ASH 2018: Professor Hillmen on Venetoclax Resistance in CLL

ASH 2018: Professor Hillmen on Venetoclax Resistance in CLL (chronic lymphocytic leukemia)

On the last day of ASH (American Society of Hematology) 2018 Annual Meeting in San Diego, CA, six late breaking abstracts were presented.

To be selected for these highly selective and influential spots, the research must represent a major scientific breakthrough or a paradigm shift in disease management.

This year at ASH, two of the six papers chosen were about CLL. The first we share today is of the first type, a discovery that explains a newly discovered mechanism of resistance to venetoclax.

This is critically important. Although venetoclax is a powerful killer of CLL cells and works in more than 80% of patients, some don’t respond at all. Some relapse during treatment. If we can understand how that happens, we can make plans to minimize the risk and discover ways to overcome the problem.

Professor Peter Hillmen, at Leeds, England has chaired the chronic lymphocytic leukaemia (CLL) trials sub-group of the National Cancer Research Institute (NCRI) since 2002. He discusses the exciting research from Melbourne, Australia where venetoclax was first discovered.

Take Aways:

• CLL cells are difficult to kill due to their very high levels of BCL-2, a cellular anti-death enzyme that blocks the chronic lymphocytic leukemia cells from dying.
• Venetoclax is a targeted therapy that binds to BCL-2, blocking its activity and switching the balance in the CLL cells towards rapid programmed death leading to rapid clearing of the cancer for most patients.
• In 7 of 15 patients who progressed on venetoclax had developed a mutation at the binding site (Gly101Val mutation in BCL2) preventing binding.
• If venetoclax can’t bind, it can’t block BCL-2 and the CLL continues to grow.
• This is analogous to the now well-understood situation with ibrutinib resistance when a mutation of C481 in its binding site prevents it from turning off the B-cell receptor.
• The Gly101Val mutation tends to happen if there is a significant number of CLL cells still around to mutate, suggesting the importance of reaching U-MRD (undetectable minimal residual disease) where the number of cancers cells left are so few that it is below our ability to find them.
• It also only happens when the cancer cells are continuously exposed to venetoclax where there is an obvious survival advantage to those cells that can find a way to mutate around its control.
• This suggests it makes sense to limit the exposure to venetoclax, especially when there is no longer any detectable disease.

Conclusions

While the numbers are small and can’t account for all the resistance to venetoclax, a coherent picture is starting to emerge as to what future trials we should be investigating. At least for those involving venetoclax it makes sense to study the value of reaching U-MRD and then stopping therapy.

You can find the actual ASH 2018 late breaking abstract: Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia here. https://ash.confex.com/ash/2018/webprogram/Paper120761.html

Please enjoy my 5-minute interview with Dr. Hillmen who is not only a great clinician and researcher, but also a gifted teacher.

ASH 2018 was bonanza for CLL research. Much more to come.

Thanks for reading.

Stay strong. We are all in this together

Brian

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Dr. Brian Koffman, a well-known doctor, educator, and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the Executive Vice President and Chief Medical Officer of the CLL Society Inc.

Originally published in The CLL Tribune Q4 2018.