Javier Pinilla-Ibarz, MD, PhD

In the last part of this wonderful conversation, we’re going to discuss the management of BTK [Bruton tyrosine kinase] inhibitor–associated toxicity. This is something we discuss among us all the time because we need to be prepared and ready to work so we can keep patients on the drug. That’s the goal. Let’s review the adverse events as we share with BTK inhibitors, and let’s go to the first questions. What monitoring and management strategies do you recommend? These are going to bring you a few issues. What are the key parameters to monitor when patients are on these BTK inhibitors? When should patients be followed? When should we do these follow-ups, and how we are sure that these patients achieve the optimal care? How do we deal with the adverse effects? Let’s start with Lisa. Katie you can jump in anytime.

Whenever it comes time to start a patient on therapy, it takes several of us to get 1 patient going. Typically, the conversation is starting with the adverse-effect profile right after the decision is made about which therapy the patient will go on. With BTK inhibitors, in general, the first thing we’re cognizant of is the patient sitting before us, that they’re likely coming in with some comorbid conditions. For the patients coming in with hypertension or a history of atrial fibrillation or arrhythmias, or perhaps are on some other medications—particularly cardiac medications, which may have significant interactions—we have to consult with pharmacy.

Katie comes into play when we’re looking at the medication list that the patient may be on, and we’re trying to see if the patient can be switched out. The first thing is concomitant medications. We’re very fortunate at our institution [Moffitt Cancer Center] to have a cardio-oncologist who’s very familiar with these agents. For patients coming in with underlying comorbid conditions—arrhythmias, on antiplatelet drugs or direct oral anticoagulants, hypertension history—we want them to be engaged with our cardio-oncologist to make sure we can fine-tune things. With BTK inhibitors, the risk for cardiac arrhythmia and bleeding are omnipresent. Hypertension isn’t an immediate adverse event or risk, but it can occur in time with the patient. Most providers and even some patients don’t think about it.

We tend to think that when we start drugs, the adverse effects that the patient is going to experience are going to be in the first few weeks, but hypertension is 1 that can come in time. We want to make sure we’re fine-tuned from the start and that our patients are on therapy. But most important, once the patient starts on drug, we want to see them pretty closely in follow-up. We recognize that the patient might be absorbing 20% of the conversation when told, “This is the therapy you’re going to be receiving. This is the adverse effect.” All that patient education is not absorbed at that appointment. We like to see those patients weekly, at least for the first month, and then graduate them out a little thereafter. At least for those first 3 months, we’re following those patients pretty closely.

Another big teaching point that we have to discuss with our patients is the mechanistic effect of the drug. We can see an increased lymphocytosis with these BTK inhibitors because of the blocking of a signal, where you’ll see an increase in peripheral lymphocytosis in addition to the regression in the lymphadenopathy. A lot of education has to go with our patients to explain that this isn’t a disease progression. Rather, this is a mechanism of the drug. But we might see this increased lymphocytosis for a while, but concomitantly we have to be monitoring out as well for uric acid levels. We don’t see true tumor lysis, but hyperuricemia can occur as well with a cell turnover.

We also have to pay attention to patients who are starting with cytopenia. BTK inhibitors don’t rapidly clean out the bone marrow, for lack of a better term. Sometimes those cytopenia do get worse before they get better, particularly the anemia from the cytopenia. We’re cognizant of looking out for neutropenia and treating that with an aggressive growth factor, but seeing that patient in pretty close follow-up at least for those initial 3 months is important. Because of those visits, you’re recirculating that patient education, which maybe they’re not absorbing in the beginning. But you’re also reiterating the adverse effects of the drug that the patient may be experiencing.

Arthralgia is probably the most difficult toxicities to manage. Why is that? Well, we know our patients can come into this disease with underlying arthritis or rheumatologic conditions, and now you’re going to impart a drug on the patient that can give them arthralgias. Sometimes we’ve seen pretty debilitating arthralgias in our patient population. The treatment of choice typically is an NSAID [nonsteroidal anti-inflammatory drug]. We all want to doit, but patients are at an increased risk for bleeding with BTK inhibitors as a class effect. Giving them a concomitant NSAID could also increase the risk for bleeding, particularly GI [gastrointestinal] bleeding. Sometimes, we have to manage that with dosing modifications. Occasionally we’ll give the patient a Medrol pack as well. But arthralgia is the 1 that can be most difficult to manage.

Sometimes we see skin rashes as well on our patients. We have to make sure we’re discerning that it’s not shingles and not TKI [tyrosine kinase inhibitor] in our patient population. We like to see those patients in clinic pretty close in the beginning. Diarrhea is 1 that we can also see in our patient population. Because this is an older population, diarrhea could be debilitating to our patients, resulting in quick electrolyte imbalances; it’s fatiguing on them too. It’s something else that we have to closely watch out for in our patient population. It takes a lot of people to get a patient started on a BTK inhibitor, from the pharmacist to the nurse, who are calling the patient within the first week to make sure the patient is doing well on the drug and taking the drug appropriately…. As Katie mentioned earlier, taking it consistently is important because sometimes, our patients may be taking it a little more or less than. Maybe at the 24-hour period or during the 12 hours or unsure. “Can I take this with food or water?” Maybe they didn’t remember, or maybe we missed a medication that perhaps should have been on their medication list but was not. Now is a good time to go through the medication list again with the patient.

 You brought up a lot of great points. The only thing that I would add is that ibrutinib and acalabrutinib, or BTK inhibitors, are most of the time prescribed from a specialty pharmacy. These patients have other comorbid conditions that they see their PCP [primary care physician] for, and they’re getting their normal medications filled at a CVS or Walgreens. These specialty medications may not be on that medication list. This is where we’ve caught a lot of potential drug interactions. It’s important that patients understand that we need to be in the know of all medications they’re on all the time. There’s also the risk of bleeding. They need to hold them at the BTK inhibitor anywhere from 3 to 7 days pre and post a procedure, including a dental pulling. The dentist may not think to ask about a bleeding recipe on a BTK inhibitor. Lisa brought up a lot of great points. It’s important that we monitor these patients up front and that patients understand that just because they aren’t having an adverse effect during the first week of treatment, that doesn’t mean it may not show up 6 months down the line.

Excellent points. You guys hit on everything. I want to emphasize the flexibility of the therapies we have, and the possibility that we can deal with modifications to improve, or at least to try to mitigate some of the adverse effects that we’re discussing. In the end, we want patients to stay on the drugs as long as they can. There’s no doubt that intolerance is something we deal with in our daily practice. The more drugs that are available, the more intolerance we’re going to see. Hopefully, we’re going to continue to take care of our patients.

I also want to emphasize that it’s a multidisciplinary team effort, as you guys pointed out multiple times. We have great pharmacists, advanced practitioners, and nurses taking on patients to see how they’re doing. At the same time, we collaborate closely with our fellow cardio-oncologists and other parts of the team because it’s important to bring it all together. More recently, IV [intravenous] also play a role in new problems with COVID-19, where we’re trying to be very careful of how our patient deals with this problem.

This was an excellent conversation. Thank you and to our viewing audience. We hope you found these 

® to be rich and informative. Thank you very much for your attention.

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Lisa Nodzon, PhD, ARNP, AOCNP; Katie Tobon, PharmD, BCOP; and Javier Pinilla-Ibarz, MD, PhD, share insight on strategies for the monitoring and management of BTK inhibitor–associated toxicities in CLL and review the importance of a multidisciplinary approach to treatment.

Managing AEs With BTK Inhibitors in CLL

Let’s review the new things coming up. We’re going to discuss many of them. I’m going to start with zanubrutinib, another second-generation BTK [Bruton tyrosine kinase] inhibitor, which has a very interesting adverse-effect profile based on the data. Lisa, do you have any comments regarding this phase 3 ALPINE trial in refractory patients?

 When it comes to the BTK inhibitors, what’s nice in the field—with ibrutinib, then acalabrutinib, and now zanubrutinib on the horizon—is that we have multiple options for our patients. It comes down to decision-making, looking at similar efficacy and adverse-effect profiles. As we were talking about earlier, when it comes to decision-making for patients, BTK inhibitors in general have a class effect. The ones that excite us the most are the cardiac ones and the ones for bleeding because the patient population we’re seeing comes into the disease with comorbid conditions, particularly hypertension or a history of cardiac arrhythmias. They may already be on an anticoagulant or an antiplatelet drug, and now the BTK inhibitors come in. We have these BTK inhibitors once or twice a day.

The ALPINE trial showed that zanubrutinib is also tolerated in patients, although we may see more hypertension. We have another drug on the market for patients to select from. A nurse practitioner sees patients and manages toxicities, and a lot of my job is in the support of the patient and those adverse events. The safety data that came out of the ALPINE trial was for a drug that’s well tolerated in the patient population. With these BTK inhibitors, their efficacy comes from the patient maintaining themselves on the drug. For the patients to be maintained on the drug, they have to tolerate the drug. The safety data that came out of the ALPINE trial looked pretty good in terms of tolerability.

 You’re completely right. There were low rates of A-Fib [atrial fibrillation] seen in the trial compared with ibrutinib. You can’t cross-compare with a trial, but you can look at acalabrutinib in ELEVATE. But the population of patients is completely different. It is not as heavily pretreated and obviously is less risk population, and this may play a role on these data. It’s a relatively short follow-up. It’s still unclear with hypertension and neutropenia, but…we can still see the signal with the bruising, hematomas, and sometimes the bleeding, and other things can be seen with BTK.

NCCN [National Comprehensive Cancer Network] recognizes zanubrutinib in situations where other BTK inhibitors can’t be given because of adverse effects. It’s very likely that we’re going to have this drug approved. As you know, it’s approved for mantle cell lymphoma, Waldenström macroglobulinemia, and marginal zone leukemia. The data were presented and a press release reported from the SEQUOIA trial, a very large trial with multiple arms that was presented at ASH [American Society of Hematology Annual Meeting]. This compared zanubrutinib with BR [bendamustine, rituximab] as the classical Alliance for Clinical Trials in Oncology trial. It seems like the adverse-effect profile was quite good.

There also was a presentation in another arm, in the high-risk population, combining zanubrutinib with venetoclax in high-risk patients, including those with 17p. It’s an early readout. We still need to have further follow-up, but they’re striking data, as we’ve seen with other BTK inhibitors in this high-risk population. There are more BTKs in the pipeline. Pirtobrutinib is a different kind of BTK inhibitor. It’s reversible. We’re dealing with irreversible, or covalent, inhibitors, like the ones we’ve discussed: ibrutinib, acalabrutinib, and zanubrutinib. However, the noncovalent, or reversible, inhibitors are coming down the pike. Pirtobrutinib was presented in the BRUIN study, a phase 1/2 study of a very heavily pretreated population of patients with more than 4 or 5 lines of therapy, many of them double refractory. 

 means refractory to BTK inhibitors as well as the BCL2 inhibitor venetoclax…. With the follow-up that we’ve already seen, there’s very good durability of a drug that’s coming up. It’s going to face many other BTKs in the market, but it’s very exciting to see these new BTK inhibitors coming up.

Another important thing is combination therapy, which was a big theme at ASH. The main one was the CAPTIVATE trial, which combined ibrutinib with venetoclax. We’ve seen the fixed-duration therapy many times. CLL14 has already been described in 4 to 5 years of follow-up. We’ve seen that the fixed duration is 1 year of this treatment. Obinutuzumab-venetoclax is feasible for patients, but we see that 17p patients relapse shortly after, or at least they have a high tendency to relapse.

The use of monoclonal antibodies is tricky because of the COVID-19 pandemic. We have patients undergoing treatment with CD20 who don’t have any immune response. This is something that may have a weight when we discuss therapy. The recently approved long-term prophylactic antibody against COVID-19 may last 6 or 7 months. It may be a very important tool when using monoclonal antibodies.

There are some other combinations with BTK. BCL2 is obviously the main 1, but there’s also zanubrutinib and venetoclax. We have already good data on ibrutinib-venetoclax from CAPTIVATE, which was presented in 2 different arms: the fixed duration and the MRD [minimal residual disease] driven. It was a very complex trial that randomized patients after treatment with 15 months of ibrutinib-venetoclax, depending on whether it was detectable or undetectable minimal residual disease. In the undetectable 1, it was randomized to observation vs ibrutinib; in the detectable, between ibrutinib and ibrutinib-venetoclax.

What’s the summary of these data after 2 years of follow-up? Everyone is doing fantastic. There’s more than 95% PFS [progression-free survival]. There are very few relapses in each group. It’s unclear how long it’s going to relapse, because it seems possible to incorporate BTK fixed-duration therapy, in this case by combining with venetoclax. Interestingly, MRD is very high this group of patients. CAPTIVATE had younger patients with a high risk of genomic abnormalities. We definitely see better data…in mutated IgA vs unmutated.

Something interesting also seen in venetoclax is that it’s very likely going to bring the approval of combination ibrutinib-venetoclax in the next year, and was combined obviously or was compared with chlorambucil-obinutuzumab. This trial was reported in the summer and at ASH in terms of MRD, which was slightly inferior because this population of patients was older. Some of these patients may not tolerate this combination well, depending on their fitness and their issues. Nevertheless, it’s very interesting.

One other interesting thing that came out the CAPTIVATE study is that the people start to do very well and become somewhat independent of their MRD. The story of the MRD and PFS…is going to be challenged by incorporating BTK into this combination. Patients are doing very well and have deep molecular responses. Lisa, do you have any other comments on the trials I discussed? What do you think is going to fit into our practice in the near future?

 Most of our patients come in recognizing that there’s an option, particularly for patients on BTK inhibitors. They always ask the question, “How can I get off this drug?” Some of our patients with CLL are savvy, recognizing that venetoclax is out and about. What’s exciting is that the regimen itself, ibrutinib and venetoclax, is pretty tolerable in that patient population. Of course, each drug is going to impart its own class effect. There’s the BTK class effect, and now we know that with BCL2 inhibitors neutropenia is of concern. That’s something to bear in mind when we’re treating our patients with 2 different classes of drugs, to be cognizant of the adverse events that can come with both drugs. It was nice that both drugs were well tolerated with very low rates of TLS [tumor lysis syndrome] as well after the ibrutinib lead-in. That’s very important, but offering the time-limited therapy for patients also gives them the freedom of the chronicity of the adverse effects as well as the financial toxicities.

 You bring up a good point because our patients are asking about fixed-duration therapy with BTK, but that’s not on the label right now. There are recently reported data for some patients on ibrutinib…. Another aspect that was surprising was that patients on ibrutinib for more than 2 years were given a regimen that we have a lot of experience with in our institution [Moffitt Cancer Center], the umbralisib-ublituximab combination. A striking amount of patients went to MRD negative, and they were able to discontinue and be off therapy with short follow-ups. These bring the possibility in the future of not only venetoclax but other combination regimens. Someone can even argue that CD20 could be another strategy to get some of our patients to discontinue therapy. Something important for our patients, as you mentioned, is financial toxicity and, more importantly, the chronic adverse events that some suffer may improve the quality of life and put them in a better situation.

Lisa Nodzon, PhD, ARNP, AOCNP, and Javier Pinilla-Ibarz, MD, PhD, evaluate novel agents and combinations in the pipeline for the management of CLL.

Emerging Therapies for the Management of CLL

Let’s discuss the pharmacodynamics and dosing of different BTK inhibitors because we’re discussing dosing ibrutinib and acalabrutinib. We’ll discuss how we’re going to overcome or manage this in our practice.

 First let’s talk about ibrutinib. The dosages of ibrutinib and CLL [chronic lymphocytic leukemia] is 420 mg once daily. It’s important to know the different indications for ibrutinib have different dosing. For CLL, it’s 420 mg. I counsel patients that the tablet should be taken whole and with a glass of water; they shouldn’t crush them. It doesn’t matter with regard to meals. I ask patients to be consistent and never to double up on a dose. If they normally take it in the morning and they realize in the afternoon that they’ve forgotten it, it’s fine to take it, but never double up the dose in 1 day.

With acalabrutinib, the dosage is 100 mg twice daily. Ideally, you want to be 12 hours, but if it’s not exact, that’s OK. This can be taken with or without food, but consistency is important. There are many drug interactions with ibrutinib and acalabrutinib, so both of these are substrates of CYP3A4. That means there are a million drug interactions. There are many inhibitors and inducers at 3A4 that will affect these medications, so it’s important to have a thorough look at the patient’s medication list. We’re seeing down the line some more infections with the BTK [Bruton tyrosine kinase] inhibitors and rarely fungal infections where patients would be put on an azole. This is a clinically significant interaction that we would have to make some adjustments for.

Your vitamin K antagonist should also be avoided because of the risk of bleeding. Caution should be used with NSAIDs [nonsteroidal anti-inflammatory drugs], fish oil, vitamin E, aspirin, and anything else that includes or that increases the risk of bleeding. That also goes for direct oral anticoagulants. It’s not contraindicated with the BTK inhibitors, but it’s something to consider, and it’s very patient specific.

Acid suppression is not an issue with ibrutinib, but it definitely is with acalabrutinib. Acalabrutinib is twice a day. PPIs [proton pump inhibitors] should be avoided altogether. If a patient truly has severe GERD [gastroesophageal reflux disease] or heartburn, you could do an antacid like Tums, but you have to separate it by 2 hours on either side. You can do that with an H2-receptor agonist as well, but it gets tricky and it’s difficult. Typically, if patients have true GERD or heartburn, acalabrutinib may not be your best option.

There was a new formulation of BTK inhibitor that will be approved soon; it was presented at ASH [American Society of Hematology Annual Meeting]. Are you familiar with this agent? Do you know what may come about with this?

 It was presented at ASH. It seems obvious that to overcome these issues with PPIs, acalabrutinib has already produced a new composition that can be given through a nasogastric tube if the patient cannot swallow. It’s not going to have the same issues. You were discussing the pharmacokinetics of these 2 drugs. Both drugs can achieve 90% to 95% of inhibition of the target. Studies have been unclear. One issue they’ve seen is how BTK drugs in general can penetrate tissues. Obviously, we’re talking about lymph nodes, where these drugs have nice activity. They’re trying to detach the lymph nodes from these niches. They release to the peripheral blood in the redistribution of lymphocytosis. That’s a fundamental aspect of the efficacy of this medication.

It’s important to discuss the dosing. You mentioned the dose for ibrutinib. At least you can dose reduce multiple times. We now have initial control of the disease, and the adverse effects can be lowered with similar efficacy. This has happened with ibrutinib. With acalabrutinib, you can go from twice a day to once a day; with ibrutinib, you can reduce to 2 pills or even 1 pill. There’s a formulation for 280 mg and 140 mg.

As you mentioned, it’s very important to have a detailed history about how many drugs patients are taking. We always discuss antibiotics like Cipro…that we use in certain infections, as well as the cardiotoxic arrhythmias or drugs that control A-Fib [atrial fibrillation], like Cardizem or verapamil. Those are things we take into consideration.

Katie Tobon, PharmD, BCOP, leads the discussion comparing dosing and drug interactions among the FDA-approved BTK inhibitors ibrutinib and acalabrutinib for the treatment of CLL. 

Pharmacodynamics of BTK Inhibitors in CLL Treatment

We’re going to review the classic FDA-approved BTK [Bruton tyrosine kinase] inhibitors ibrutinib and acalabrutinib. Before, I mentioned that the first trial that put together ibrutinib in the second line was RESONATE, where it was compared with ofatumumab. Obviously, we had nice data, but later on in the front line was the RESONATE-2 trial data that was published. In our previous meetings, a 7-year follow-up was reported. Still, a significant amount of patients had a low amount of progression. However, we see that discontinuation for toxicity may happen in about 20% of patients. This emphasized, in the long-term data, that patients who tolerate this drug may do well in the long run.

One of the caveats is this trial did not include 17 prepatients, so we can’t make a conclusion. That’s the reason the Alliance for Clinical Trials in Oncology trial compared ibrutinib with or without bendamustine-Rituxan. PFS [progression-free survival] had very good data in 17p. This is for ibrutinib. As mentioned, ibrutinib is being compared with the best chemoimmunotherapy strategy in the younger population. We’re discussing ECOG-E1912, which compared ibrutinib-Rituxan against fludarabine-Rituxan-Cytoxan. It had a superior PFS and overall survival. It was well received, and at least the benefit mostly comes from unmutated patients. Mutated patients can surely benefit, but someone may argue that chemoimmunotherapy in younger populations may be a choice for some patients or for doctors who believe in these long-term data for FCR300, CLL8, and CLL10. However, in our institution [Moffitt Cancer Center], because of the long-term possibilities to produce MDS [myelodysplastic syndrome] and even in the other case of AML [acute myeloid leukemia], we try to stay away from fludarabine because the younger population may have a long time until they have multiple lines of therapy, and it could negatively influence the future of these patients.

I want to discuss the FLAIR trial, which was also presented at ASH [American Society of Hematology Annual Meeting]. That was the response to the ECOG-E1912 presented a group led by Pete Hillmen. They were introducing the same concept. However, it was interesting that in this case, the trial allowed older patients until 75…. The bottom line is that the PFS was superior to FCR [fludarabine, cyclophosphamide, rituximab] as we have in the ECOG-E1912. However, there was no difference in survival. There’s a lot of discussion around that. Obviously there are toxicities from FCR [fludarabine, cyclophosphamide, rituximab], but maybe in this case the older population may have worse tolerance to ibrutinib in some cases. Also, they may be compensated by the superior survival that we saw in the US trial.

In terms of second-generation BTKs, acalabrutinib, which is more specific than ibrutinib and has fewer targeted effects, mainly EGFR and other kinases that may be responsible for some of the adverse effects, like diarrhea. BTKs in general have a class effect, but it seems that acalabrutinib has diminished these issues. In this case, we’ve seen the ELEVATE-TN, which was treatment-naïve and compared acalabrutinib with or without obinutuzumab against obinutuzumab-chlorambucil. It had superior PFS reaching all the levels. It’s slightly superior when we compare acalabrutinib vs acalabrutinib-obinutuzumab. There’s not really a significant difference, and the trial did not statistically have the power to have this difference. It doesn’t have a role with ibrutinib, but it’s still unclear that obinutuzumab may have a role. The iLLUMINATE trial compares ibrutinib-obinutuzumab against obinutuzumab-chlorambucil. It didn’t have a single ibrutinib, so we can’t make this conclusion with ibrutinib. In the future, it’s unclear that we are going to make this conclusion with acalabrutinib.

It’s important to discuss another trial presented over the summer, the ELEVATE-RR, which compared head-to-head the best 2 BTK inhibitors on the market: ibrutinib and acalabrutinib. We also noticed that this trial was done in 11q and 17p. This is the hardest population. It’s heavily pretreated and very high risk—more than 50% has 17p and TP53 abnormalities. What comes from this study is that the efficacy was similar in both groups. There was a trial designed for noninferiority for acalabrutinib that was reached. The primary end point of the trial was to see toxicities. In this sense, there was less atrophy relation, something that can be seen with BTK inhibitors and that we’ve seen with ibrutinib. This was less of a problem with atrial fibrillation, when we compared with acalabrutinib. Other adverse effects were decreased, including headache, which is more common with acalabrutinib. The difference is they’re obviously very patient dependent on the patients. Certain patients may tolerate better or worse dependent of comorbidities, but I see something to discuss. This is something that has been well reported and something that also takes a role when we discuss the toxicity of these 2 different BTKis.

Javier Pinilla-Ibarz, MD, PhD, highlights key clinical trials in CLL assessing the safety and efficacy of FDA-approved BTK inhibitors ibrutinib and acalabrutinib.

Key Clinical Trials for BTK Inhibitors in CLL

In terms of selecting a BTK [Bruton tyrosine kinase] inhibitor for CLL [chronic lymphocytic leukemia] therapy, Katie, what do you think about cytogenetic abnormalities, patients, and other factors that can weigh when we start to select BTK inhibitors?

 It’s a great question. Shared decision-making is our approach when it comes to BTK inhibitor therapy at our institution [Moffitt Cancer Center]. Data have shown a prolonged progression-free survival, particularly with the ability to overcome adverse prognostic factors, such as IGHV. That typically would give us shorter progression-free survival. All cytogenetic abnormalities are eligible, but it’s important to keep in mind that our 17p or 

 patients have the shorter progression-free survival. For patient-related factors, there are a lot of things that we have to think about. We have to consider the patient’s age and what comorbid conditions they may have, especially cardiac history. Cardiac history is a big thing to keep in mind when we’re talking about BTK inhibitors, as well as the first and second generation. This includes arrhythmias, hypertension, a history of bleeding, and any other concomitant medications these patients are on. There are a lot of drug interactions that we’ll talk about shortly. We also have to consider how frail the patient is as well as the overall cost. Typically, if we have an older patient or a patient with multiple comorbid conditions that may be exacerbated, we’d prefer the second-generation BTK inhibitors. In terms of treatment-related factors, it’s a shared decision-making approach at our institution. Dr Pinilla-Ibarz, what other treatment factors do you consider with these discussions with your patients besides what I’ve discussed?

 You discussed very important points. I want to emphasize the issue of cytogenetic or genomic factors. All these generic factors predict times to reach first therapy. When the therapy comes, obviously BTK is 1 of the important aspects and therapeutic strategies that we discuss with our patient. It depends on the comorbidities. We may rely more on a second- vs third-generation BTK inhibitor. At the same time, it’s important to consider patient preference in the terms do they want to go to fixed-duration therapy in combination with BTK, can they come to an academic institution despite the distance? In our state, people are old and may not be able to get on the road.

I want to emphasize that the issue with 17p. Obviously, with 17p or 

 mutation in the front line, we do not recommend [chemoimmunotherapy]. My opinions will be almost contraindicated to use chemoimmunotherapy. For sure, BTKs are a very important aspect of how we’re dramatically improving the outcomes of patients with these genomic abnormalities. At the same time, there’s no doubt that the fixed duration can be used. But we already have data showing that as soon as we stop therapy, those patients’ tend to relapse shortly. It’s unclear how they can be re-treated.

In general, we prefer to reuse BTK inhibitors until this disease progression. In fact, we have good data coming, and we’ll discuss that later. For example, in the Alliance for Clinical Trials in Oncology trial that was updated, we saw that after almost 4 years of follow-up, the 17p is similar to non-17p. This trial is really encouraging and reinforces the idea that BTK inhibitors are an excellent choice for patients with these “high risk” cytogenetic abnormalities. In the past, with chemoimmunotherapy, with the new targeted therapies, it may not be as high. It’s completely different in the second and third line. The outcomes for those patients with targeted therapy may not be as good because we don’t have those kinds of therapies, but it’s an important factor to consider.

Katie Tobon, PharmD, BCOP, and Javier Pinilla-Ibarz, MD, PhD, discuss factors to consider when selecting a BTK inhibitor for CLL therapy, including cytogenetic abnormalities as well as patient- and treatment-related factors.

BTK Inhibitor Selection for CLL Therapy

We’re going to discuss the role of BTK [Bruton tyrosine kinase] inhibitors and CLL [chronic lymphocytic leukemia] treatment. We’ll discuss chemoimmunotherapy as recommended to the approach in the old times. Obviously, what are these benefits and how does the NCCN [National Comprehensive Cancer Network] guide that? It has been a dramatic change in paradigm in the last 7 or 8 years with the introduction of BTK inhibitors. We’ve switched for chemoimmunotherapy because these new therapies, BTK inhibitors, and oral therapies can provide long-term progression-free survival. However, these therapies can be checking until disease progression or unacceptable toxicity, which can bring financial toxicity and chronic problems that may in some cases give our patient some issues. Some of them don’t want to be on therapy for life.

There’s no doubt that there are multiple trials. We always say that BTK inhibitors—ibrutinib, acalabrutinib, and others that come in—are being compared with everything. The main example is ibrutinib is compared with chlorambucil, bendamustine-rituximab, FCR [fludarabine, cyclophosphamide, rituximab], obinutuzumab-chlorambucil. In all these trials, there has consistently been superior PFS [progression-free survival] and in some instances even improved overall survival. It’s hard to demonstrate overall survival because the incorporation of these new drugs is able to breach our patients to truly get better outcomes. NCCN Guidelines make category 1 for BTK inhibitors—ibrutinib, acalabrutinib plus or minus obinutuzumab, as well the classic combination of venetoclax plus obinutuzumab. NCCN Guidelines put together every strategy that we can choose depending on the condition of the patient, genomics, age, and preference about which strategy we’re going to choose.

Dr Javier Pinilla-Ibarz leads the discussion on the role of targeted therapy over chemoimmunotherapy as a CLL therapeutic approach and shares NCCN Guidelines recommendations for the use of BTK inhibitors.

Javier Pinilla-Ibarz, MD, PhD

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