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Expert Answers to Frequently Asked Questions on BTK Inhibitors for Treatment of 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 and 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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Susan M. O'Brien, MD

Associate Director for Clinical Science, Chao Family Comprehensive Cancer Center
Medical Director, Sue & Ralph Stern Center for Clinical Trials & Research
Professor, Division of Hematology/Oncology
School of Medicine
University of California, Irvine
Orange, California


Susan M. O’Brien, MD, has disclosed that she has received consulting fees from AbbVie, Alexion, Amgen, Aptose Biosciences, Astellas, Celgene, Eisai, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Juno Therapeutics, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Vaniam, Verastem, and Vida and funds for research support from Acerta, Gilead Sciences, Kite, Pfizer, Pharmacyclics, Regeneron, Sunesis, and TG Therapeutics.


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John Pagel Headshot
John Pagel, MD, PhD

Chief of Hematologic Malignancies
Swedish Cancer Institute
Seattle, Washington


John Pagel, MD, PhD, has disclosed that he has received consulting fees from AstraZeneca, BeiGene, Gilead Sciences, and Loxo.


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Released: January 15, 2021

In this commentary, Ian W. Flinn, MD, PhD; Susan M. O’Brien, MD; and John Pagel, MD, PhD, answer questions posed by the audience of a live CCO Webinar on the optimal use of BTK inhibitors for patients with chronic lymphocytic leukemia (CLL).

A 60-year-old man presents with CLL with unmutated IGHV, 11q deletion, hypertension, and hyperlipidemia. Which of those characteristics—the prognostic factors, age, or comorbidities—would most influence your treatment selection?

John Pagel, MD, PhD:
The most important factor when I am selecting first-line treatment for a patient with CLL is whether the patient has del(17p) or a TP53 mutation. For patients with del(17p) or TP53 mutation, I generally recommend first-line therapy with a BTK inhibitor. For patients without a del(17p) or TP53 mutation, many patients are candidates for finite therapy with venetoclax/obinutuzumab and others may still be suitable for treatment with a BTK inhibitor. Because del(17p) or TP53 alterations are absent in this case, I would most consider his age and del(11q) status.

First, there is the patient’s young age. Next, he has del(11q), which is usually associated with more adenopathy and more bulky disease—the latter sometimes factoring into treatment selection. Subgroup analyses of clinical trial populations have indicated that single‑agent BTK inhibition is associated with efficacy in this patient population. Thus, it would be reasonable for this patient to decide whether he prefers indefinite therapy with a single-agent BTK inhibitor or finite therapy with venetoclax/obinutuzumab.

Is there still a role for fludarabine, cyclophosphamide, and rituximab (FCR) or other chemoimmunotherapy in current practice?

John Pagel, MD, PhD:
I have not used FCR in at least 6 years. Most of my patients with CLL are older and/or less fit, rendering them poor candidates for this more aggressive regimen. FCR is associated with long‑term cytopenias and a risk for secondary malignancies (eg, therapy-related myeloid neoplasms).

The only instance where I would consider FCR is with younger patients who have favorable IGHV‑mutated disease. However, early data suggest that BTK inhibitors and venetoclax-based regimens may be as efficacious as FCR in this population.

Ian W. Flinn, MD, PhD:
I agree. I also have not used FCR in more than 5 years. I think it is certainly reasonable to consider FCR for a young patient with IGHV-mutated disease who has very good risk factors, but currently, I do not.

Susan M. O’Brien, MD:
I would not consider FCR now because of the ongoing COVID-19 pandemic. Before the pandemic, I routinely considered this regimen for my younger, fit patients with IGHV-mutated disease because of the long‑term plateau observed in the PFS curve. The longest follow‑up data are from MD Anderson Cancer Center, which had initially developed FCR. In 2016, my colleagues and I reported that after a median follow-up of 12.8 years, 53.9% of FCR-treated patients with IGHV-mutated disease maintained PFS. Those patients generally visit MD Anderson once per year, and their peripheral blood measurable residual disease assessments remain negative.

Based on these and similar data, I believe there is a fraction of this population who potentially achieve cure with FCR. Yes, there are some risks, and I would not use FCR without prophylactic growth factor support. Although there is the late risk of myeloid neoplasms (eg, acute myeloid leukemia or myelodysplastic syndromes), data suggest that those are most likely to occur in older patients—a population in which we no longer use FCR.

How would autoimmune manifestations (eg, hemolytic anemia or immune thrombocytopenia) affect treatment options?

Ian W. Flinn, MD, PhD:
I have competing thoughts here. On the one hand, I consider it easier to administer a BTK inhibitor either alone or in combination with an anti-CD20 antibody rather than venetoclax in a patient who has autoimmune problems. On the other hand, if you are attempting to ameliorate the autoimmune manifestations, does depth of remission matter? Does the patient need to achieve a deep remission (ie, with venetoclax-based therapy) to be rid of some of these clones?

The difficulty with that second thought is that venetoclax is associated with myelosuppression, which is concerning when the patient already has cytopenias. In this situation, I have used both approaches, but most recently, I have been using a BTK inhibitor with rituximab.

Susan M. O’Brien, MD:
Would you treat the autoimmune phenomena first, or would you initiate treatment for both the autoimmune manifestations and the CLL at the same time?

Ian W. Flinn, MD, PhD:
I have started patients first on steroids to try and bring the autoimmune manifestations under control before starting CLL treatment.

John Pagel, MD, PhD:
I agree. If you can control the autoimmune component, patients will often do fine, sometimes even without CLL‑directed therapy.

Regarding infection with COVID-19, does venetoclax/obinutuzumab have a disadvantage compared with BTK inhibitors?

John Pagel, MD, PhD:
We do not yet know whether venetoclax/obinutuzumab increases a patient’s risk of infection with COVID-19, although there are several reasons why we would think so. First, patients come into clinic more frequently early on with venetoclax/obinutuzumab than with a single‑agent BTK inhibitor. Second, venetoclax/obinutuzumab requires an intravenous infusion, so patients are potentially exposed more and for longer periods of time. 

We do know that patients with marked B-cell depletion—which occurs with anti‑CD20 antibody–based therapies—do not mount nearly as good an immune response to other infections or vaccinations.

What are your thoughts on the preliminary data suggesting that BTK inhibitors may protect against COVID-19?

John Pagel, MD, PhD:
Ongoing clinical trials are evaluating the interaction of BTK inhibitor use and COVID-19. If a protective effect exists, it is most likely due to how BTK inhibitors tamp down hyperinflammatory responses. I would not expect BTK inhibitors to directly prevent COVID-19 or even reduce hospitalization due to COVID-19, but these agents might decrease the risk of needing to be in the ICU and/or on a ventilator.

If you have a patient who develops atrial fibrillation while receiving ibrutinib treatment, would you discontinue BTK inhibitor therapy or would you try to continue the therapy?

Ian W. Flinn, MD, PhD:
In my current clinical practice, I would likely discontinue ibrutinib therapy and switch to a different BTK inhibitor, particularly for lower-grade atrial fibrillation events or those that may not need anticoagulation therapy. Even if someone has asymptomatic atrial fibrillation, continuing therapy without taking steps to manage the atrial fibrillation is not in their best interests long term. It is easier to hold the BTK inhibitor and get the patient’s heart back into a normal rhythm and then switch to acalabrutinib.

John Pagel, MD, PhD:
I agree. I will add, however, that some patients who are in remission with minimal risk factors or favorable FISH findings and stop their BTK inhibitor therapy due to an adverse event are able to remain off therapy for an extended time before they need additional treatment. For these patients, they may be able to hold ibrutinib for an extended time and restart therapy when their disease begins to progress.

Largely, I have had success switching patients from ibrutinib to acalabrutinib once atrial fibrillation resolves without a recurrence of the atrial fibrillation.

Susan M. O’Brien, MD:
So, when would you discontinue BTK inhibitor therapy and switch to something like venetoclax?

John Pagel, MD, PhD:
Generally, I try to stay in the same class of drugs until disease progression to get the most clinical utility out of BTK inhibition before switching to a new mechanism of action. I find it effective to keep venetoclax available for salvage or rescue therapy, since this is a potent therapy.

I do switch to venetoclax if the patient requires significant anticoagulation or there is a major risk for bleeding, a hemorrhage, or a stroke. For example, if a patient had a coronary stent placed and require clopidogrel, this will escalate the risk of bleeding while receiving a BTK inhibitor, so I would switch to venetoclax.

How do drug–drug interactions and dosing requirements affect the choice of BTK inhibitors for individual patients?

John Pagel, MD, PhD:
Absorption of acalabrutinib requires an acidic stomach, so use of gastric acid–reducing agents requires careful timing considerations and proton pump inhibitors should be avoided if possible. In patients for whom a gastric acid–reducing agent is needed, an H2-receptor antagonist or an antacid can be considered. If an H2-receptor antagonist is used, it should be taken 2 hours after acalabrutinib. If an antacid is used, dosing of the antacid and acalabrutinib should be separated by at least 2 hours.

However, treatment with ibrutinib and zanubrutinib do not have any contraindications for proton pump inhibitors or other gastric acid–reducing agents. Therefore, patients who require treatment with a proton pump inhibitor may consider one of these 2 agents instead of acalabrutinib. Zanubrutinib is not yet approved for CLL, but trials are currently ongoing in CLL.

As far as dose schedule, ibrutinib is taken once daily and acalabrutinib should be taken twice daily. Zanubrutinib has a flexible dosing schedule and can be taken either once daily or twice daily, with the dose adjusted depending on the frequency of dosing.

What are your thoughts on the use of zanubrutinib in CLL?

Ian W. Flinn, MD, PhD:
The BTK inhibitors zanubrutinib, ibrutinib, and acalabrutinib are all FDA-approved therapies for different hematologic malignancies—ibrutinib is approved in CLL/small lymphocytic lymphoma (SLL) with or without del(17p), Waldenström macroglobulinemia, mantle cell lymphoma after ≥ 1 previous therapy, and marginal zone lymphoma after ≥ 1 anti-CD20-based therapy; acalabrutinib is approved in CLL/SLL and in mantle cell lymphoma after ≥ 1 previous therapy; and zanubrutinib is approved in MCL after ≥ 1 previous therapy.

These 3 agents are all in the same class of BTK inhibitors, in that they are all irreversible, covalent inhibitors. None of these agents is completely selective for BTK, and all of them can inhibit other kinases as well. This nonselectivity may explain some of the off‑target adverse events that are described in clinical trials. There has been one randomized phase III trial—the ASPEN trial—comparing ibrutinib with zanubrutinib, but this trial was in patients with relapsed/refractory Waldenström macroglobulinemia after ≥ 1 previous line of therapy or treatment-naive patients not eligible for other therapy. Efficacy between these 2 BTK inhibitors was similar, and the most pronounced difference between ibrutinib and zanubrutinib in this trial was increased rates of adverse events, in particular the difference in the rate of atrial fibrillation with 15% of patients receiving ibrutinib experiencing this adverse event vs 2% with zanubrutinib.

John Pagel, MD, PhD:
Yes, these data are certainly interesting, and zanubrutinib is also being explored further in CLL. SEQUOIA is a phase III trial assessing zanubrutinib in CLL. At ASH 2020, results from arm C of this trial were presented for zanubrutinib in treatment‑naive patients with CLL and del(17p). The best ORR was 94.5%, 18-month duration of response was 87.7%, 18‑month PFS estimate was 90.6%, and the 18-month OS was 95.4%. These data seem quite promising and additional trials are also underway, including the phase III ALPINE trial comparing zanubrutinib and ibrutinib in patients with relapsed/refractory CLL after ≥ 1 previous therapy.

More Information on CLL and BTK Inhibitors
Click here to use CCO’s Interactive Decision Support Tool: Expert Guidance for the Treatment of CLL to receive management recommendations from a panel of 5 experts for a wide variety of patient presentations.

Click here to use CCO’s An Interactive Algorithm Tool: Assessment and Management of BTK Inhibitor Adverse Events to receive management recommendations from a panel of 5 experts for a wide variety of patient presentations.

For easy access to these and several other patient management tools from CCO, download the CCO Decision Support app from the app store on your phone!

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