A Rapid Shift in Treatment for Chronic Lymphocytic Leukemia - Episode 9

Resistance Mechanisms Associated With BTK Inhibitors


Nicole Lamanna, MD: Let’s hit the relapsed/refractory population. Let’s talk about mechanisms of resistance with ibrutinib. Who wants to?

Javier A. Pinilla-Ibarz, MD, PhD: Jan, of course.

Jan Burger, MD, PhD: Resistance to BTK [Bruton tyrosine kinase] inhibitors is a topic, but we should first say it’s not a very common clinical problem. It is a problem we encounter in high-risk patients, oftentimes patients with either 17p deletion or maybe who have 17p deletion and prior exposure to chemoimmunotherapy or complex karyotype. Those patients have remission duration on BTK inhibitors that are approximately 3 years or so.

There’s a sizable number in this high-risk population who eventually progress. They respond well but then progress. In those patients, oftentimes what is seen are point mutations or PLC-gamma-2 mutations, which are related to a kinase that’s in the B-cell receptor signaling pathway and that turns on the pathway independent of BTK.

Interestingly, they are oftentimes not found in the majority but oftentimes in a small subpopulation of CLL [chronic lymphocytic leukemia] cells. Whether they are driving the resistance is not entirely clear. From a practical standpoint, it is good to identify high-risk patients in the relapsed setting and to be aware that patients, if they respond to BTK inhibitors, if that’s used, to identify those that relapse and then what is the salvage strategy right now. If a clinical trial is not available, then there are good data with BCL2 antagonist or with venetoclax to be used in that situation.

Nicole Lamanna, MD: We saw lots of data about some of the new noncovalent BTK inhibitors at this meeting. Do you want to comment a little briefly before we go more into the relapsed?

Javier A. Pinilla-Ibarz, MD, PhD: They are quite interesting data. Today the LOXO-305 data were presented for the first time as far as I know. It’s quite exciting to really understand that. I fully agree about the onset of these resistant mutations. I know that’s not as common, or at least really limited to this high-risk population. Definitely, in the future we’re going to have another alternative besides the classic BCL2 inhibitor. It seems that they are reversible, contrary to the irreversible action of the ones that are available. They may have a role in those patients, who once again may benefit from these long-term therapies.

It has been shown that all those patients with a specific mutation, with C481S, can be salvaged. And obviously there’s very short follow-up and these are very early data. This still need to be expanded. The same thing, we are waiting to see the data with ibrutinib to mature as well the R51. I think it’s quite an exciting time, because we are really bringing more drugs to the treatment of patients, who may not go well at some point with the standard BTK therapies.

Richard R. Furman, MD: It’s very important, whenever you’re discussing the cysteine 481 serine mutation, that we talk about Dr Burger’s data with regard to the appearance of that mutation or that mutation probably preexisting the initiation of therapy.

Javier A. Pinilla-Ibarz, MD, PhD: Absolutely.

Richard R. Furman, MD: And explaining how that might impact future therapeutic options. I think that’s something we talk about when these novel reversible inhibitors prevent those clones from growing out, because they’re already there. That would be how we most immediately see that result in different outcome.

Farrukh Awan, MD: If I may add to that, these are again extremely important research questions. Again, that assay is not widely available outside a few academic centers. We still don’t know what level of mutational burden correlates with progressive disease. Patients with a low burden of mutations can still have progressive disease, and patients with a high burden may not have progressive disease clinically. The other question is that not everyone who has the mutation progresses.

It still is an excellent tool to identify those patients who would be at high risk for progression. But does that really change how we manage our patients, the vast majority of our patients, right now? I’m not sure if that’s the case. Most of our patients would progress clinically, and then they would be treated with an alternative agent at this point.

In that regard, having access to that test would be very helpful for these alternative BTK inhibitors. But we also have to caution that when patients do progress on BTK inhibitors, typically we suggest that they don’t have a long disease or drug holiday when they transition from 1 agent to another, because a lot of us have seen patients progress fairly rapidly once we stop the BTK inhibitor if they have documented clinical progression.

Transcript Edited for Clarity