BTK Inhibitors as Treatment for B-Cell Lymphomas

Harry P. Erba, MD, PhD:Before we dive into more of the clinical data and the use of BTK [Bruton tyrosine kinase] inhibitors, let’s back up a little bit. Why don’t you give us an overview of what we’re talking about in terms of B-cell lymphomas?

Anthony R. Mato, MD, MSCE:In terms of where these drugs are utilized at this time?

Harry P. Erba, MD, PhD:Well, just the subtypes, for our audience.

Anthony R. Mato, MD, MSCE:Sure. So we would need a lot more time to go into all of the subtypes of B-cell lymphoma. There are so many. But essentially, we can break it down into the indolent B-cell lymphomas and the aggressive B-cell lymphomas. The indolent subtypes that we’ll discuss today are CLL [chronic lymphocytic lymphoma]; or SLL [small lymphocytic lymphoma]; marginal zone lymphoma; Waldenström macroglobulinemia; mantle cell, which morphologically looks like an indolent lymphoma, but biologically is more aggressive; diffuse large B-cell lymphoma, one of the more aggressive types. That’s kind of the spectrum of lymphomas where these drugs are tested. I didn’t mention follicular lymphoma because these drugs have been tested there and largely have not been very effective.

Harry P. Erba, MD, PhD:So prior to the advent of the BTK inhibitors, what were the therapeutic options? Let’s focus first on kind of low-grade lymphomas like CLL, SLL.

Anthony R. Mato, MD, MSCE:First of all, when the BTK inhibitors were approved for these diseases, it was a major paradigm shift. That was because these patients were largely treated with chemotherapy, chemoimmunotherapy combinations, or immunotherapies, anti-CD20 antibodies. There were very few so-called targeted agents available for patients prior to the advent of ibrutinib and other BTK inhibitors. So the standards of care, for example, which still are for some of these lymphomas, are chemotherapy combinations with anti-CD20 antibodies.

Harry P. Erba, MD, PhD:And we might have observed many of these patients with B-cell lymphomas for a while.

Anthony R. Mato, MD, MSCE:That is true. Indolent lymphomas are treated when they warrant intervention. Because the treatments are really palliative or are used to control the disease, we’re not starting a treatment for a patient just based on the presence of a diagnosis, but whether a patient has symptoms or signs present that are causing some issue that warrants an intervention. Across the B-cell lymphomas, there are different criteria that help one decide if a therapy is needed, but they’re all similar.

Harry P. Erba, MD, PhD:It does brace the question, though, that we know that the natural history of CLL could be quite heterogeneous. And we’ve learned about some of the prognostic factors—TP53mutations, 17p deletions, the unmutated immunoglobulin heavy-chain variable region, for example. And we know that those patients may have a worse survival, and a shorter time to requiring therapy. With all of these new drugs that we have, including the BTK inhibitors, do you think clinicians should think about treating those patients sooner?

Anthony R. Mato, MD, MSCE:I think it’s a research question at this time. There are no data yet published that have ever suggested that intervening on an indolent lymphoma or CLL changes the natural history or the biology of the disease. I think it’s very hard to design a study to answer that question appropriately, just because there are so few patients that a clinician would feel comfortable to randomize. I think we all feel strongly about individual patients, whether they warrant therapy or they do not. So I think it’s something to think about, but I don’t think we have enough information to know that the natural history would be altered, or the long-term effects for exposure to a drug that’s not needed for a patient.

Harry P. Erba, MD, PhD:Let’s come back to that. I think when we get to the end we’re going to talk about future directions. Maybe this idea of cure may start coming up as we develop all of these new therapies, and we’ll come back to that. So what BTK inhibitors are available or are nearly available for treating a patient with CLL and other lymphomas?

Anthony R. Mato, MD, MSCE:Well, there are 3 that are either available or are nearly available. Ibrutinib is the only BTK inhibitor that’s approved for treating patients with CLL. Acalabrutinib has been extensively studied in CLL, but is not yet approved in the frontline or relapsed/refractory setting. And zanubrutinib has been studied in CLL, but it is not yet approved in any setting. Ibrutinib’s approval really spans frontline and relapsed/refractory, so all patients.

Harry P. Erba, MD, PhD:Can you give us some insight as to the differences between these therapies? Is it AEs [adverse events], dosing schedules, things like that?

Anthony R. Mato, MD, MSCE:It’s a bit hard to draw differences across trials, and I think that’s probably one of the mistakes that’s made in the field—to take the collective experience of ibrutinib across thousands of patients on study, and many more in clinical practice, and then look at the smaller phase Ib/II trials that have been conducted. The hope of the next generation of BTK inhibitors is that they’re as active with maybe less toxicity. But it’s harder to judge that because of the fact that some of the newer drugs have less follow-up, [fewer] patients.

There have been head-to-head comparisons that have been conducted, but they have not yet reported. Those will probably be the most telling in terms of differences in efficacy and/or adverse events. Right now, I would say, as a class, they have similar activity and similar adverse events. It may be that there are subtle differences in the proportion of adverse events associated with 1 drug or another, or the AE profile may be slightly different because of off-target effects. But I think it’s a little bit dangerous to try to say right now that one is more effective or less effective or better tolerated or not. Fortunately, these trials have been conducted, so we’ll have answers but just not imminently.

Transcript edited for clarity.