ASH 2017: Atlanta Professor Michael Hallek on MRD Negativity in CLL

Dr. Michael Hallek from Cologne (Koeln) leads the German team that does so much important chronic lymphocytic leukemia research and has changed how we treat CLL.

In my interview from the American Society of Hematology Annual Meeting in 2017 (ASH 2017), Professor Doctor Hallek shares his enthusiasm about the expanding role of minimal residual disease negativity (MRD-) in managing chronic lymphocytic leukemia.

Some investigators are asking to rename MRD- to “MRD undetectable,” a more accurate and understandable name as the finding of no cells by modern techniques does not mean there are no cells to be found. They are just at a level below detection and maybe below where they will ever rise again to cause active disease. As we have a finite number of cancer cells, at some point, we may be able to kill off the very last one and that would be a CURE.

Prof. Hallek and I discuss this in our video interview below in much more detail.

Takeaways:

• MRD negativity is a standardized measure of the amount of disease that is of clinical significance and predictive of more durable remissions.
• MRD negative means that less than one in ten thousand white blood cells is a CLL cell.
• The most common way to measure MRD is by flow cytometry that looks at the cell surface for its immunophenotype or immune fingerprint that says it is a clonal CLL cell. For more on this, scroll down to this interview with Dr. Kipps to the section on immunophenotyping.
• Another method is PCR (polymerase chain reaction) which exponentially amplifies a single copy or a few copies of a specific segment of DNA generating thousands to millions of copies. In CLL, PCR is used to look for clonal sequences of the immune globulin heavy chain.
• For more on these techniques see this older article.
• Now there are even more sensitive techniques using next generation sequencing that might be able to find one CLL cell in a million. This involves finding short sequences of DNA unique to the cancer and looking for them again as the treatment progresses. This was one of the methods used on my bone marrow post CAR-T. My blog explains more.
• Multiple combinations of drugs with and without chemotherapy have been shown to reach MRD- as explained in this review with Dr. Wiestner.
• MRD can guide when is best to stop treatment.
• By understanding the dynamics of how long it takes to get the cancer cells below 1/10,000, it might be possible to predict how much longer that we need to continue therapy assuming the same dynamics to reach a cure for CLL.

Here is my interview with Dr. Hallek from ASH 2017 that covers more topics related to MRD and CLL:

Some of the combination trials referenced by Dr. Hallek are accessible here:

• Ian Flinn presenting his data on the combination of venetoclax and obinutuzumab(Gazyva) at ASH 2017 where in a small study 100% of patients achieved MRD neg. in their peripheral blood.
• Matt Davids’ research on the combination of FRC plus ibrutinib (FCRi)with “83% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone.”
• Nitin Jain’s abstract in the combination of ibrutinib and venetoclax.
• We have frequently referenced the MURANO includinghere that combines venetoclax with rituximab.

Conclusion:

Using MRD as a marker of when to guide and when to stop therapy, with today’s potent combinations of novel agents being used in clinical trials, may lead to very long remissions, dare I say CURE, while being able to stop all drugs after some fixed amount of time.

Now that would be something!

Stay strong.

We are all in this together

Brian

Brian Koffman MDCM DCFP, DABFM, MS Ed
Co-Founder and Volunteer Medical Director, CLL Society Inc.

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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 medical director of the CLL Society Inc.

Originally published in The CLL Tribune Q3 2018.