Sunday, January 11, 2015

ESH 2014: Prof. Stephan Stilgenbauer Discusses Prognostic Factors, FCR and Implications for Therapy in CLL (chronic lymphocytic leukemia)

In part two of my interview from ESH in November 2014 from Greece with Professor Stilgenbauer of the University of Ulm, Germany we go deeper on the topics we cover in part one and introduce new subjects. I recommend you take a look at that post if you haven't already. That prior post also has links to even earlier reviews of some of the same areas of discussion.

In this segment, the doctor starts by using the examples of 11q or 17p deletion that help explains some of the subtleties of the difference between prognostic and predictive factors.

It is a nuanced subject, but one worthy of our efforts to understand as it can help guide our therapeutic choices.  His examples clearly outline the differences. Hopefully my brief introductory notes that follow also help.

The best known bad player found by FISH or interphase fluorescence in situ hybridization is deletion of 17p.

When the short arm of the 17th chromosome (17p) is deleted, gone with it is TP53 that is important in maintaining genomic stability when our DNA is reproducing itself. Because of its critical role in guarding the fidelity of each copy of the genome when our cells are replicating, it is considered a tumor suppressor. The doctor explains how it also fosters resistance to most chemo-immunotherapies.

The number two bad boy is 11q deletion.

The 11q arm carries ATM that is also involved, those less critically, in the same pathway protecting the stability of our genome. But the new discovery is that 11q deletion may also lead to loss of BIRC3 that leads to the jamming on of the pro-survival and anti-apoptotic NF-κB signaling pathway. More on this in later posts.

It's complicated, but the pieces are coming together.

Dr. Stilgenbauer points out that in those of us with 17p deletion with the relatively good news of having a positive mutation status, our CLL may be slow to progress. This combination of + mutation status and 17p deletion is an example of a prognostic factor- prognosticating about how we will do in the future.

He next points out that when patients with that same combo eventually do need treatment, it will most likely not respond to conventional chemo-immunotherapy (CIT) such as FCR. This is an example of a predictive factor, representing a "prediction" of the likelihood of a given therapy working.

If we are both unmutated and 17p deleted, sadly odds are we will both progress quickly and do poorly with traditional therapies. A double whammy. Bad prognostic and predictive factors. That's me.

He correctly points out the good initial response rates to CIT for those with 11q deletion (I am in this group too), but he neglects to point out that while we might get a deep response, it is not durable, possibly due to our cancer's ability to mutate more freely. He is right in highlighting the strong correlation between unmutated status and 11q deletion, which raises the questions about which is these two gives us the bad prognostic.

The professor's take on the possible "cures" with FCR is also instructive. Please give a critical listen.Much to ponder.

We also talk about the need for deep sequencing to search for 17p deletion or to check for TP53 function. He explains the new versus old ways to look at the chromosome.

Dr. Stilgenbauer outlines the sinister consequences that happens when the selective pressure of CIT is applied to even the smallest subclone population of 17p deletion cells. They can rise up and take charge when the cancer returns.

I believe that FISH is important but only a first step. Today we need to look for both deletions missed by FISH and smaller but critical subclones that are beyond the resolution of FISH. CLL management needs to move in this direction.

I don't want this post to be too much of a downer. While all statistics and cellular biology are important for predicting what happens to different groups, they do not determine individual destiny. And many of the new therapies' responses are blissfully blind to FISH status. I myself am unmutated, 11q deleted, 17p deleted, ZAP 70+, CD38+, have a complex karyotype and I am doing fine, thank you, but knowing this helped informed my decisions.

He closes with the familiar clarion call of the twin needs of having a CLL expert on our team and for more research.

More from ESH, Greece coming soon, including Dr. Wu on clonal heterogeneity and Dr. David Porter of U. Penn on CAR-T in CLL.

Many interviews to share from ASH last month in San Francisco are on the way.

Stay strong. We are all in this together.

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Blogger Anne L said...

Thank you so very much, Brian (if I may be so informal). I deeply appreciate your wisdom. It does seem like our understanding of cellular and molecular features as well as the cellular environment still has a ways to go. Thank you for your blog!

January 12, 2015 at 12:07 AM  

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