Updates in CLL: What’s on the Horizon in CLL? - Episode 4

Resistance Mechanisms to BTKi in CLL


Richard R. Furman, MD, reviews resistance mechanisms to BTK inhibitors and how they affect treatment selection for patients with CLL.

Nitin Jain, MD: Now we’ll move to the third section, which will be led by Dr Furman, and talk about the evolving treatment landscape and new BTK [Bruton tyrosine kinase] inhibitors. We’ll first talk about what causes resistance to the BTK inhibitors. Dr Furman?

Richard R. Furman, MD: Thank you. Everyone often worries about the discontinuation of BTK inhibitors and rapid progression. It’s important to understand that in a patient who’s developing resistance, most of the mechanisms of resistance involve the BTK inhibitor going from being an irreversible covalent inhibitor to just being a reversible or partial inhibitor. We see the CLL [chronic lymphocytic leukemia] slowed but not stopped. When you remove the brakes, you sometimes have a release where you get a lot of rapid proliferation. Importantly, that’s only going to happen in patients who were stopping a BTK inhibitor as they’re progressing. We don’t see that happening in patients who are discontinuing in a deep remission or due to an adverse event. It’s only once the resistance has developed.

The interesting thing about resistance is there’s probably a lot we don’t understand. We have identified a number of single base pair mutations, the first one being a cysteine to serine mutation at position 481. The cysteine is required for the covalent inhibitor—ibrutinib [Imbruvica], acalabrutinib [Calquence], and zanubrutinib [Brukinsa]—binding to that sulfhydryl group and then blocking the pocket in BTK where ATP is supposed to go and activate the enzyme. The on-target effect of all 3 covalent BTK inhibitors is identical. That’s always important to remember. Any change in that pocket—either a mutation from the cysteine to serine and the absence of the sulfhydryl group preventing the BTK inhibitor from covalently binding and blocking the pocket, or the development of a bypass track like what we see with PLCG mutations that lead to constitutive activation—are going to be the same for all 3 BTK inhibitors. Patients who progress on acalabrutinib wouldn’t benefit from ibrutinib or zanubrutinib treatment and vice versa.

We have these defined mutations, but I’ve always been most interested in the idea that when we see a patient progress, the variant allele frequency for the mutation is never 100% of the cells. It’s always an important question as to what’s really driving all of the cells. We might see a variant allele frequency of 25%, which would mean half of the cells have an allele in them that will allow them to resist the BTK inhibitor. But we don’t know what’s driving the others. It’s far more complicated than we ever imagined, and this single base pair mutation might be a little simplistic.

What’s going to be most important is seeing the clinical outcomes of what would be the next-generation BTK inhibitors. By working through different modalities—basically reversibly blocking the pocket and not requiring that cysteine at position 481—it’ll be interesting to see whether they’re able to succeed. Importantly, if someone has a BTK bypass mechanism for their resistance, you wouldn’t expect these other BTK inhibitors to work. There’s a lot we need to figure out in terms of identifying ahead of time who’s likely going to respond and who won’t.

What I also find very helpful is trying to predict patients who are likely going to develop resistance. The 17p-deleted, TP53-mutated, and complex karyotype cases represent the majority of patients who are developing resistance to covalent BTK inhibitors. These are people who have CLL who get treated and respond but then progress. That’s different from those who progress through developing a Richter’s transformation where the CLL becomes a large cell lymphoma and the BTK inhibitors are ineffective at controlling that disease.

It’s interesting to think about all this. Going back to our previous segment, I believe that the combination of a BTK inhibitor and venetoclax [Venclexta] would be very effective in knocking out those resistant cells as well when you think about the fact that these single base pair mutations have been identified prior to the initiation of BTK therapy, suggesting that they’re there and developing during the watch and wait period and it’s only when we apply the pressure and eliminate the sensitive cells that they grow out.

Transcript Edited for Clarity