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BTK Inhibitors for Treatment of CLL


Lori A. Leslie, MD, an expert on chronic lymphocytic leukemia, provides a comprehensive overview of BTK inhibitors used in the treatment of CLL.


Lori A. Leslie, MD: Let’s talk a bit more about Bruton tyrosine kinase inhibitors, or BTK inhibitors. A question we get a lot is, what are these medications doing? It’s not chemotherapy, it’s not immune therapy. They’re called small molecular inhibitors. It’s a much more common type of medication that we use across oncology. These target a protein or an enzyme that the cancer cells are addicted to. In the case of BTK, all B cells have a pathway that tells them to grow and divide, or to stop. That growth loop goes through this enzyme Bruton tyrosine kinase. It’s been an appealing thing to target throughout B-cell cancers because we know that not only are normal cells reliant on this protein to survive, but many cancers, including CLL [chronic lymphocytic leukemia], are addicted to this protein. If we could block that growth loop, we potentially would have a great therapeutic target. That’s shown to be true in CLL.

The way BTK inhibition works is, you’ve got this overactive growth loop, so that stops. BTK also helps the cells hide and aggregate to what’s called their microenvironment. That’s where they get their nutrients and things like that, the cancer cells. Some examples of that are the lymph node space, bone marrow space, and the spleen. All of these cancerous CLL cells kind of grasp on. BTK inhibition helps to release that hold on their protective lymph node, bone marrow, or spleen space. When we start someone on a BTK inhibitor, examples of that include medications called ibrutinib, acalabrutinib, and zanubrutinib. Usually if they have a lymph node or something they can feel, if they have an enlarged spleen and they’ve lost their appetite due to that, they typically feel better as early as the first week they’re on treatment. What also happens commonly is as you release these cancerous cells from the lymph node and the bone marrow, the white [blood cell] count shoots up, and that can be very alarming to our patients if we don’t talk about that in advance. They’ve usually spent a lot of their time worried about the white count, trending it. We have patients who make an Excel spreadsheet about what their white count is over the year.

When you start a BTK inhibitor and you release the grasp on the microenvironment, it’s not that the cells are dividing, it’s just we can now see them on the blood work. I love how we tell patients to expect your white count to go up. We have patients who start with a white count of 200 cells per mm3, and it goes up to 400 cells per mm3. That’s OK. They feel well. We empower them with that information so that they don’t coincidentally end up at their primary care doctor with a high white count, and they send them to the ED [emergency department] thinking something is wrong. That’s a great marker of response to the treatment. Understanding how those therapies work helps our patients know what to expect. It’s very satisfying when they have these symptoms slowly accumulate, and all of a sudden they start a pill, and within usually a week or two, they’re already noticing significant improvement in symptoms.

We now have 3 FDA-approved options of BTK inhibitors in the frontline and relapsed/refractory setting for patients with CLL. The first approved was ibrutinib, and that’s a BTK inhibitor, but it’s less specific to BTK. It can also target a few other proteins. That has been available in the frontline setting based on a study called RESONATE-2, where they compared ibrutinib to an old antibiotic that had some chemotherapy properties called chlorambucil. It was a randomized study, so flip a coin, patients get one or the other. Across the board, patients who had ibrutinib did better than those who got the chemotherapy version, which was chlorambucil. Some of those outcomes we look at commonly include progression-free survival, like how long the drug is working. That was better with ibrutinib. And even overall survival on the longer follow-up several years in found that patients who started ibrutinib rather than chemotherapy in the frontline setting survived longer. This was one of the first studies that shifted us away from chemotherapy in the frontline setting and toward these targeted agents.

Since then, we’ve had 2 approved what they call next-generation BTK inhibitors, and they target BTK differently. They still target BTK the same way ibrutinib does, roughly speaking, but they’re a little more specific to that target. There have been head-to-head comparisons in the relapsed/refractory setting that show the next-generation [inhibitors] are better tolerated overall. The study that was looking at acalabrutinib in the frontline setting is ELEVATE-TN [treatment-naïve]. That’s looking at acalabrutinib with or without immune therapy vs chlorambucil chemotherapy in patients who have never had treatment before in CLL. It was the same trend that showed acalabrutinib, the BTK inhibitor, with or without the immune therapy was superior to the chemotherapy-based regimen in the frontline setting in terms of how long people stay in remission. It also has a favorable toxicity profile compared with chemotherapy.

The most recent kid on the block, zanubrutinib, which is also a next-generation BTK inhibitor, a little more specific than our first-generation ibrutinib, was approved based on multiple studies, including SEQUOIA. That looked at zanubrutinib compared with another previously common chemotherapy that we used in CLL, called bendamustine and Rituxan, or BR. Again, the BTK inhibitor was superior to chemotherapy with immune therapy. So across the board, we know—and there are several other studies that I’m not mentioning—that targeted therapy compared with chemotherapy in frontline CLL is preferred across the board. Chemotherapy has exited our treatment landscape and is no longer a recommended option in our guidelines based on the overwhelming data that not only are targeted therapies including BTK inhibitors better from an efficacy standpoint, but they also have a favorable toxicity profile overall.

Transcript edited for clarity.

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