CLL Expert Insights on Choosing Treatment and BTK + BCL-2i Combos

In a PeerView educational session at the 2024 American Society of Hematology (ASH) conference, specialists discussed common questions and controversies clinicians have about treating chronic lymphocytic leukemia (CLL). 

In this article, we’ll discuss portions of the session that include things to consider with your first CLL treatment and insights on combining BTK and BCL-2 inhibitors. 

To read other segments from this session that discuss third-line CLL therapy options and strategies for managing treatment-related side effects, click here.

Things to Consider with Your First CLL Treatment 

Dr. Jeff Sharman from Willamette Valley Cancer Institute shared that CLL treatment starts when one or more of the iwCLL guidelines are met. Click here to read about the criteria for starting CLL treatment. 

He discussed whether it is beneficial to treat CLL before one of the guidelines is met. When looking at the total amount of time a person with CLL has been alive since diagnosis (overall survival), patients lived the same amount of time whether they received ibrutinib treatment early or not.  

Although receiving an early CLL diagnosis is beneficial, Dr. Sharman recommended not starting treatment before one of the iwCLL guidelines is met to help reduce the amount of time patients are exposed to possible side effects.  

When it is Time to Start Treatment, What can People with CLL Expect?

• If patients take the pill continuously, ibrutinib (Imbruvica, Johnson & Johnson) works for about 9-10 years before it becomes ineffective.
• Zanubrutinib (Brukinsa, BeiGene) is similar in its effectiveness to acalabrutinib (Calquence, AstraZeneca). These second-generation BTK inhibitors are preferred over ibrutinib as they have fewer side effects.
• Adding obinutuzumab (Gazyva, Genentech) to acalabrutinib helps patients achieve an improved outcome for a longer period of time than taking acalabrutinib alone.
• If you have the IGHV mutation, the fixed-duration one-year combination of venetoclax (Venclexta, AbbVie) with obinutuzumab helps patients achieve longer remissions than other CLL types.
• After you finish your first treatment, just because CLL may come back does not necessarily mean you need to start another therapy right away. Rather, you wait for treatment indicating symptoms to appear once again. 

Click the button below to read about the potential benefits and drawbacks of choosing between different CLL therapies, such as BTK inhibitors and venetoclax. 

Considerations for Selecting a CLL Treatment

Combining BTK Inhibitors and BCL-2 Inhibitors 

Dr. Kerry Rogers from Ohio State University shared that BTK inhibitors and BCL-2 inhibitors, when taken together, improve the effectiveness of each other for targeting CLL cells. 

She also stated that anti-CD20 antibodies like obinutuzumab enhance the effectiveness of these therapies and should be added to the BTK and BCL-2 inhibitor combination. 

Many CLL clinical trials are underway or have been completed evaluating these treatment combinations. If you are interested in joining one of the studies, the trial’s page is hyperlinked below if it is still recruiting patients. 

Studies enrolling participants as of December 2024:

• Dr. Ahn’s study evaluating zanubrutinib + venetoclax for relapsed/refractory patients (recruiting).
• BOVen trial reviewing zanubrutinib + venetoclax + obinutuzumab as patients’ first CLL treatment (recruiting).
• Phase 1 study testing sonrotoclax by itself or in combination with zanubrutinib + obinutuzumab (recruiting).
• Phase 3 study reviewing sonrotoclax + zanubrutinib vs. venetoclax + obinutuzumab for first-time treated CLL (recruiting).
• BELLWAVE-010 trial testing nemtabrutinib + venetoclax vs. venetoclax + rituximab for relapsed/refractory CLL (recruiting). 

Studies that are completed or active but not recruiting: 

• GLOW study testing ibrutinib + venetoclax (active, not recruiting).
• Alliance trial evaluating ibrutinib + venetoclax + obinutuzumab vs ibrutinib + obinutuzumab (active, not recruiting).
• CLL13 study reviewing venetoclax + obinutuzumab vs. venetoclax + obinutuzumab + ibrutinib (completed).
• AMPLIFY trial testing acalabrutinib + venetoclax vs. acalabrutinib, venetoclax, and obinutuzumab (active, not recruiting).
• SEQUOIA arm D study reviewing zanubrutinib + venetoclax for first-time treated patients (active, not recruiting).
• BRUIN CLL-322 study evaluating pirtobrutinib + venetoclax + rituximab vs. venetoclax + rituximab (active, not recruiting).

Summary 

Dr. Jeff Sharman emphasized that CLL treatment should begin only when iwCLL criteria are met, as treatment before this does not improve overall survival and may expose patients to unnecessary side effects. When treatment starts, second-generation BTK inhibitors like zanubrutinib or acalabrutinib are preferred over ibrutinib due to fewer side effects, and combinations such as venetoclax with obinutuzumab offer promising options for the majority of CLL patients, specifically for those with the IGHV mutation. 

Dr. Kerry Rogers highlighted that combining BTK inhibitors and BCL-2 inhibitors enhances their effectiveness in targeting CLL cells and that adding anti-CD20 antibodies like obinutuzumab further boosts this effect. Numerous clinical trials are evaluating these treatment combinations, offering potential opportunities for patients interested in participating. 

Continue Reading CLL News 

Click the button below to keep reading news about chronic lymphocytic leukemia (CLL). 

Continue Reading CLL News

Sources: 

• Addressing Current Questions and Controversies in the Management of Chronic Lymphocytic Leukemia
• What Clinicians Want to Know: Addressing Current Questions and Controversies in the Management of Chronic Lymphocytic Leukemia - A CME Friday Satellite Symposium and Webcast Preceding the 66th ASH Annual Meeting