MCL at First Relapse: Selecting a First- vs Second-Generation BTK Inhibitor

Christopher R. Flowers, MD, MS

Director, Lymphoma Program
Medical Director, Oncology Data Center
Associate Professor
Bone Marrow and Stem Cell Transplantation
Department of Hematology and Oncology
Emory University
Atlanta, Georgia

Christopher R. Flowers, MD, has disclosed that he has received fees for consulting from Abbvie, Bayer, Denovo Biopharma, Gilead, Karyopharm, OptumRx, Pharmacyclics/Janssen, and Spectrum and funds for research support from Abbvie, Acerta, Burroughs Wellcome Fund, Celgene, Gilead, Genentech/Roche, Janssen Pharmaceutical, Millennium/Takeda, TG Therapeutics, and V Foundation.

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Released: August 10, 2018

Although there are multiple options available to our patients with mantle cell lymphoma (MCL) at first relapse, there is growing evidence that BTK inhibitors are the most effective class of therapy to use in this setting. Both the first-generation BTK inhibitor ibrutinib and the second-generation BTK inhibitor acalabrutinib are highly active in relapsed/refractory MCL, with response rates of approximately 70% with ibrutinib and, according to the recent ACE-LY-004 trial, 81% with acalabrutinib. Given that the FDA has approved both agents for patients with MCL who have received at least 1 previous therapy, how can we decide between ibrutinib and acalabrutinib in the setting of first relapse?

First Relapse: Deciding Between Ibrutinib and Acalabrutinib
Because ibrutinib and acalabrutinib have similar efficacy, I consider other factors when deciding which to recommend: long-term data, safety, pill burden, and cost. To date, we have much more experience and longer follow-up data on survival and safety with ibrutinib in the relapsed setting. Thus, ibrutinib is still the main agent I consider for patients in first relapse, although it is important to have a discussion with each patient on the benefits and risks of each BTK inhibitor and the relative amount of data available between the 2 agents.

Safety is a very important consideration, particularly among my patients who have concerns about the risk of bleeding and atrial fibrillation associated with ibrutinib. These are the most common scenarios where I have selected acalabrutinib over ibrutinib. Current data indicate that acalabrutinib is associated with fewer grade ≥ 3 bleeding events compared with historical data with ibrutinib (2% vs 6%, respectively). Atrial fibrillation is also less common with acalabrutinib, as is grade ≥ 3 diarrhea. However, the caveat here is that with ibrutinib, longer follow-up was needed before some of these associated adverse events became apparent. Therefore, it is possible that we may see some of these same events with longer follow-up for acalabrutinib, but as of yet, it appears that bleeding and atrial fibrillation are less frequent.

Additional factors that could affect the choice between ibrutinib and acalabrutinib include pill burden and cost of therapy. I have had patients who expressed a preference for taking a pill once daily—meaning they would prefer ibrutinib—instead of twice daily as with acalabrutinib. Regarding cost of therapy, it has not yet been one of the differentiating factors in my practice, although I anticipate it being relevant in certain patient‑specific and insurance plan–specific situations.

Finally, for patients who do start therapy with ibrutinib and have a good response, but who are intolerant to ibrutinib or develop any of the mentioned adverse events, it may be reasonable to consider switching to acalabrutinib. I have not yet taken this approach in my clinical practice, but there are some data from the phase I/II ACE-CL-001 trial in CLL that support this approach.

Progression on BTK Inhibitors: Next Options
When our patients with MCL progress on BTK inhibitor therapy, what options can we offer them next? The FDA-approved agents in this setting are lenalidomide and bortezomib. Lenalidomide has a relatively high ORR for relapsed/refractory MCL whereas the ORR for bortezomib is lower than either BTK inhibitor or lenalidomide. Another treatment under investigation is venetoclax, which has activity against relapsed/refractory MCL both as a single agent and in combination with ibrutinib. Venetoclax is already approved for relapsed CLL, and I definitely would consider using venetoclax outside of a clinical trial for patients with relapsed MCL. Clinical trials should also be considered in this setting, and there are multiple ongoing trials of CAR T-cells and other targeted agents.

A Tool to Help Guide MCL Treatment Decisions 
To help you address the challenges associated with treatment decisions for your patients with MCL, my colleagues and I are developing a new CCO Interactive Decision Support Tool for MCL. This tool will be designed to help you as you select individualized treatment approaches for your patients. You will be able to enter your patient’s specific disease characteristics to receive personalized recommendations from 5 expert faculty specifically for the case you enter in the tool. Check back on CCO’s Web site for the new tool along with several other online activities and additional commentaries on MCL to optimize the care of your patients with this disease!

How are you using ibrutinib and acalabrutinib in your clinical practice? Which treatments do you consider after your patients with MCL progress on BTK inhibitor therapy? Please share your perspective in the comments below.

Jointly provided by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC

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This activity is supported by educational grants from
AstraZeneca Pharmaceuticals
Pharmacyclics Inc.

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