Making the Choice in CLL: Acalabrutinib or Zanubrutinib

Patients with CLL often are presented with a treatment choice between acalabrutinib and zanubrutinib. While the efficacy of these second-generation BTK inhibitors is similar to that of ibrutinib, the first BTK inhibitor approved for the treatment of CLL, they are less toxic than ibrutinib. Therefore, acalabrutinib and zanubrutinib tend to be preferred options over ibrutinib in patients with both previously untreated and relapsed/refractory disease. 

Acalabrutinib and zanubrutinib have similar efficacy and side-effect profiles. Both are oral medicines that target specific proteins to restrict CLL cell growth. Both may be prescribed to patients with previously untreated CLL or relapsed/refractory CLL, as monotherapy or in combination with obinutuzumab. (See “Innovation of CLL Treatments: Modern Targeted Therapies” for a brief overview.) How do you choose between them? Your doctor’s recommendation is important, of course – but you are engaged in your healthcare and wish to participate in the decision.

Newest Analysis Shows Effectiveness is Not the Same

In 2023, HealthTree reported study results from a statistical comparison of ASCEND trial data (which evaluated acalabrutinib) and ALPINE trial data (which evaluated zanubrutinib) that suggested similar efficacy for the two medicines, but a better side-effect profile for acalabrutinib. Both trials were in patients with relapsed/refractory CLL. 

Now, different researchers have completed a newer statistical comparison based on data from the same two trials but focused solely on efficacy. Study author Mazyar Shadman, MD, MPH, at the Fred Hutch Cancer Center and the University of Washington, notes that the 2023 analysis had significant limitations hindering the efficacy comparison, like the exclusion of data from the final analysis of ALPINE and lack of adjustment for the impact of the COVID-19 pandemic on outcomes.

The current effectiveness results show, for zanubrutinib versus acalabrutinib:

• Longer-last remission 
• Greater chance of a complete response
• Favorable overall survival trend

Considering effectiveness only, zanubrutinib may be a better choice than acalabrutinib for patients with relapsed/refractory CLL. However, a consideration of tolerability is desirable. 

Acalabrutinib Continues to Have a More Favorable Safety Profile

In the 2023 analysis, Dr. Adam Kittai, a CLL specialist with the Ohio State University Comprehensive Cancer Center, and team found that acalabrutinib had fewer side effects than zanubrutinib. The advantages were found mostly in high blood pressure and hemorrhage, and in any medically significant but not immediately life-threatening side effect that may require hospitalization (ie, grade 3 side effects). 

Of note, a poster at the European Hematology Association 2023 annual congress presented an analysis of ibrutinib, acalabrutinib, and zanubrutinib side effects across 61 trials. (Most of the trials were in CLL/SLL.) The comparison between acalabrutinib and zanubrutinib showed a higher risk with zanubrutinib for a large number of serious (≥ grade 3) side effects.

Medical research in B-cell malignancies such as CLL is extremely active right now, which is exciting for patients but also potentially confusing as newly released data updates previous knowledge. You and your doctor will have even more options as investigations proceed on a new class of drugs called BTK degraders. They are for patients with CLL that has developed mutations, making the disease resistant to BTK inhibitors. BTK degraders are still in the early phases of testing in humans, but subscribe to the “HealthTree for CLL” Newsletter for updates on this potential treatment option. 

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Sources:

• Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version (2024)
• Zanubrutinib vs Acalabrutinib in Relapsed or Refractory CLL: New Efficacy Analysis (2024)
• Efficacy of Zanubrutinib Versus Acalabrutinib in the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia (R/R CLL): A Matching-Adjusted Indirect Comparison (MAIC) (2024)
• Treating Chronic Lymphocytic Leukemia (2024)
• P632 Comparison of Treatment-Emergent Adverse Events of Acalabrutinib and Zanubrutinib in Clinical Trials in B-Cell Malignancies: A Systematic Review and Meta-analysis (2023)