The Current State of BTK Inhibition in Chronic Lymphocytic Leukemia

Amber Koehler

Josie, before we really dive deep into the first of our three conversations all about chronic lymphocytic leukemia (CLL), why don't you start us off by setting the scene. When we're talking about our patients with CLL, what would you say are our main areas of focus?

Josie Montegaard

An important topic in the world of CLL is finding better tolerated treatments. While there is also a heavy focus on finding durable treatments that can lead to deep remission, half the battle is ensuring that treatments are well-tolerated so that patients can remain on them and derive long-term benefit. An area where we see this focus is in the evolution of BTK inhibitors. We have the first-generation BTK inhibitor ibrutinib, and now we also have the second-generation BTK inhibitors acalabrutinib and zanubrutinib. Although all of these drugs are FDA approved, zanubrutinib is currently only approved for mantle cell lymphoma. However, it is likely only a matter of time before it gets approved for CLL.

The big difference between the first- and second-generation BTK inhibitors is that the second-generation drugs are more selective for CLL cells. Although targeted therapies such as BTK focus on CLL cells primarily, they still have targets in other parts of the body, which can cause side effects. We're seeing that second-generation BTK inhibitors have fewer off-target side effects and are, therefore, better tolerated. The data show that this is specifically true for EGFR inhibitors.^1-3 We're seeing fewer skin and gastrointestinal (GI) toxicities and less activity in the Tec family of kinases, which we suspect has a role in the bleeding risk associated with BTK inhibitors.

These are all important pieces to consider when prescribing these medications to patients who have preexisting comorbidities. Down the line, we're going to see these drugs become even better tolerated with fewer incidences of bleeding risk, skin toxicities, diarrhea, hypertension, atrial fibrillation, and cardiac toxicities. Already we are seeing data in clinical trials supporting that second-generation BTK inhibitors are better tolerated.

Amber, have you seen these data?

Amber Koehler

I have, absolutely. One of the most important studies that compares first- and second-generation BTK inhibitors is the ELEVATE-RR trial.⁴ It's important to note that the data from this trial are specific to the relapsed setting, so there is some question about how generalizable it is to the front-line setting. I personally think that it is probably pretty translatable. This non-inferiority trial looked at higher-risk patients with CLL (those with 17p deletion or 11q deletion) in the relapsed setting who were randomly assigned to receive either acalabrutinib or ibrutinib. The researchers found that acalabrutinib was noninferior to ibrutinib in terms of progression-free survival, with fewer cardiovascular side effects. Specifically, acalabrutinib demonstrated decreased rates of high blood pressure, atrial fibrillation, and the more concerning ventricular arrhythmias or episodes of sudden cardiac death compared to ibrutinib. That certainly is an important factor to consider for patients with CLL who have cardiac comorbidities.

Another important study comparing BTK inhibitors in CLL was the 2019 work by Dr. Farrukh Awan and colleagues.⁵ This study evaluated acalabrutinib monotherapy in patients with CLL who were intolerant to ibrutinib due to side effects. They found that among patients who were taken off ibrutinib and placed onto acalabrutinib monotherapy, 72% did not experience recurrence of the side effects that they had with ibrutinib, 13% had recurrence of those same side effects at a lower grade, 11% had recurrence at the same grade, and 3% had recurrence at a higher grade.

Josie Montegaard

Amber, you touched briefly on the scary risk of sudden cardiac death or sudden unexplained deaths that we’ve seen on the ibrutinib arms of a variety of trials. To look at more specific examples of that, there was the FLAIR trial,⁶ which looked at ibrutinib plus rituximab vs. chemoimmunotherapy. On the ibrutinib arm, they saw eight sudden cardiac deaths compared with two on the chemoimmunotherapy arm. In this trial, they did find that preexisting cardiac disease and hypertension were risk factors. Additionally, use of angiotensin-converting enzyme inhibitors (ACEi) was also correlated with sudden cardiac death. That's something to keep in mind when choosing patients for these treatments and when reviewing their medication lists. Not only should medication lists be reviewed for drug-drug interactions but also for whether a patient who is on an ACEi may be switched to a different antihypertensive while on ibrutinib.

Similarly, in the ALLIANCE trial,⁷ they saw a 7% rate of unexplained, sudden death on the ibrutinib arms. That trial looked at ibrutinib plus or minus rituximab, again, vs. chemoimmunotherapy. The trial identified age as a primary risk factor for the sudden cardiac death or unexplained death. Again, this is something to keep in mind when choosing these treatments.

Amber, how do you choose whether a patient is a good candidate for ibrutinib vs. acalabrutinib?

Amber Koehler

That's a great question. One of the first branching points in the treatment decision for a patient with CLL is BTK inhibition vs. venetoclax-based therapy. From a BTK inhibitor standpoint, drug-drug interactions are going to be pretty similar between the two. The current formulation of acalabrutinib cannot be given with proton pump inhibitors (PPIs), so individuals who have Barrett's esophagus or severe reflux, who might not tolerate being switched from a PPI to an H2 blocker like famotidine, may be better candidates for ibrutinib (as opposed to acalabrutinib) due to that unique drug-drug interaction. As we've mentioned, for patients with CLL who have significant cardiac comorbidities, I tend to lean toward acalabrutinib over ibrutinib, or even outside of BTK inhibition toward a venetoclax-based therapy. 

A lot of the side effects from ibrutinib are dose dependent. In our practice, we feel pretty comfortable dose-reducing ibrutinib. Looking at some of the data, in the lab anyway, there is pretty equivalent BTK occupancy with ibrutinib doses of at least 2.5 mg/kg. For most people, that's a dose of 280 mg. We try to avoid dose reductions beyond that if possible, but I do have several patients on doses as low as 140 mg per day who have done well for several years.

Dose reduction has several implications. The first is that since many of the toxicities associated with ibrutinib are dose dependent, if you cut the dose, the side effects decrease. There are also financial implications for patients who are on the capsule formulation. These patients are now getting two vs. three capsules a day, which can cut down on cost.

Acalabrutinib tends to be a little bit harder to dose-reduce, simply because of its pharmacokinetics, but we can and do dose-reduce acalabrutinib for side effects as well.

The last thing I'll say about choice of BTK inhibitor in patients with CLL is that certain insurance companies are beginning to require patients to start on ibrutinib as opposed to acalabrutinib, at least from what I’ve seen. Josie, has this been your experience?

Josie Montegaard

Yes. That’s been something we've been contending with quite a bit lately. It’s really unfortunate because, as you said, based on their comorbidities, some people seem to be better candidates for acalabrutinib. That's why it's so important to know about the head-to-head data between the first- and second-generation BTK inhibitors and the cardiac side effects. We can use these studies to help get insurance companies to overturn denials and allow our patients to start on this class of drugs safely. Ultimately, everyone's goal is to get patients to have a great treatment response and to keep them on this treatment, usually indefinitely. Therefore, it needs to be tolerable and safe for them.

We’ve talked quite a bit about the more life-threatening side effects of these treatments, but let’s now talk about the day-to-day toxicities, such as rashes, GI toxicities, and arthralgia. These toxicities can be nagging, which can sometimes cause patients to want to stop treatment prematurely, before they’ve derived the maximum benefit from it. How do you typically help manage these toxicities on a day-to-day basis?

Amber Koehler

One of my tricks for ibrutinib specifically is having patients take it in the evenings as opposed to the mornings. That seems to help cut down on some of the GI toxicities, such as stomach upset, nausea, and diarrhea.

This is entirely anecdotal, but I've seen it several times and have heard it from others that if patients are on the tablet formulation of ibrutinib and they are switched over to the capsules, it can decrease or resolve some of the arthralgias and myalgias that can occur with ibrutinib. I've had some patients try a shot of pickle juice or use magnesium supplementation for cramping—it helps for some people, but not all. Staying well hydrated is, of course, important to cut down on some of the cramping as well. What are some of your tricks, Josie?

Josie Montegaard

We have a similar bag of tricks. For the arthralgia and myalgia, in addition to the magnesium supplements, we'll sometimes recommend tonic water because the quinine can be really helpful to soothe the muscles. We sometimes recommend non-steroidal anti-inflammatory drugs (NSAIDs) sparingly because they can increase the risk of bleeding along with the BTK inhibitors. It's not our first choice for pain management, but if someone's platelet count looks good and they historically don't have any other bleeding risk factors, then sometimes we'll tell them that NSAIDs are OK to take. We’ve even had good success with COX-2 type of anti-inflammatory medication, where we don’t see as many bleeding risks. Specifically for acalabrutinib, when we see some of those nagging headaches, especially in the beginning of treatment, caffeine seems to do the trick to manage those. Patients really do not mind being told to have an extra cup of coffee throughout the day to manage that side effect.

Amber Koehler

Absolutely. Thankfully, with regard to the headaches we can see with acalabrutinib, if we can support patients through those first few weeks with caffeine, acetaminophen, and hydration, they do tend to resolve.

Another less serious side effect I’ve seen quite a bit with ibrutinib is brittle nails and nail splitting. I haven’t found a great solution to that. I’ve had some patients who saw some improvement with biotin, but I’m curious about how you manage that.

Josie Montegaard

Similar to your experience, we’ve found that biotin doesn't work for everyone. A couple of my patients have tried the clear cuticle-strengthening nail polish. Some of them have found a little bit more of a benefit there than with the biotin. What are you and your colleagues doing, if anything, for the skin side effects like rashes?

Amber Koehler

That's tough. Most commonly we see pimply follicular rashes, so we use low-dose steroid creams if it's bothersome, or dose reductions, depending on the circumstances. The other thing that can get a little tricky, particularly when starting patients on ibrutinib on a clinical trial where they're also starting drugs like trimethoprim/sulfamethoxazole and allopurinol, is making sure that the rash is truly due to the BTK inhibitor as opposed to something else that they've started at the same time. Beyond the topical corticosteroid creams, I haven't found anything else other than good moisturizers that seem to help. What about you?

Josie Montegaard

Yes, our experience has been similar. The topical steroids tend to do the trick. In line with data showing second-generation BTKs having less activity on EGFR and thus fewer skin toxicities,⁸ I don't tend to see the skin side effects quite as much with acalabrutinib as I do with patients on ibrutinib.

What do you all typically do in terms of holding BTK inhibitors perioperatively to reduce bleeding complications?

Amber Koehler

We follow the package insert recommendations to hold BTK inhibitors 3 to 7 days before and after any procedure. For lower-risk procedures such as colonoscopy, esophagogastroduodenoscopy, and bronchoscopy, I would typically say 3 days before and after. For more significant procedures, such as total hips, total knee, any sort of orthopedic or major surgery, BTK inhibitors should be held for 7 days before and after.

As we know, CLL is associated with a significantly increased risk of non-melanoma skin cancers; there is a 6 to 8 times higher risk for basal cell and squamous cell carcinomas compared to the general population. For that reason, we see many patients getting Mohs procedures. I used to say to hold BTK inhibitors only 3 days before and after, but even then, we saw some pretty significant bleeding with Mohs procedures. Most of the time in our practice, we now recommend holding BTK inhibitors for 3 to 5 days before and after a Mohs procedure.

It's important to remember that there is a risk for flare when we hold BTK inhibitors. Approximately one quarter of patients who hold ibrutinib will develop a disease flare. This can present with increasing white blood cell count and lactate dehydrogenase, drenching night sweats, fevers, and just generally feeling really unwell. I have also seen it present with resurgence of thrombocytopenia. This can be managed by restarting the BTK inhibition plus or minus steroids. Is that pretty consistent with your experience?

Josie Montegaard

Yes, that's what we'll do as well. The other thing we do to try to prevent the flare is encourage our patients to delay any non-emergent procedures until they've been on treatment consistently for at least 6 months to 1 year. Obviously, if someone needs an urgent Mohs procedure—that typically tends to be the most common procedure that comes up out of the blue—we work around it. We try to minimize the perioperative hold as much as is safe and potentially use steroids on top of it if patients show evidence of disease flare. If we can get patients to delay their routine colonoscopy, dental procedures, or elective hip replacement, that's much more helpful. We see the flares across the board regardless of the generation of the BTK inhibitor. Unfortunately, I don't think we're going to get around that because it's more of the nature of CLL as opposed to the drug itself. At the very least, there are steps we can take to prevent and/or manage flares.