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First- vs Second-Gen BTKi
How I Use First-Generation vs Second-Generation BTK Inhibitors in CLL and MCL

Released: April 13, 2018

Expiration: April 12, 2019

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The development of irreversible Bruton’s tyrosine kinase inhibitors (BTKi)—such as the first-generation BTKi ibrutinib—has transformed our management of B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, the lack of selectivity of ibrutinib can be viewed as a glass either half full or half empty. The agent’s effects on other targets can lead to clinical benefits (ie, immune modulation and dual suppression of kinases promoting chronic graft-vs-host disease), but they can also lead to adverse events requiring discontinuation (eg, diarrhea, atrial fibrillation, rash).

The clinical success and limitations of ibrutinib prompted development of irreversible BTKis with increased selectivity. Of these, acalabrutinib is the first second-generation BTKi approved by the FDA, in this case for relapsed MCL. Although not currently approved for CLL, promising clinical trial results led consensus treatment guidelines to include acalabrutinib as a treatment option for relapsed CLL. Currently, clinicians are facing several important questions: In which settings should we use acalabrutinib, and what are its advantages and disadvantages vs ibrutinib?

When I Use Acalabrutinib vs Ibrutinib
Compared with ibrutinib, acalabrutinib is considerably more selective for BTK and, thus, avoids inhibiting off-target kinases associated with ibrutinib’s adverse events. Whereas ibrutinib is dosed once per day, the selectivity and short half-life of acalabrutinib allow twice-daily dosing (100 mg BID), although I would consider 200 mg QD if I were concerned about adherence.

In my practice, I consider acalabrutinib for patients who develop intolerable adverse events on ibrutinib that prevent further administration or considerably compromise quality of life. Acalabrutinib usually does not lead to the same adverse events—or at least diminishes the symptoms. I consider it more appropriate to switch to an alternative BTKi rather than a different class of agent, given the prolonged durability of response and survival advantage associated with BTKis. Furthermore, the growing experience with acalabrutinib in both CLL and MCL may support choosing it first over ibrutinib when we are concerned about ibrutinib tolerability. Ibrutinib tolerability issues exist in very elderly patients and those with profound bradycardia, other arrhythmias, or preexisting diseases driven by Th1 T-cells (eg, inflammatory bowel disease, sarcoidosis); in patients with comorbidities such as these, I would treat with acalabrutinib instead of ibrutinib.

In patients with relapsed MCL or CLL without potential ibrutinib tolerability issues, I hesitate to recommend acalabrutinib over ibrutinib. Currently, acalabrutinib lacks the long-term safety and efficacy data that we have for ibrutinib. Furthermore, the only data currently available for acalabrutinib as an initial treatment for CLL are conference abstracts.

Acalabrutinib: Future Directions
The answers to our questions about “which BTKi is better” require phase III trial data. The ongoing phase III Elevate CLL R/R trial is comparing the efficacy and tolerability of these two agents in previously treated CLL. Although we must wait for comparative data, it is nonetheless clear that BTKis are a phenomenal therapeutic class that has greatly transformed the treatment of CLL and MCL.

A Tool to Help Guide CLL Treatment Decisions
To help you address the challenges associated with treatment decisions for your patients with CLL, please refer to CCO’s Interactive Treatment Decision Tool. This tool is undergoing continual updates and is designed to help you rapidly select individualized treatment options based on your patient’s specific disease characteristics and overall fitness by offering recommendations from 5 expert faculty specifically for the case you enter into the tool. Use this tool, along with several other online activities and additional commentaries on CLL to optimize the care of your patients with CLL.

Your Thoughts
When do you consider acalabrutinib vs ibrutinib for your patients with CLL or MCL? Please share your experiences in the comments box below and by responding to the question at the right of your screen.

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In your current practice, do you recommend acalabrutinib over ibrutinib for patients with relapsed CLL?
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