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Director, Lymphoma Research Program
Sarah Cannon Research Institute/Tennessee Oncology
Ian W. Flinn, MD, PhD, has disclosed that he has received consulting fees paid to his institution from AbbVie, Seattle Genetics, TG Therapeutics, and Verastem and funds for research support paid to his institution from AbbVie, Acerta, Agios, ArQule, AstraZeneca, BeiGene, Calithera, Celgene, Constellation, Curis, Forma, Forty Seven, Genentech, Gilead Sciences, Incyte, Infinity, Janssen, Juno, Karyopharm, Kite, Merck, Novartis, Pfizer, Pharmacyclics, Portola, Roche, Takeda, Teva, TG Therapeutics, Trillium, Unum, and Verastem.
At a recent Clinical Care Options symposium at the 2019 ASH meeting, my colleagues and I discussed our perspectives on the use of BTK inhibitor therapy for B-cell malignancies. During the program, we collected questions from our live and online simulcast audience, and here I have provided insights into to some of the major themes asked on this topic.
BTK Inhibitors in Mantle Cell Lymphoma (MCL)
We currently have 3 different BTK inhibitors available in MCL: ibrutinib, acalabrutinib, and zanubrutinib. All 3 of these agents are approved by the FDA for treatment of MCL after ≥ 1 previous line of therapy and all 3 have demonstrated similar efficacy in clinical trials. Preclinically, acalabrutinib and zanubrutinib appear to be more specific inhibitors of BTK and have fewer alternative kinase targets, which may lead to a cleaner toxicity profile with fewer off-target effects. In addition, there are some differences in administration: Ibrutinib is given once daily; zanubrutinib can be administered once or twice daily; and acalabrutinib is given twice daily and cannot be taken with proton pump inhibitors. Finally, zanubrutinib is the most recently approved and has the shortest follow-up data available to date.
I do not have a single standard approach for the use of BTK inhibitors for MCL. Instead, I use different BTK inhibitors in different patients based on their preferences, characteristics, and comorbidities, which might lend me to use one BTK inhibitor over another.
Frontline Treatment in MCL
In our symposium, we had a question on whether to use a BTK inhibitor as frontline therapy for select patients with MCL, and this is one question I thought a lot about. When selecting frontline therapy, I typically divide patients into 3 major groups: those with indolent MCL, those with classic MCL, and those with a very aggressive blastoid or pleomorphic variant MCL. I also use biomarker testing to understand more about a patient’s disease. For instance, TP53 can help risk stratify disease and is associated with blastoid morphology and a more aggressive clinical course. In addition, SOX11 is a very important test in identifying the subgroup of patients with indolent MCL. If there is clinical suspicion of low-grade MCL, I would recommend requesting that the pathologist include that test.
I do not routinely start people with MCL on a BTK inhibitor in the frontline setting. It is tempting to extrapolate from studies in CLL and patients with TP53 abnormalities and consider forgoing chemoimmunotherapy and starting immediately with a BTK inhibitor. However, we really do not have those data yet in MCL, and until we do, we should probably resist that temptation to take this approach, even in high‑risk patient populations with TP53 abnormalities. In clinical trials, in the blastoid and pleomorphic variants, unfortunately, there is not as much success as we would hope with either a BTK inhibitor alone or in combination. Based on that, I generally recommend chemoimmunotherapy in the frontline setting for almost all patients with MCL.
BTK Inhibitors in Chronic Lymphocytic Leukemia (CLL)
For patients with CLL, there are some differences in how I approach treatment selection as compared with MCL. Specifically, for the vast majority of patients, there is no need to use chemoimmunotherapy in the frontline setting. Instead, in my view, either a BTK inhibitor or venetoclax‑based regimen is the frontline treatment of choice for almost all patients with CLL.
In determining which BTK inhibitor to use, the key choices are acalabrutinib or ibrutinib. Both of these agents are approved by the FDA for patients with CLL: Ibrutinib is approved as a monotherapy and in combination with obinutuzumab or bendamustine/rituximab, and acalabrutinib is approved as a monotherapy or in combination with obinutuzumab. Again, there are key patient characteristics that drive my choice between ibrutinib or acalabrutinib. The same considerations regarding dosing and coadministration with proton pump inhibitors, as described above, also apply in the CLL setting. Beyond those considerations, it is difficult to tease out the two options. We are awaiting results from head-to-head randomized trials to have a better understanding of the relative efficacy and incidence of different adverse events. Theoretically, acalabrutinib may have less cardiotoxicity and I might choose this agent in patients with atrial fibrillation or other cardiac arrythmia. However, that is noted with the acknowledgement that we do not yet have comparative data to back up these theoretical differences seen in some preclinical models.
BTK Inhibitors as Monotherapy vs Combination Therapy in CLL
Many clinicians ask about using BTK inhibitors as monotherapy vs in combination therapy. I generally do not use combination approaches with an anti-CD20 monoclonal antibody with either ibrutinib or acalabrutinib for patients with CLL. This approach was investigated in the phase III ELEVATE TN trial of acalabrutinib with or without obinutuzumab vs chlorambucil plus obinutuzumab in previously untreated CLL. In this trial, a strong PFS benefit was observed with both acalabrutinib-containing arms compared with the chemoimmunotherapy arm. While there was a mild improvement in the media PFS with the addition of obinutuzumab to acalabrutinib, the added inconvenience and increase in potential for adverse events with the anti-CD20 antibody may not be worthwhile for many patients. There was no significant difference in the median OS with any of the 3 study arms at this time point.
The relative inconvenience of giving an anti-CD20 antibody vs an oral agent, like ibrutinib or acalabrutinib, alone and the potential for increased toxicity with combination therapy prevents me from recommending this approach on a regular basis. There are exceptions, but for most people for whom I recommend acalabrutinib, I prescribe it as a single agent. Finally, I am not aware of any data showing that combining an anti-CD20 antibody with ibrutinib improves outcomes, and therefore, I do not use this approach. I do think the ibrutinib plus venetoclax (a BCL-2 inhibitor) combination is very exciting with the potential to reach a deep remission and have a defined duration of treatment. However, the data on this combination have not yet matured and I limit its use to clinical trials.
BTK Inhibitors and Resistance
In both MCL and CLL, patients can become resistant to BTK inhibitors. The best characterized mechanisms of resistance are in CLL, where the C481 mutation has been well described and confers resistance to the covalently bound BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, and others). It is expected that this mutation confers equivalent resistance across these different BTK inhibitors, and I do not routinely check for this, or other, resistance mutations in current clinical practice except in patients who might be eligible for clinical trials evaluating noncovalently bound BTK inhibitors to overcome this resistance.
There are multiple ongoing trials with noncovalent BTK inhibitors such as LOXO-305, vecabrutinib, and ARQ 531, which target both wild-type and C481-mutated BTK. At ASH 2019, for example, phase I studies provided proof of principle that one can overcome resistance to these binding site mutations by using these noncovalently bound inhibitors. This was important and provided hope that there will be a next generation of BTK inhibitors that may be available in practice in the future.
For patients who are unable to participate in these clinical trials because the known resistance mutations convey resistance across all covalently bound BTK inhibitors, it is important to note that once resistance mutations develop, switching to another FDA-approved BTK inhibitor would not be expected to be effective. Instead, my approach would be to switch to a new drug class. For patients with CLL, I would choose venetoclax. In MCL, I would either choose a different drug class or try chemoimmunotherapy.
Adverse Events (AEs) and Comorbidities Management
BTK inhibitors do have unique toxicities that require monitoring and prompt management; understanding and early detection of these AEs can help mitigate the need for BTK inhibitor discontinuation.
Very little comparative data exist to know whether one BTK inhibitor is better than others in terms of bleeding risk. A press release from the phase III ASPEN trial of zanubrutinib vs ibrutinib in Waldenström macroglobulinemia suggests a lower bleeding risk with zanubrutinib vs ibrutinib. However, we will need to see these data presented in a public forum before we can draw conclusions and act on them in a clinical setting. Once these data are available, it will be important to note that the bleeding issues with BTK inhibitors seem to be largely independent of the underlying malignancy, allowing us to apply results across malignancies.
Bleeding management with BTK inhibitor use is complex and is often dictated by individual patient characteristics. The primary reason people require an anticoagulant while on a BTK inhibitor is because of atrial fibrillation. Consultation with the patient’s cardiologist to determine bleeding risk and need for an anticoagulant is required.
As clinicians, we must consider why we are recommending a specific therapy for their hematologic malignancy and then decide whether the bleeding risk seen with BTK inhibitors is worth taking or whether it is prohibitive. For instance, if the patient has CLL and has gone into atrial fibrillation, there are other frontline treatment options and it may be best to discontinue the BTK inhibitor and switch to a venetoclax‑based regimen to avoid bleeding risk. However, if there are no other alternatives and the patient really does need to be on a BTK inhibitor, then I use one of the direct-acting inhibitors, avoid any other anticoagulant such as warfarin, provide extensive counseling regarding bleeding risk, and encourage the patient to call immediately if he/she sees any evidence of bleeding, signs or symptoms of intracranial bleeding, or other symptoms of hemorrhage. Finally, although we have minimal clinical data to date, there is a suggestion that acalabrutinib or zanubrutinib may have lower bleeding risk. Thus, it is reasonable to try switching the patient, if receiving ibrutinib, to one of these alternative BTK inhibitors along with close monitoring. On the other hand, atrial fibrillation and hypertension were slow to evolve in the setting of ibrutinib, and it is also possible that will be the case for other BTK inhibitors. We know that the follow-up is a lot shorter for acalabrutinib and zanubrutinib. However, acalabrutinib trials are reaching the point where this risk emerged with ibrutinib in some trials, and clinicians are more aware of the potential risk. In select patients who need to stay on BTK inhibitors but cannot tolerate anticoagulation, a nonpharmacologic approach with a device implanted in the left atrial appendage that removes most of the need for anticoagulation is an alternative approach that may be considered.
Arthralgias and Myalgias
In my practice, arthralgias and myalgias are the most common AEs I encounter, in addition to muscle cramping. My approach for managing these AEs is to consider a treatment break and then restart BTK inhibitor treatment once symptoms resolve. Over-the-counter analgesics such as acetaminophen or ibuprofen can help patients experiencing these AEs, and using short-term steroids might also help with more severe symptoms.
There are some important potential drug–drug interactions to consider when using BTK inhibitors. CYP3A inhibitors can increase the concentration of ibrutinib, acalabrutinib, and zanubrutinib in the blood, and dose modifications are needed with coadministration of weaker CYP3 inhibitors, whereas moderate or strong CYP3 inhibitors should be avoided when treating with BTK inhibitors. In addition, coadministration of acalabrutinib with proton pump inhibitors, H2 receptor agonists, and antacids may decrease concentrations of acalabrutinib. Proton pump inhibitors should be avoided while taking acalabrutinib, whereas antacids and H2 receptor agonists can be taken at least 2 hours after acalabrutinib. Because of the interaction between proton pump inhibitors and acalabrutinib, patients can sometimes switch to an H2 blocker such as famotidine. Alternatively, another BTK inhibitor could be used.
For patients who are planning therapy with acalabrutinib, it is important that someone on the care team ask patients directly about these medications. For instance, in the case of a proton pump inhibitor, instead of asking, “What medications are you taking,” you might ask “Are you on Prilosec?” It is important to be specific and to use brand names, as patients may not know what class of drug they are taking or whether occasional use is important to disclose.
BTK Inhibitors and Dosing
With single‑agent BTK inhibitors, patients need to remain on therapy for as long as it is effective and as long as they are not having significant AEs. Evidence suggests that patients should remain on their optimal dose during that period, and I avoid reducing dosage except in the case of AEs. If patients are experiencing AEs and you are unable to keep them on their BTK inhibitor at near-normal doses, one approach might be to try switching to another BTK inhibitor, depending on the type of AE. Infrequently, a drug holiday can be considered for a period of time before restarting on an alternative BTK inhibitor.
In terms of selection of dosing strategy, it is important to recognize that zanubrutinib has 2 potential dosing options: once daily or twice daily. I plan to use the twice-daily dose rather than the once-daily dose largely based on pharmacokinetic data and the fact that most of the studies going forward use twice-daily dosing. Although they appear to be approximately equivalent from available data, the data are limited. However, if once-daily dosing were more appropriate for an individual patient based on compliance or other factors, we know that dosing strategy has been tested and seems efficacious and was included on the FDA label.
What are your biggest challenges regarding the use of BTK inhibitors in your practice? Please share your thoughts in the comments box below.