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ASH 2020: Dr. Paul Barr on Combining Rituximab with BTK Inhibitors for Treatment of Chronic Lymphocytic Leukemia (CLL)

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CD20 is a protein expressed on the surface of B cells, including malignant B cells such as in chronic lymphocytic leukemia (CLL). Anti-CD20 antibodies (i.e., rituximab and obinutuzumab) are like flags that identify B cells and tag them for destruction. These antibodies are commonly combined with chemotherapy and targeted agents for enhanced efficacy in treating CLL. For more detailed information on how anti-CD20 antibodies work, see this article.

Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib are a first-line treatment for CLL. The combination of ibrutinib and rituximab improved progression free survival when compared with chemoimmunotherapy (FCR: fludarabine, cyclophosphamide, and rituximab). However, when compared with ibrutinib alone, adding rituximab to ibrutinib did not show any additional clinical benefit. This suggests that ibrutinib is doing the heavy lifting in the ibrutinib and rituximab combination. Scientists have been studying why this occurs and whether rituximab can be combined with other BTK inhibitors such as acalabrutinib.

At the annual meeting of the American Society of Hematology (ASH) 2020, our own Dr. Brian Koffman interviewed Dr. Paul Barr, an Associate Professor of Medicine at the Wilmot Cancer Institute in Rochester, NY. They discussed which BTK inhibitor is best in combination with rituximab.

Takeaways:

  • Rituximab is an anti-CD20 antibody that is commonly used in combination therapies to enhance efficacy.
  • The combination of ibrutinib with rituximab has not shown any additional clinical benefit when compared to ibrutinib alone.
  • Ibrutinib may actually inhibit some of the effects of rituximab, because it has off-target effects on a process known as antibody-dependent cellular phagocytosis (ADCP), which is the major mechanism through which anti-CD20 antibodies work.
  • Inhibition of BTK by itself does not block ADCP.
  • The next-generation BTK inhibitor acalabrutinib has fewer off-target effects and doesn’t seem to inhibit ADCP.
  • Acalabrutinib may be a better partner to combine with anti-CD20 antibodies such as rituximab or obinutuzimab.

Conclusions:

Sometimes drugs can have unexpected effects on processes unrelated to the original drug target. In the case of ibrutinib, off-target effects on ADCP mean that it decreases the efficacy of rituximab. However, more specific BTK inhibitors such as acalabrutinib could potentially be combined with rituximab while still maintaining efficacy.

Please enjoy this brief interview with Dr. Barr from the virtual ASH meeting which was held December 2020.

You can read the actual abstract here: Ibrutinib Off-Target Inhibition Inhibits Antibody-Dependent Cellular Phagocytosis but Not Efferocytosis of CLL Cells

Take care of yourself first.

Ann Liu, PhD