richter's transformation.

But there is some thought that there may be some relationship, of course, when you suppress a disease such as CLL. And there may be sub clones, and they're lurking, that are less sensitive to this drug. I'm struck by the use of some of the medications in some of these other hematologic indications and how well it's able to control the clone. It may differ, and so it's possible there could be some selection, although my impression is not.

Transcript Edited for Clarity