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Resistance to Therapy in CLL

Panelists: Jacqueline Barrientos, MD, Zucker School of Medicine at Hofstra/Northwell; Stephen Opat, MBBS, Monash Health; Carolyn Owen, MD, University of Calgary; Shuo Ma, MD, PhD, Feinberg School of Medicine at Northwestern Medicine; William Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center
Published: Thursday, Mar 12, 2020



Transcript:

William Wierda, MD, PhD: Let’s talk a little bit about resistance and mechanisms of resistance. Maybe start first with BCL2 [B-cell lymphoma 2 protein] inhibitor resistance and what do we know about that?

Stephen Opat, MBBS: Venetoclax resistance occurs, there are some mutations that affect the binding of the drug to BCL2, but there are also changes in other antiapoptotic proteins that confer resistance and perhaps even other mechanisms that haven’t been explored. The other issue when we’re thinking about resistance is also adherence. Sometimes you think a patient is resistant, but if you don’t take the medication it’s not going to work. I think less is known about resistance to the BCL2 inhibitors like venetoclax just because it’s a newer drug.

Whereas, much more is known about BTK [Bruton tyrosine kinase] inhibitors, with ibrutinib. It appears that all the BTK inhibitors share a common resistance mechanism; there has been a specific mutation described with zanubrutinib that doesn’t appear to happen with the other inhibitors. It’s usually mutations in the kinase domain, C481S, and there’s also PLC-gamma-2 activating mutations. And there’s also activation of other pathways that bypass it. These are all acquired resistance. Primary resistance does occur but it’s rare. It’s rare in CLL [chronic lymphocytic leukemia], but in other diseases there can be mutations where the requirement for B-cell receptor pathway signaling is not so important. I don’t think we are quite at the stage where we can do a gene profile on the tumor and decide you should have this drug rather than that drug. But I can foresee a day where that may be possible when we get more information on how the genetic complexity fits in in the overall treatment schema.

William Wierda, MD, PhD: Mutations in BTK and PLC-gamma-2 are seen in patients who are developing clinical resistance. I think one concept is monitoring for those mutations, and if that’s important, then I wonder if Dr Ma, you can give us your thoughts on monitoring for mutations, whether we should be doing that, and when testing for mutations in BTK and PLC-gamma-2 might be helpful and informative for us.

Shuo Ma, MD, PhD: I think clinically just finding a small amount of mutation doesn’t necessarily need to change your management. But if I’m seeing a patient for whom I have some suspicion that there might be disease progression, for example, if a patient had previously been very well controlled for a number of years and all of a sudden is starting to have rising white cells or maybe borderline size lymph node that’s starting to get a little bit bigger, it’s not a very clear progression yet, but I’m sensing something is happening. I think that’s the time that’s most helpful to me to send a mutation analysis. And if I do see a mutation being present, for example, the BTK C481S mutation or the PLC-gamma-2 mutation, I’ll have a very high level of suspicion, I’ll be planning my next step. I don’t necessarily need to switch treatment if there’s no overt clinical progression, but I will have my next step ready when the time comes.

Transcript Edited for Clarity

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Transcript:

William Wierda, MD, PhD: Let’s talk a little bit about resistance and mechanisms of resistance. Maybe start first with BCL2 [B-cell lymphoma 2 protein] inhibitor resistance and what do we know about that?

Stephen Opat, MBBS: Venetoclax resistance occurs, there are some mutations that affect the binding of the drug to BCL2, but there are also changes in other antiapoptotic proteins that confer resistance and perhaps even other mechanisms that haven’t been explored. The other issue when we’re thinking about resistance is also adherence. Sometimes you think a patient is resistant, but if you don’t take the medication it’s not going to work. I think less is known about resistance to the BCL2 inhibitors like venetoclax just because it’s a newer drug.

Whereas, much more is known about BTK [Bruton tyrosine kinase] inhibitors, with ibrutinib. It appears that all the BTK inhibitors share a common resistance mechanism; there has been a specific mutation described with zanubrutinib that doesn’t appear to happen with the other inhibitors. It’s usually mutations in the kinase domain, C481S, and there’s also PLC-gamma-2 activating mutations. And there’s also activation of other pathways that bypass it. These are all acquired resistance. Primary resistance does occur but it’s rare. It’s rare in CLL [chronic lymphocytic leukemia], but in other diseases there can be mutations where the requirement for B-cell receptor pathway signaling is not so important. I don’t think we are quite at the stage where we can do a gene profile on the tumor and decide you should have this drug rather than that drug. But I can foresee a day where that may be possible when we get more information on how the genetic complexity fits in in the overall treatment schema.

William Wierda, MD, PhD: Mutations in BTK and PLC-gamma-2 are seen in patients who are developing clinical resistance. I think one concept is monitoring for those mutations, and if that’s important, then I wonder if Dr Ma, you can give us your thoughts on monitoring for mutations, whether we should be doing that, and when testing for mutations in BTK and PLC-gamma-2 might be helpful and informative for us.

Shuo Ma, MD, PhD: I think clinically just finding a small amount of mutation doesn’t necessarily need to change your management. But if I’m seeing a patient for whom I have some suspicion that there might be disease progression, for example, if a patient had previously been very well controlled for a number of years and all of a sudden is starting to have rising white cells or maybe borderline size lymph node that’s starting to get a little bit bigger, it’s not a very clear progression yet, but I’m sensing something is happening. I think that’s the time that’s most helpful to me to send a mutation analysis. And if I do see a mutation being present, for example, the BTK C481S mutation or the PLC-gamma-2 mutation, I’ll have a very high level of suspicion, I’ll be planning my next step. I don’t necessarily need to switch treatment if there’s no overt clinical progression, but I will have my next step ready when the time comes.

Transcript Edited for Clarity
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