Treatment Resistance With Novel Therapies in CLL

Nicole Lamanna, MD:With these new agents, however, none of these novel therapies are necessarily curative just yet. We know that there are resistant mutations that have developed with folks even on ibrutinib. Many of us are familiar with BTK [Bruton tyrosine kinase] and PLC-gamma [phospholipase C-gamma] mutations, and these are something that we can obtain for our patients.

Another presentation that is being highlighted at this meeting was actually looking at a resistance mechanism for venetoclax, looking at a mutation called the Gly101Val mutation. This can confer resistance to venetoclax, and this is something that obviously is brand new for us. This is one of those things that obviously there are, since venetoclax is newer on the scene than ibrutinib, we are starting to now see some folks who will progress on venetoclax. And so we’re learning about resistant mutations with the use of this drug.

And interestingly enough, the data had serial samples on their patients. And so they identified this mutation many months earlier than the patient actually presented with true progression. So this could be utilized going forward. This might be important when we start talking about how we can combine these agents, and, looking at minimal residual disease, whether we can identify some of these mutations earlier on, so you’ll sort of then know that the patient may become resistant eventually or have actual true progression, and what are we going to do about it at that point? Do we intervene sooner or do we not?

So, I think as we learn about some of these mutations with these novel agents more and more, that will help us make treatment recommendations or change treatment recommendations in our patients possibly sooner, depending upon their disease characteristics, age, and comorbidities. This will be important going forward to learn more and more about the biology and about some of these mutations with these novel agents.

The treatment of relapsed/refractory patients with CLL [chronic lymphocytic leukemia] is emerging. Now that a lot of folks are getting ibrutinib as their frontline therapy, there’s obviously more and more emerging data on what do you do post-ibrutinib. One of the key therapies that many of us are using after ibrutinib failure tends to be venetoclax or a Bcl-2 inhibitor. For ibrutinib patients who haven’t failed but are intolerant, I think you have more options. You can go to another B-cell receptor agent, whether it be a PI3-kinase inhibitor, there are definitely more options to do that if you’re just intolerant to the drug. But true failures or progressions of their disease on ibrutinib, there’s definitely emerging data showing that venetoclax can salvage those individuals. And I think that’s extremely important and key.

We don’t necessarily have the contrary. For folks who may have started venetoclax first with some of these new trials that are running, can you salvage then to ibrutinib? The likelihood is yes because they’re different pathways. And so I think that you can, but we still have to gain that data as well. But for the majority of patients who are getting ibrutinib in the front line, this is completely a reasonable pathway approach. And we have much data that was updated and presented at ASH [the American Society of Hematology meeting] this year, looking at the MURANO data, looking at venetoclax and rituximab in the relapsed/refractory population. So that’s completely an acceptable means of therapy for those relapsed/refractory folks.

Transcript edited for clarity.