BTK Inhibitor Treatment Strategies in Chronic Lymphocytic Leukemia

Patient Case

The Around the Practice Panel

At an Around the Practice®program hosted by CancerNetwork®, a panel of experts from Mayo Clinic in Jacksonville, Florida, discussed therapeutic strategies including Bruton tyrosine kinase (BTK) inhibitors in patients with chronic lymphocytic leukemia (CLL). Specifically, they discussed the selection of specific second-generation BTK inhibitors, cardiovascular toxicities, and challenges surrounding treatment intolerance in the context of a specific patient case. The panel was led by Asher A. Chanan-Khan, MBBS, MD, a professor of medicine at Mayo Clinic Alix School of Medicine.

Other panelists included Ricardo D. Parrondo, MD, an assistant professor of hematology/oncology, and Pooja Advani, MBBS, MD, a medical oncologist.

Chanan-Khan: What are your thoughts on approaching treatment with this patient? Would you recommend chemoimmunotherapy, a single-agent BTK inhibitor, a BTK inhibitor plus a CD20 monoclonal antibody, a BCL2 inhibitor plus a CD20 monoclonal antibody, or a BTK inhibitor plus a BCL2 inhibitor?

Parrondo: Of all those options, the only one I would not select is chemoimmunotherapy due to the better understanding of CLL disease biology and the subsequent explosion of targeted agents [such as] BTK inhibitors and BCL2 inhibitors. All those therapies have been proved to be superior to chemoimmunotherapy. It would not be wrong to use a single-agent BTK inhibitor in this case. You could use a BTK inhibitor plus a CD20 antibody, [such as] obinutuzumab [Gazyva] and acalabrutinib [Calquence]. You could use venetoclax [Venclexta] plus obinutuzumab. In this young, fit patient without TP53 mutations, you could use a BTK inhibitor plus a BCL2 inhibitor.

There are so many options, but you must have a discussion with the patient. What are their preferences? Do they want time-limited or continuous therapy? Do they want entirely oral treatment or intravenous plus oral therapy? It’s an exciting time in CLL because there’s a multitude of treatment options.

Chanan-Khan: Is there anything concerning about the patient’s history that would raise a red flag from a toxicity perspective? Would anything make you not consider a specific treatment option?

Advani: It’s important to get a good history from patients. There have been several risk scores that have been proposed for evaluating cardiovascular adverse effects [AEs] specifically for BTK inhibitors, which have taken the CLL scene by storm. Age, male sex, and existing valvular heart disease have consistently been risk factors for cardiovascular AEs. There are many more complex factors, but gathering this basic history will at least be very important for patients as you’re considering them for BTK inhibitor therapy.

Chanan-Khan: What are the goals of treatment selection for a patient like this? Do you select therapy based on predisposed risk factors of toxicity?

Parrondo: The treatment goals for patients with CLL are to alleviate their constitutional symptoms, improve their cytopenias, alleviate bothersome splenomegaly and lymphadenopathy, and ideally provide long-term disease control. Of all the options that we have, the chosen therapeutic option should be tailored to the patient, their preferences, and their comorbidities. If a patient desires oral therapy, we have the BTK inhibitors. If the patient has extensive uncontrolled cardiovascular disease [such as] poorly controlled hypertension or uncontrolled atrial fibrillation, I tend to initially avoid the BTK inhibitors until those conditions are better controlled. In those cases, I may use a BCL2 inhibitor plus a CD20 antibody.

Another important factor is risk stratification, particularly if the patient has 17p deletions or TP53 mutations. In my treatment paradigm, those patients receive continuous BTK inhibitor therapy; I don’t like time-limited therapy for those patients. We have good data supporting the use of continuous BTK inhibitor treatment for patients with TP53 mutations. We know that the outcomes of those patients are inferior with time-limited therapy. Those are the main factors that I consider when selecting initial therapy for patients with CLL.

Chanan-Khan: Are data seen in clinical trials translating to real-world practice?

Parrondo: There was an abstract presented at the 2023 European Hematology Association Congress on real-world data from a multicenter, retrospective study evaluating treatment use patterns for first-line therapy in CLL.¹ Some of the results were interesting. The study confirmed that novel agents—BCL2 inhibitors and BTK inhibitors—lead to superior outcomes compared with chemoimmunotherapy. That confirms the results of all these clinical trials. Interestingly, the use of chemoimmunotherapy has not been completely removed from clinical practice. Some physicians continue to use chemoimmunotherapy or even single-agent anti-CD20 monoclonal antibodies even though the outcomes appear to be worse with those strategies.

Toxicity With Second-Generation BTK Inhibitors

Chanan-Khan: Data from the phase 3 SEQUOIA trial [NCT03336333] showed that atrial fibrillation and flutter occurred in approximately 5% of the patients treated with zanubrutinib [Brukinsa].² Is that out of the norm when treating patients?

Advani: When we think about atrial fibrillation and flutter, where we
historically start with the first-generation BTK inhibitor ibrutinib [Imbruvica], the all-grade atrial fibrillation and flutter rate ranges from 10% to 17%. However, grade 3 or higher events are 2% to 9%. When we think about the second-generation irreversible BTK inhibitors [such as] acalabrutinib and zanubrutinib, the all-grade atrial fibrillation and flutter that has been reported not only in clinical trials but in real-world experiences has been 3% to 4%. More importantly, the grade 3 or higher events have been less than 2%. We’re certainly seeing that the second-generation BTK inhibitors are relatively safer when it comes to atrial fibrillation and flutter.

When we think about hypertension overall, the rates are quite similar between ibrutinib, acalabrutinib, and zanubrutinib. Thankfully, the rate of ventricular arrhythmias is also very low with all these agents.

Chanan-Khan: Would you agree that the toxicity profile has evolved in favor of second-generation BTK inhibitors, especially cardiac toxicity?

Parrondo: I agree. The second-generation BTK inhibitors have a better toxicity profile not only in terms of cardiovascular toxicity but also in other toxicities such as diarrhea, myalgia, and arthralgia. Those appear to be less common with the second-generation BTK inhibitors as well. Treatment is very well tolerated, too. For something that’s meant to be taken until disease progression or continuously, that’s ideal. You want a low toxicity profile so that patients can continue to take it.

Chanan-Khan: The role of first-generation BTK inhibitors like ibrutinib is becoming less clear in the frontline setting compared with [that of] second-generation BTK inhibitors due to their toxicity profiles, not necessarily because of efficacy. If a BTK inhibitor is the way to go for this patient, would a second-generation inhibitor be more relevant than a first-generation inhibitor?

Parrondo: I agree that the field is using more second-generation BTK inhibitors [such as] acalabrutinib or zanubrutinib due to better toxicity profiles and other factors. We have data from the phase 3 RESONATE-2 study [NCT01722487, NCT01724346], which has the longest follow-up of any BTK inhibitor at 8 years. We see that approximately 65% of patients are still in remission 8 years out.³ We start to see the cumulative toxicities. Hypertension and risk of atrial fibrillation go up over time, and we see that discontinuation rates of ibrutinib are quite high. Some studies report discontinuation rates as high as 50%. With a longer follow-up of acalabrutinib and zanubrutinib, we [may] see…less discontinuation of these second-generation BTK inhibitors. We’re also already seeing that zanubrutinib is superior to ibrutinib in the relapsed/refractory setting, both in terms of toxicity and efficacy. Everything is pointing toward the second-generation BTK inhibitors in the first-line setting and even in relapsed CLL.

Second-Generation BTK Inhibitor Selection

Chanan-Khan: A paper presented at the 2023 American Society of Clinical Oncology Annual Meeting reported findings from a matching-
adjusted indirect comparison of efficacy and toxicity of acalabrutinib vs zanubrutinib in relapsed CLL.⁴ What do the data show about selecting one of these second-generation therapies?

Parrondo: Those data are hypothesis generating because it was not a direct comparison of acalabrutinib and zanubrutinib; it was an indirect cross-trial comparison of the agents from the phase 3 ALPINE study [NCT03734016] and the phase 3 ASCEND trial [NCT02970318]. It showed that the risk of having grade 3 or higher AEs [such as] atrial fibrillation or hemorrhage or having an AE leading to discontinuation was similar with acalabrutinib compared with zanubrutinib. However, the risks of having any-grade serious AEs [such as] hypertension or hemorrhage and an AE leading to a dose reduction were lower with acalabrutinib. That is thought-provoking, but in the first-line or even the relapsed setting, acalabrutinib and zanubrutinib have not been compared head-to-head. These data are helpful, but we can’t make any definitive conclusions.

Chanan-Khan: From a toxicity perspective, should oncologists lean toward using either zanubrutinib or acalabrutinib in this setting? Do you think toxicity data allow us to make that choice, or should it be a case-based analysis?

Advani: It’s definitely case based. There is no head-to-head comparison between these agents. When thinking about what causes arrhythmias in patients who are receiving BTK inhibitors, it’s postulated to be the inhibition of HER2, HER4, TEK, and downstream the PI3K signaling pathways. When we look at the second-generation BTK inhibitors acalabrutinib and zanubrutinib, they’re mostly inhibiting HER4 and maybe TEK. That may be one of the reasons why the safety profile for cardiac AEs is much better than [that for] the first-generation BTK inhibitors, which are inhibiting more kinases. However, there is no mechanistic difference between acalabrutinib and zanubrutinib from a cardiac arrhythmia perspective, and that translates well into clinical numbers. An atrial fibrillation and flutter rate of 3.7% with zanubrutinib is quite comparable with approximately 4% in acalabrutinib when we think about all-grade atrial fibrillation and flutter.

We must personalize therapy in patients with CLL and match the right patient to the right treatment. However, I would say that the second-generation BTK inhibitors are comparable as far as their AE profiles go. Additionally, atrial fibrillation, hypertension, and other cardiovascular AEs can also happen later after therapy. It can be a lifelong event for the patient considering the added toxicity of taking more medications. The challenge, especially if the patient continues to be [taking] a BTK inhibitor, is that we must think about cross-drug interaction. There are challenges when selecting therapy for these patients and managing hypertension and atrial fibrillation.

Rechallenging Treatment and BTK Inhibitor Intolerance

Chanan-Khan: When limited-duration treatment stops, what do you do when considering retreatment? Should re-treatment in this setting include a BTK inhibitor?

Parrondo: When patients progress after a fixed-duration BTK inhibitor plus BCL2 inhibitor, you can use either drug class at the time of relapse. At least with venetoclax, we have data highlighting that you can reuse it after patients progress with a venetoclax-based regimen, and they achieve quite high response rates. There was a retrospective study from Memorial Sloan Kettering Cancer Center [whose data showed] that the progression-free survival [PFS] with a rechallenge of venetoclax was about 25 months, and the overall response rate was 80%.⁵ You can rechallenge with venetoclax, and the same goes with a BTK inhibitor. It’s not a bad idea to get next-generation sequencing for mutation testing. It’s possible that when patients were treated for that limited duration, they may have developed mutations that make them resistant to a rechallenge with BTK or BCL2 inhibitors. That’s an important aspect to consider when rechallenging.

Chanan-Khan: What approach would you take if a patient is intolerant to a BTK inhibitor?

Parrondo: I would define BTK intolerance as having intolerable AEs despite maximum supportive care and holding and restarting a BTK inhibitor. In the case of ibrutinib, there are persistent AEs despite dose reductions to 280 mg or 140 mg. We have data that show that treatment discontinuation due to BTK intolerance occurs less frequently with acalabrutinib and zanubrutinib, which is somewhere from 10% to 15% compared with ibrutinib, which ranges from 20% to 50%. If a patient is intolerant to ibrutinib, it’s OK to switch them to another covalent BTK inhibitor because they’re not resistant to it, which is all based on the AE profiles of the drugs. For example, if patients have intolerable arthralgia and myalgia on ibrutinib, changing the patient to a second-generation BTK inhibitor is the correct thing to do because they cause less arthralgia and myalgia. Alternatively, if a patient is [receiving] acalabrutinib and develops difficult-to-control headaches, switching them to zanubrutinib would be the correct choice. The most common causes of BTK intolerance are fatigue, arthralgia, myalgia, musculoskeletal complaints, diarrhea, bleeding, and bruising events. Those can be quite difficult and distressing [for] the patients. However, the second-generation BTK inhibitors are better tolerated than ibrutinib. If a patient develops intolerance to ibrutinib, you should switch them to a second-
generation BTK inhibitor. Don’t give up on the BTK pathway. Try changing them to another BTK inhibitor…that they may tolerate better.

Chanan-Khan: Do you have any other comments on retreatment with second-generation BTK inhibitors? What would you recommend from a mechanistic perspective?

Advani: It’s important to recognize that atrial fibrillation is believed to be an off-target AE. Acalabrutinib and zanubrutinib mostly inhibit HER4 and tyrosine-protein kinase. It is not without reason that they have fewer AEs, particularly as you switch from ibrutinib to the second-generation BTK inhibitors, as ibrutinib tends to inhibit a lot more off-target kinases, [such as] HER2, HER4, and a higher degree of tyrosine-protein kinase. Clinically, it translates well.

Closing Remarks

Chanan-Khan: Do you have any parting comments following this discussion?

Parrondo: I would like to address the unmet needs that are still present in CLL. For patients with deletion 17p or TP53 mutations, their outcomes are still inferior [to those of] patients without TP53 mutations. Many strategies are being developed to treat these patients. One of them is triplet therapy with a CD20 monoclonal antibody, a BCL2 inhibitor, and a BTK inhibitor. The data are emerging with those triplets in that high-risk patient population. Novel therapies are also needed for patients with double-refractory CLL that is refractory to a covalent BTK inhibitor and a BCL2 inhibitor. With the available therapies, the outcomes are not that great for those patients. With a PI3K inhibitor or chemo-immunotherapy, the median PFS is less than 6 months. Even with an allogeneic transplant, the median PFS in this double-refractory patient population is approximately 11 months. Fortunately, we have many drugs in the pipeline. We have the emergence of noncovalent BTK inhibitors [such as] pirtobrutinib [Jaypirca], BTK degraders, next-generation BCL2 inhibitors, CAR [chimeric antigen receptor] T [cells] in development, and bispecific antibodies. The outcomes in these patients and all patients with CLL will continue to improve over time.

Advani: CLL therapy is personalized. It’s important to know your patient well to assess the efficacy of agents as well as toxicity. Working closely with a patient’s primary care physician and cardiologist, if needed, in optimizing therapies for preexisting risk factors or cardiovascular AEs that developed during BTK inhibitor therapy will not only allow our patients to have improved tolerance but continue this important therapy for these patients. Additionally, second-generation BTK inhibitor therapy has a lower risk of cardiovascular AEs, specifically atrial fibrillation and hypertension. Encouragingly, the third-generation BTK inhibitor therapies are not only known to be efficacious but less risky for cardiovascular AEs. This is particularly the case for hypertension, where that risk is estimated to be less than 5%. There is more to come in the space, but there are very encouraging results so far with second-generation BTK inhibitor therapy.

References

1. Lansigan F, Eyre TA, Ghosh N, et al. Real-world treatment and outcomes of patients with chronic lymphocytic leukemia (CLL) receiving first-line (1L) therapy in the novel agent era: an international study. Hemasphere. 2023;7(suppl):e6855326. doi:10.1097/01.HS9.0000969496.68553.26

2. Shadman M, Munir T, Roback T, et al. Zanubrutinib (ZANU) versus bendamustine + rituximab (BR) in patients (PTS) with treatment-naïve (TN) CLL/SLL: extended follow-up of the SEQUOIA study. Hematol Oncol. 2023;41(S2):235-238. doi:10.1002/hon.3163_154

3. Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6(11):3440-3450. doi:10.1182/bloodadvances.2021006434

4. Kittai A, Skarbnik A, Miranda M, et al. A matching-adjusted indirect comparison (MAIC) of the efficacy and safety of acalabrutinib (acala) versus zanubrutinib (zanu) in relapsed or refractory chronic lymphocytic leukemia (RR CLL). J Clin Oncol. 2023;41(suppl 16):7540. doi:10.1200/JCO.2023.41.16_suppl.7540

5. Thompson MC, Harrup RA, Coombs CC, et al. Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen. Blood Adv. 2022;6(15):4553-4557. doi:10.1182/bloodadvances.2022007812