William Wierda, MD, PhD: There are 2 main reasons why patients come off BTK [Bruton tyrosine kinase] inhibitor-based therapy, and 1 is for toxicities and intolerance, the other is for resistance. In patients who are coming off because they’re progressing on a BTK inhibitor, I think it’s important to have a discussion about how we manage those patients. Because we have seen patients have explosive disease if we abruptly stop the BTK inhibitor, particularly in those patients who are progressing. I wonder if, Carolyn, you can give us your practice on how you manage those patients progressing on a BTK inhibitor.

Carolyn Owen, MD: I think one of the interesting presentations at this ASH [American Society of Hematology] 2019 meeting was the update of the ECOG-ACRIN E1912 study that didn’t really, not to insult them, didn’t show a lot of new information but did comment on the population of patients who stopped the ibrutinib for intolerance, and then obviously at that point were doing well. They’d had a response to the drug. They didn’t have treatment requirements, so they were simply followed. And the median time to needing the next treatment was around 2 years.

And that actually has been my experience as well. We have always, when the patient stops therapy because they choose to, if you can’t manage the adverse event well enough and then they wish to discontinue, I wouldn’t normally immediately move to another line of therapy if they don’t have treatment requirements. And I have seen many patients go for a very long time because obviously, we’re using ibrutinib now in a very different context from the original patients in the phase I studies who were highly refractory and nearly dead before they started on the drug. When they stopped the agent, their disease took off. That’s not true for most patients today being treated with these agents.

From a true progression perspective, there’s still so much debate about what to do with a lymphocytosis change, and you’ve got the company providing you with advice, “Oh, you shouldn’t worry about it until it’s more than a certain level.” But in all honesty, the studies originally, they did have a treatment to progression. If the lymphocyte count is doubling and the patient is still asymptomatic, to me that is overt progression and I would, as you’re saying, plan to move to a next therapy not necessarily as an emergency.

Patients who have a lymphocyte progression and even if they have no symptoms, I do think that that’s a patient who still needs to be transitioned to another therapy, and I wouldn’t leave them off treatment for a long time and just stop the drug. If they’re clearly progressing, I tend to move to another therapy directly. For lymph node progression, I think that’s much more concerning, and then you’ve always got this risk of the rare patient who develops Richter transformation, usually lymph nodes, when they occur on a BTK inhibitor, those are the patients who I think tend to take off if the drug is stopped. I’m much quicker to transition and transition very closely even with overlap between ibrutinib and the venetoclax in a patient who has lymph nodes as their progression.

William Wierda, MD, PhD: Stephen, do you routinely overlap therapy if you’re transitioning from a BTK inhibitor to venetoclax-based therapy?

Stephen Opat, MBBS: Unfortunately, we don’t often have that opportunity. Many of our patients are treated on clinical trials, and there’s a washout period. But we do notice some patients, when you pause the BTK, even for surgery, they can have fairly rapid progress in their disease. The thing I wanted to add to what Carolyn was saying before is the effect of stopping the BTK depends on their disease status at the time of cessation. If they’ve had a complete remission, they’ve been on it for a while, and they’ve got a deep, complete remission, they’re likely to have quite a durable treatment-free period when you stop it. But if their disease isn’t controlled and you stop it, they’re likely to progress much sooner. So, I guess if a patient has to come off the drug, assessing their disease status at the time can be useful to predict what’s likely to happen.

Transcript Edited for Clarity