ASH 2017: Dr. Adrian Wiestner on Resistance Mechanism in CLL (chronic lymphocytic leukemia)

I had the opportunity to interview Dr. Adrian Wiestner from the National Institutes of Health at ASH 2017 in Atlanta GA about his and other researchers work on how CLL cells become resistant to ibrutinib and venetoclax.

Take Away Points:

• Ibrutinib works so well in chronic lymphocytic leukemia because it blocks the B-cell receptors (BCR) by binding to Bruton’s Tyrosine Kinase (BTK). This blocking of the BCR leads to cell death.
• About 7-8 out of 10 patients who become resistant to ibrutinib develop a mutation C481 that prevents it from it binding and thus fully blocking BCR, allowing the CLL to progress.
• PCLƔ2 mutation is another cause of resistance as it turns back on the BCR pathway and gives a lifeline back to the chronic lymphocytic leukemia cells.
• Cells with the PCLƔ2 mutation tends to grow more slowly and the CLL tends to clinically progress more slowly.
• Notch1 mutation can be associated with early progression on ibrutinib which is often not CLL but instead Richter’s Transformation that carries a poor prognosis.
• Many patients do well on ibrutinib who have a Notch1 mutation.
• Richter’s is rare after the first year on ibrutinib suggesting that blocking B-cell signaling may block the stimulation that leads to Richter’s
• Less is known about the mechanism of venetoclax resistance, but upregulation of MCL-1 might play a role.

Conclusion:

While the numbers are small, we are starting to better understand the mechanisms of resistance for some but not nearly all patients who progress on ibrutinib. Our understanding of venetoclax resistance is much less mature. As this research develops, there is reason to be optimistic that we can develop drugs to overcome the resistance.

Here is my interview with Dr. Wiestner from ASH 2017 in snowy Atlanta Georgia:

Here are links to some of the research referenced by Dr. Wiestner

• Mechanisms of Venetoclax Resistance in Chronic Lymphocytic Leukemia
• Dissecting the Role of Individual Bcl-2 Members in Response and Resistance to Ibrutinib or Venetoclax in CLL
• Apoptosis Resistance and NOTCH1 Mutations Impair Clinical Outcome in Chronic Lymphocytic Leukemia (CLL) Patients Treated with Ibrutinib

Here is more on resistance from Dr. Furman from our website.

Thanks for reading.

Stay strong

We are all in this together.

Brian Koffman