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FAQs: BTKi for CLL
Answers to Frequently Asked Questions on Optimizing CLL Management With BTK Inhibitors

Released: May 21, 2021

Expiration: May 20, 2022

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In this brief commentary, Jeff P. Sharman, MD, answers questions on the management of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with BTK inhibitors that were submitted by an audience of healthcare professionals during a live CCO webinar held May 6, 2021.

How concerned are you with secondary malignancies due to treatment with fludarabine, cyclophosphamide, and rituximab (FCR)?
I think secondary primary malignancies due to treatment with FCR is a valid concern and can occur in approximately 5% of patients receiving this regimen. However, there is a very limited role for chemoimmunotherapy now that the novel agents such as ibrutinib have demonstrated superiority compared with FCR. The only patients for whom a chemoimmunotherapy-based regimen might be considered includes young, fit patients with IgHV-mutated CLL and both favorable fluorescence in situ hybridization and no del(17p)/TP53 abnormalities.

Do you think selectivity of acalabrutinib makes it a better combination partner with anti-CD20s due to neutral ADCC impact?
We don’t know yet why adding obinutuzumab to acalabrutinib results in improved progression-free survival whereas ibrutinib plus rituximab was equivalent to ibrutinib alone. The phase III GENUINE trial evaluated yet another novel anti‑CD20, ublituximab, among patients with relapsed/refractory high-risk disease. The combination of ublituximab with ibrutinib resulted in an increased overall response rate compared with ibrutinib alone. Thus, I think the add-on benefit is more about the second generation anti‑CD20 antibody vs the BTK inhibitor itself, but time will tell on that with additional studies.

Do you consider using ibrutinib for patients intolerant to acalabrutinib? What data are there to support your assertion that acalabrutinib performs better than ibrutinib with anticoagulants?
I’ll start with the anticoagulant part of the question because I want to make sure that I’m speaking clearly here on an area that I think is still a little bit unclear. Both of these BTK inhibitors have bruising and bleeding as a concern, and the studies for both of them excluded patients who were receiving warfarin. I think that really the answer to the first part of the question will come out in the upcoming release of studies directly comparing acalabrutinib with ibrutinib (ELEVATE-RR) as well as zanubrutinib with ibrutinib (ALPINE), and any subtle differences between these 2 BTK inhibitors will be seen there. Generally, if I had a patient intolerant of acalabrutinib, I would be more likely to try zanubrutinib than ibrutinib unless neutropenia was the cause of acalabrutinib intolerance. Zanubrutinib appears to have more neutropenia than ibrutinib, but we have press releases indicating lower rates of cardiac toxicity and higher response rates for zanubrutinib than ibrutinib.

What degree of baseline cardiac disease would warrant avoidance of BTK inhibitors?
I think that I may have reservations for a BTK inhibitor in patients who have symptomatic atrial fibrillation where they are subjectively bothered by the palpitations or require procedural intervention for rate control. Fortunately, the 2 second-generation BTK inhibitors (acalabrutinib or zanubrutinib) reportedly have lower rates of atrial fibrillation than ibrutinib although that data have not yet been presented. So, I might favor acalabrutinib or zanubrutinib vs ibrutinib in that setting. I don’t think that BTK inhibitors are contraindicated in patients with baseline cardiac disease or atrial fibrillation, but you need to be familiar with the possible exacerbation of underlying symptoms. BTK inhibitors are a very effective therapeutic class as a whole and I would hate to take it off the table as an option for my patients.

Other than favoring BTK for del(17p) mutation like was mentioned, do other high-risk features (TP53 or del11q) sway your choice of one therapy over another in the relapsed/refractory setting?
In the most recent update of the CLL14 trial of first-line venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab in patients with CLL and coexisting medical conditions, we are starting to see the Kaplan-Meier curves separating along the lines of IgHV mutation status. I will be interested to see how that evolves with time because it may suggest that the same characteristics that historically led to better outcomes with chemotherapy may be similar for the BCL-2 inhibitors.

What do you think about the use ublituximab plus ibrutinib in the near future?
The phase III GENUINE study was not sufficiently powered for the results to enable FDA approval of the combination. Therefore, I think we will not be adding ublituximab to ibrutinib in the near future. However, we have seen that the combination of umbralisib and ublituximab is likely to gain approval in the coming year based on improved progression-free survival vs chlorambucil plus obinutuzumab in the UNITY-CLL trial.

I read about this hypothesis linking acalabrutinib and twice-daily dosing to higher intratumoral BTK occupancy and potentially superior outcomes. It sounds a bit like hype. What do you think?
Both acalabrutinib and ibrutinib are present in the circulation for a short period of time. Their efficacy is based on permanently inactivating the BTK enzyme until it is resynthesized in the cells. Therefore, it is possible that exposing cells twice in a day could offer theoretical advantage, but we will soon have the head-to-head data from ELEVATE-RR to give us an answer. Zanubrutinib stays in the circulation the longest of the 3 covalent inhibitors, so it may be best to see if any differences emerge between ibrutinib and zanubrutinib from the ALPINE trial. Finally, the coming reversible inhibitor pirtobrutinib maintains serum levels around the clock and appears to be very effective.

More on Expert Management of CLL/SLL on the CCO Web site!
Remember to download the PowerPoint Slidesets associated with the live webinar for this program, check back for a CPE-certified on-demand webcast from the live event, and read a short expert commentary featuring a pharmacist’s perspective on the care of patients with CLL/SLL with BTK inhibitors.

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