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BTKis for CLL
BTK Inhibitor Therapy for CLL: An International Perspective

Released: March 28, 2023

Expiration: March 27, 2024

Stephan Stilgenbauer
Stephan Stilgenbauer, MD
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Key Takeaways
  • Targeted therapies, including BTK inhibitors and combinations incorporating BCL-2 inhibitors, have replaced chemoimmunotherapy as the standard of care for treating CLL.
  • Second-generation BTK inhibitors (acalabrutinib and zanubrutinib) have an improved safety profile for specific adverse events compared with the first-generation BTK inhibitor ibrutinib.
  • Combining BTK inhibitors with venetoclax is an emerging therapeutic strategy that may decrease the risk of venetoclax-associated tumor lysis syndrome and provide a fixed-duration regimen.

The treatment of patients with chronic lymphocytic leukemia (CLL) has evolved rapidly in recent years. For most patients, the previous standard of chemoimmunotherapy has been replaced with novel targeted therapies. Randomized trials have shown that, compared with chemoimmunotherapy, these targeted therapies are associated with superior progression-free survival and—in some instances—overall survival. In addition, targeted therapies are associated with better tolerability compared with chemoimmunotherapy.

There are 2 major classes of targeted therapies: Bruton tyrosine kinase (BTK) inhibitors (including acalabrutinib, ibrutinib, and zanubrutinib) and the BCL-2 inhibitor venetoclax. In this commentary, I discuss my thoughts on contemporary use of BTK inhibitor therapy for CLL.

First-Generation BTK Inhibitors
Ibrutinib was the first BTK inhibitor developed and is approved in the European Union for treatment-naive and relapsed/refractory CLL. Ibrutinib has shown superior progression-free survival compared with standard of care chemoimmunotherapy regimens in various patient groups. However, ibrutinib is associated with off-target adverse events (AEs), including diarrhea, which is early onset and often self-limiting; arthralgia and myalgias, which also are often self-limiting; cardiac AEs (eg, arrhythmias and atrial fibrillation); and hypertension.
  
In addition, ibrutinib can be associated with bleeding events. This is especially problematic for patients who also develop ibrutinib-associated atrial fibrillation, because atrial fibrillation is often treated with anticoagulants. Consequently, many patients who develop these AEs must temporarily—or sometimes permanently—discontinue ibrutinib therapy. 

The off-target AEs associated with ibrutinib presented a clear need for developing BTK inhibitors with higher specificity. This led to the development of the second-generation BTK inhibitors acalabrutinib and zanubrutinib. 

Reduced AEs With Second-Generation BTK Inhibitors
Head-to-head, randomized clinical trials have compared ibrutinib with acalabrutinib and ibrutinib with zanubrutinib. These trials demonstrated that the second-generation BTK inhibitors have an improved safety profile compared with ibrutinib. In these clinical trials, the second-generation BTK inhibitors were associated with fewer AEs. In particular, rates of atrial fibrillation and cardiac arrhythmias were reduced. Therefore, the second-generation BTK inhibitors currently are preferred first-line agents.

It also has been demonstrated that when patients develop atrial fibrillation or other ibrutinib-related AEs while receiving ibrutinib, ibrutinib can be discontinued and the patient can be switched to a second-generation BTK inhibitor. This allows patients to continue BTK inhibitor treatment while minimizing the risk of specific AEs. BTK inhibitors constitute a mainstay therapeutic approach for CLL, and using this therapy class for as long as it is safe and efficacious before switching to another therapy class (eg, the BCL-2 inhibitor venetoclax) is important. Therefore, having the option of switching from the first-generation BTK inhibitor ibrutinib to a second-generation BTK inhibitor is valuable. 

Combination Therapy
In addition to continuous BTK inhibitor monotherapy, another first-line therapy option for CLL is combination therapy with venetoclax plus obinutuzumab, an anti-CD20 antibody. This time-limited, 12-month regimen achieves deep responses and has the added benefit of being a fixed-duration (vs continuous) therapy. A limitation of venetoclax is that at therapy initiation it causes rapid tumor cell destruction, which may result in tumor lysis syndrome (TLS). Therefore, prophylactic measures must be taken, and laboratory and clinical management is essential. In addition, obinutuzumab can be associated with infusion-related reactions, which can cause treatment initiation to be cumbersome.  

The first-line combination regimen of venetoclax plus ibrutinib was approved recently in Europe. This regimen usually includes a 3-month lead-in with ibrutinib before venetoclax is added. The ibrutinib lead-in reduces the tumor mass and, consequently, the likelihood of TLS. This alleviates and mitigates the issue of TLS management, which makes initiating venetoclax easier. The venetoclax plus ibrutinib combination is a fixed-duration option that, as demonstrated in the GLOW trial, results in deep responses and outcomes that are superior to chemoimmunotherapy. 

Ongoing trials are investigating combinations of second-generation BTK inhibitors (eg, acalabrutinib) plus venetoclax. Based on the improved tolerability profiles of these second-generation inhibitors compared with ibrutinib, it is anticipated that combinations of these BTK inhibitors with venetoclax will provide better treatment tolerability compared with the venetoclax plus ibrutinib combination. 

In addition to doublet combinations of venetoclax with either obinutuzumab or BTK inhibitors, triplet combinations comprising venetoclax, anti-CD20 antibodies, and BTK inhibitors are being investigated. However, these regimens are experimental, not currently approved, and do not yet have a firmly established role in the treatment armamentarium based on clinical data.  

Venetoclax-based combinations appear particularly attractive for patients with mutated IGHV, who often enjoy durable responses after time-limited treatment. For patients with unmutated IGHV, venetoclax-based regimens and continuous BTK inhibitor therapy both appear to be equally valid options, while for patients with CLL with del(17p) and/or a TP53 mutation, continuous treatment with BTK inhibitor may be preferred. 

Final Thoughts
The development of targeted therapies has resulted in highly efficacious and well-tolerated treatment options for patients with CLL. BTK inhibitor monotherapy and the combination of venetoclax with either an anti-CD20 antibody or ibrutinib can be considered as frontline treatments for CLL. Determining which of these options is optimal for a particular patient should be an individualized decision based on patient characteristics and preferences, the patient’s other medications, and disease characteristics, in particular, IGHV and TP53 mutations and del(17p) status.  

Clinical Care Options’ Global Interactive Decision Support Tools for CLL
In collaboration with Florence Cymbalista, MD, PhD; Toby Eyre, MBChB, MD; Arnon Kater, MD, PhD; Alessandra Tedeschi, MD; and myself, Clinical Care Options has developed 2 online support tools to provide international expert recommendations on CLL treatment and BTK inhibitor AE management based on the specific characteristics of your patient. A series of multiple-choice questions allows the user to select individual patient characteristics that are necessary to consider when making treatment choices. Based on the characteristics entered, the tool will display evidence-based recommendations for that specific patient case. These tools will be available here.

Your Thoughts?
Do you recommend second-generation BTK inhibitors exclusively when discussing first-line BTK inhibitor treatment for your patients with CLL? Have you considered combination therapy with a BTK inhibitor plus venetoclax? What AEs do you encounter most often with BTK inhibitors, and how do you manage these? Please leave a comment or answer the polling question to join the conversation.  

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In your current practice, how often do you recommend first-line ibrutinib monotherapy for patients with CLL for whom you would plan to use a BTK inhibitor? 

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