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A Matching-Adjusted Indirect Comparison (MAIC) of the Efficacy and Safety of Acalabrutinib Versus Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

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Authored by Dr. Brian Koffman

The Bottom Line:

Acalabrutinib and zanubrutinib have similar excellent efficacy in relapsed or refractory chronic lymphocytic leukemia (CLL). However, acalabrutinib had a lower rate of serious hemorrhage, hypertension, and the need for dose reduction due to adverse events compared to zanubrutinib.

Who Performed the Research and Where Was it Presented:

Dr. Adam Kittai of Ohio State University led a group of international researchers who presented the result of the comparison between acalabrutinib and zanubrutinib at the American Society of Clinical Oncology (ASCO) annual meeting in 2023 in Chicago.


BTK Inhibitors (BTKi) have revolutionized the treatment of CLL. All three approved BTKi have similar impressive efficacy, so treatment choices are often guided by which drug is safer and better tolerated. Direct comparisons between acalabrutinib and zanubrutinib are lacking, so this research was an effort to start answering the questions about safety and tolerability.

Methods and Participants:

Matching-adjusted indirect comparison (MAIC) is a method to compare data from different trials. For this MAIC, individual patient data on acalabrutinib from the ASCEND trial were weighted to match zanubrutinib patient data from the ALPINE trial.

Weighted variable included:

  • Sex
  • ECOG, a measure of a patient’s ability to care for themself, daily activity, and physical ability (walking, working, etc.) developed by the Eastern Cooperative Oncology Group (ECOG),
  • Bulky disease
  • Prior chemoimmunotherapy
  • del(11q) status
  • del(17p) status
  • TP53 without del(17p)
  • IGHV status
  • Region
  • Age
  • Prior lines of therapy
  • Rai stage


  • Progression-free survival (PFS) was similar for both drugs.
  • There were similar risks for those on either drug development:
    • Any grade ≥ 3 adverse events (AE). Grade 3 adverse events are serious and interfere with a person’s ability to do basic things such as eating or getting dressed without help. Grade 3 events may also require medical intervention. Grade 4 AE results in being hospitalized, and a Grade 5 event is “medical jargon” for the patient dying.
    • Atrial fibrillation
    • Grade ≥ 3 atrial fibrillation/atrial flutter
    • Grade ≥ 3 hemorrhage
    • An AE leading to discontinuation
  • Those taking acalabrutinib had a lower risk than those taking zanubrutinib of having:
    • A serious AE
    • Any grade and ≥ 3-grade hypertension
    • Any grade hemorrhage
    • An AE leading to dose reduction


Progression-free survival was similar for both drugs, but acalabrutinib led to fewer specific adverse events. However, MAIC is, at best, an imperfect way to compare therapies, and we really won’t know the validity of these results until we make a head-to-head comparison between the two drugs as has already been done by each medication with ibrutinib (both drugs caused CLL patients fewer problems than ibrutinib). There are, however, reasons to doubt that we will ever see a trial comparing acalabrutinib and zanubrutinib.

Links and Resources:

Watch Dr. Brian Koffman’s monologue on the abstract:

Efficacy and Safety of Acalabrutinib Vs. Zanubrutinib for CLL

To read all the details of the ASCO abstract, please click on A Matching-Adjusted Indirect Comparison (MAIC) of The Efficacy and Safety of Acalabrutinib Versus Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia.

Stay strong. We are all in this together.

Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.