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My Perspective on 3 Questions I Am Asked on BTK Inhibitors for CLL

Ian W. Flinn, MD, PhD

Director, Lymphoma Research Program
Sarah Cannon Research Institute
Nashville, Tennessee

Ian W. Flinn, MD, PhD, has disclosed that Sarah Cannon has received consulting fees from AstraZeneca, BeiGene, Curio, Gilead Sciences, Iksuda, Nurix, Pharmacyclics, Roche, and TG Therapeutics; has received funds for research support paid to his institution from AbbVie, Acerta, Agios, ArQule, AstraZeneca, BeiGene, Calithera, Celgene, Constellation, Curis, F. Hoffmann-La Roche, Forma, Forty Seven, Genentech, Gilead Sciences, IGM Biosciences, Incyte, Infinity, Janssen, Juno, Karyopharm, Kite, Loxo, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium, Triphase Research & Development, Unum, and Verastem.

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Released: November 16, 2020

Treatment of B-cell malignancies with the BTK inhibitors acalabrutinib, ibrutinib, and zanubrutinib has led to a dramatic improvement in patient outcomes. However, the use of these agents in clinical practice continues to evolve. In this commentary, I answer questions on the current and near-future use of BTK inhibitors to treat patients with chronic lymphocytic leukemia (CLL).

Can Patients With CLL Stop Treatment With BTK Inhibitors?
The most common question I get is: Can I stop BTK inhibitors in CLL? The answer is, for the most part, no. That said, it is warranted in specific situations, such as BTK inhibitor–associated adverse events that force the issue. For those patients who have no other options and need to discontinue therapy with a BTK inhibitor, they can stop therapy and be observed but will eventually progress and will need additional therapy. Most patients have better outcomes when they remain on their BTK inhibitor, with dose interruptions or dose reductions as needed, to maintain response for as long as possible.

Of importance, unlike other agents such as the BCL-2 inhibitor venetoclax, the vast majority of patients with CLL will never experience a CR with single-agent BTK inhibition and even fewer will achieve measurable residual disease (MRD) negativity. Therefore, the goal is to keep patients on their BTK inhibitor for as long as possible. Newer combinations in development, such as a BTK inhibitor plus venetoclax, are showing promising results: Many patients in the clinical trials are achieving a very deep, MRD‑negative remission and may eventually be able to stop the BTK inhibitor (ie, fixed-duration therapy). At ASH 2020, 1-year disease-free survival results from the phase II CAPTIVATE study of ibrutinib plus venetoclax will be presented, which should clarify how MRD negativity can guide the choice of whether a patient needs to stay on a BTK inhibitor (ASH 2020 abstract 123). 

Can an Anti-CD20 Antibody Be Combined With a BTK Inhibitor in CLL?
Another common question I get is: Should I combine an anti-CD20 antibody with BTK inhibitors in CLL? The data here are mixed, with little support for adding an anti-CD20 antibody to a BTK inhibitor as a way to improve outcomes in CLL. In the randomized, double-blind phase III Alliance A041202 study, 547 patients aged 65 years or older with untreated CLL were randomized to receive ibrutinib or ibrutinib plus rituximab pr standard bendamustine plus rituximab. Although PFS was significantly improved with ibrutinib vs bendamustine/rituximab (HR: 0.39) and for ibrutinib/rituximab vs bendamustine/rituximab (HR: 0.38), there was no significant difference for ibrutinib plus rituximab vs ibrutinib alone (HR: 1.00). In other words, it appears that ibrutinib alone was responsible for demonstrating superiority over bendamustine/rituximab. It is possible that the only thing rituximab adds for patients receiving ibrutinib is the potential for increased adverse events.

The phase III iLLUMINATE trial also evaluated combining a CD20 antibody with ibrutinib or with chlorambucil. Results showed that, in patients with previously untreated CLL/small lymphocytic lymphoma, the combination of ibrutinib plus obinutuzumab significantly improved PFS vs chlorambucil plus obinutuzumab (median: not reached vs 19.0 months, respectively). But, unlike A041202, there was no ibrutinib-only third arm, so it remains unclear how much benefit, if any, obinutuzumab added to ibrutinib. All we know is that this combination is superior to obinutuzumab plus chlorambucil. Given both A041202 and iLLUMINATE, I typically do not use the combination of an anti-CD20 antibody and a BTK inhibitor to treat my patients with CLL.

The phase III ELEVATE TN trial was a 3‑arm study comparing single‑agent acalabrutinib vs acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil in patients with treatment-naive CLL (N = 535). In this study, in contrast to the data with ibrutinib, the combination of obinutuzumab and acalabrutinib improved PFS vs acalabrutinib alone (HR: 0.49), and both of these approaches were more effective vs obinutuzumab plus chlorambucil (HR: 0.10 with acalabrutinib plus obinutuzumab; HR: 20 with acalabrutinib monotherapy). Overall, the PFS difference between the 2 acalabrutinib arms was relatively modest: 30-month PFS estimate of 90% with the combination vs 82% with acalabrutinib alone at the last analysis. Of note, no significant OS difference was seen between arms. In my opinion, if I were to add an anti-CD20 antibody to BTK inhibition, it would be reasonable to add obinutuzumab to acalabrutinib, although the magnitude of difference is small and may not be worth the additional hematopoietic toxicity. We usually do not do so in our clinic.

Lymphocytosis can occur in patients with CLL during BTK inhibitor therapy and can be extreme; some clinicians use this as a rationale for adding an anti-CD20 antibody to a patient’s CLL regimen. That said, I have only rarely seen this to be a real issue in my patients with CLL—frankly, I worry more about infusion‑related reactions that occur by administering an anti-CD20 antibody to a patient with such a high white blood cell count than I worry about the potential of lymphocytosis harming the patient. In general, I do not see lymphocytosis as a good reason to add an anti-CD20 antibody to a BTK inhibitor.

Which BTK Inhibitor Is Optimal in CLL?
Many clinicians ask: Which BTK inhibitor should I use for my patients with CLL? My answer is that we choose different BTK inhibitors for different patients based on their comorbidities and other medications. Although there is currently no randomized trial data comparing the 2 approved drugs in CLL, ibrutinib and acalabrutinib, there are some preclinical data to suggest that acalabrutinib may have a slightly less associated toxicity based on the target inhibition of different kinases—acalabrutinib may have less inhibition of off‑target kinases compared to ibrutinib. However, the magnitude of these differences, and whether this makes a clinical difference, is difficult to determine in the absence of randomized data.

That said, there are recognized advantages and disadvantages of each drug. I believe ibrutinib is the gold standard to compare with other BTK inhibitors. Most data suggest that acalabrutinib has similar efficacy compared with ibrutinib. Therefore, the choice of BTK inhibitor therapy is based mainly on which types of adverse events a patient can tolerate better and on the ease of use. For ibrutinib, dosing is once daily, which might help with patient compliance. Also, ibrutinib carries fewer issues regarding interactions with other medications.

The biggest issue with acalabrutinib is it has to be given on an acidic stomach and in the absence of proton pump inhibitors. H2 blockers should also be avoided or at least be very carefully scheduled when a patient is also receiving acalabrutinib. Of note, acalabrutinib is also associated with mild headaches. These are typically grade 1 and self-limiting, resolve within a few weeks, and do not occur in all patients. Some clinicians recommend caffeine to help resolve acalabrutinib-related headaches.

Regarding ibrutinib, consider avoiding it in patients with a history of atrial fibrillation or who have significant cardiovascular issues with hypertension that increase the risk of developing atrial fibrillation. Otherwise, I think these 2 BTK inhibitors are largely equal. It is possible that acalabrutinib is associated with less bleeding, but this will need to be determined in a large, randomized phase III trial.

What Are Your Thoughts on Zanubrutinib in CLL?
Finally, another question I hear often is: What are your thoughts on the newest BTK inhibitor zanubrutinib for my patients with CLL? Zanubrutinib is not (yet) approved for CLL, but there is reason to believe that it has a better adverse event profile than ibrutinib. The sole randomized trial of BTK inhibitors to be reported to date is the phase III ASPEN head-to-head study of zanubrutinib vs ibrutinib in Waldenström macroglobulinemia. Results showed approximately equal efficacy: Zanubrutinib was associated with numerically improved response vs ibrutinib but the primary endpoint (CR or very good PR) was not appreciably different between the 2 inhibitors. However, this was a relatively small study (N = 229). Of more importance, the adverse event profile dramatically differed in that the incidence of atrial fibrillation was remarkably different with zanubrutinib compared with ibrutinib, at 3.0% vs 18.4%, respectively, and grade 3 or worse in 7.1% of patients on ibrutinib vs 0% in the zanubrutinib group. However, zanubrutinib did result in more neutropenia compared with ibrutinib, but most oncologists are familiar with managing neutropenia. Currently, zanubrutinib is only approved for mantle cell lymphoma and is difficult to obtain for patients with CLL, although I do think that ultimately it will be proven in randomized studies and approved in this setting.

To hear more about the use of BTK inhibitors for your patients with CLL, please join my colleagues, Susan O’Brien, MD, and John Pagel, MD, PhD, and me for our upcoming virtual satellite symposium at ASH 2020 on Friday, December 4.

How is your CLL clinical practice changing with the use of BTK inhibitors? Share your thoughts on these developments in the comment box below!

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