Treating CLL That Progress With BTK Inhibitor Therapy

Richard Furman, MD, Morton Coleman MD, Distinguished Professor of Medicine, Weill Cornell Medicine, New York, NY, explains how best to control CLL patients who progress on BTK inhibitor therapy.

Transcript

I'm Richard Furman, MD. I am the Morton Coleman MD, Distinguished Professor of Medicine at Weill Cornell Medicine, in New York, New York. I'm here today to discuss my presentation on BTK inhibitor progressors.

One of the things I think that is important is for us to try to identify ahead of time who are those people that are likely to progress on BTK inhibitors. What's important is also the 2 types of progressors that we have.

One group are going to be those people who develop a Richter's transformation. The second group are going to be those who develop a resistant mutation, most commonly of BTK cysteine 481 cyrine mutation, or a PLC-gamma mutation that leads to a bypass pathway, both of which lead to resistance BTK inhibitors.

Being able to identify these patients ahead of time can afford us different opportunities to treat these patients in different ways. But it's also important for us to know what to do when we have a patient who does progress.

With regard to those patients who progress while on BTK inhibitors, we have an array of different agents that are certainly very helpful and effective. Single agent venetoclax would currently be considered the standard of care.

We are working on a series of reversible BTK inhibitors, namely, ARQ 531, SNS-062, and LOXO-305, all of which are able to bind BTK as a reversible or non-covalent interaction. This non-covalent interaction allows it to work even in the presence of the BTK mutation. That might enable us to obtain or have efficacy in patients who do have resistance.

This would, in theory, allow us to not lose effectiveness in patients who do develop these mutations. That's certainly one strategy going forward for helping prevent or deal with these situations as they arise.

Most notably, using these instead of ibrutinib or acalabrutinib, both of which are sensitive to the mutations, would allow these patients to never actually progress and maintain efficacy.

Unfortunately, those people who have a PLC-gamma mutation would still demonstrate disease progression and not respond to the novel BTK inhibitors. It is important to have other therapeutic modalities that would work.

There are a large array of other molecules in clinical trials, including VLS-001, CAR T-cells, AZD-5991, all targeting different molecules that will hopefully obtain efficacy and reinduce remissions. With regard to predicting patients who are likely to develop the resistance ahead of time, certainly, trying to intervene in a different manner might help.

One option would be a combination of ibrutinib plus venetoclax, with the combination of a BCR antagonist and a BCL-2 antagonist, being able to, one, avoid having the resistant cells grow out, and two, also generate very deep remissions very rapidly.

Another option would be to see that if we intervene early in patients who are likely to develop the BTK resistant mutations, if we can actually intervene before those mutations develop.

We have data now from Jan Burger at MD Anderson that shows that the BTK mutation often develops while the patient's in watch-and-wait, and then we actually select for it when we start ibrutinib therapy.

If we were to be able to predict ahead of time who these people are going to be, and actually start them at that time, maybe earlier, before they would have developed a BTK mutation, we might be able to even prevent it from actually occurring at all.

Important risk factors for the likelihood of developing progression on a BTK inhibitor include p53 dysfunction, complex karyotype, all the things that really predict for genomic instability and the ability to have ongoing mutation.

Those are the things that I think that are really important now for trying to identify how best to control those CLL patients who are going to progress on BTK inhibitor therapy.

The one other group to mention is actually those patients who are going to develop a Richter's transformation. Of course, BTK inhibitors don't control Richter's transformations very effectively.

If we couldn't somehow predict ahead of time who are those people that are likely to develop a Richter's transformation, that may also be an opportunity to intervene earlier, hopefully, before the Richter's develops, or also intervene differently.

What I find most interesting are data looking at NOTCH1 mutations, certain stereotyped V genes, and TP53 abnormalities and complex karyotype, all being important risk factors for Richter's transformations.

Once again, with these novel prognostic markers, being able to predict ahead of time who are the ones that are going to run into trouble would allow us to intervene differently, and hopefully, prevent these events from happening.