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.

ESH 2014: Prof. Stephan Stilgenbauer Reviews Predictive and Prognostic Markers in CLL (chronic lymphocytic leukemia)

I was asked to present the patient's perspective in CLL at a satellite symposium to the annual congress of the Hellenic Society of Hematology held in Thessaloniki in northern Greece near the birthplace of Alexander the Great last month. The sponsors took a risk in inviting a patient to speak to a group of hematologists but my reception was warm and enthusiastic despite my inability to speak in the native language.

As a result of the positive response I received for my 30 minutes on the podium, I was asked if I could shoot a series of monologues that address various aspects of why it is so critical that our voices be heard by the professional community that treats us. I will posting those here and later our CLL website soon.  Check out the first monologue here filmed soon after I flew home. More monologues to follow on other topics.

The Hellenic hematology congress was co-incident with another valuable meeting in Thessaloniki organized by the European School of Hematology (ESH), ESH 2014: International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment so I stayed in town for an extra few days to attend the CLL sessions and shoot some videos for the blog.

On a personal note, on my one half day free in Macedonia, I did rent a car and drove in the rain to see the amazing underground museum that includes the unspoiled grave of Philip II, father of Alexander the Great. Don't miss it. I loved my much too brief return visit to Greece.

 

Grave of Phillip II

My ESH videos were embargoed until after ASH, so I am only able to share them now.

The first video interview is with Prof. Dr. med. Stephan Stilgenbauer of the University of Ulm.

We revisit the topic of prognosis and predictive factors. Here is a link to an earlier post on another aspect of this subject with Dr. Bill Wierda from MD Anderson. Dr. Jeff Sharman gets into some of the same material in this helpful post from iwCLL 2013.

The first message that I gathered from Prof. Stilgenbauer is that the significance of all these factors must be reassessed in this era of novel therapies and that process has only just begun. How they may have predicted and prognosticated about treatment with FCR is not always going to match up as to their relevance for therapy with ibrutinib or idelalisib. 

This should be an active area or reassessment and research. One possible example seems to be that patients with 17p deletion respond differently when treated upfront with ibrutinib versus when treated after they have relapsed with 17p deletion. More predictive and prognostic factors will emerge if we look. 

My next take way: It is no longer sufficient to test only only for the deletion of the short (p for petite) arm of the 17th chromosome (17p deletion), but we also must ask our hematologists to check the function of the TP53 gene. TP53 has been called the guardian of the genome because when it is functioning well, it protects our genetic information from being miscopied and thus spawning a malignant offspring. When it is missing or dysfunctional, cancers are both meaner and harder to kill. Here is a nice overview on TP53 from the NIH. Dr. Stilgenbauer discusses the relation between TP53 and 17p deletion.

Finally we touch briefly on some of the new prognostic factors found in CLL with the advent of deeper probing of our cancer's genetic makeup with next generation sequencing. These include mutations in NOTCH1 (a signaling pathway between adjacent cells) and SF3B1 (a surprise finding, a important in gene splicing). Here's the original article from the NEJM that goes into much greater detail.

Here is Dr. Stilgenbauer.




More soon from ESH and ASH.

As I write and edit these recent blog posts, it has become increasingly clear to me that the scope of what needs to be done to teach about CLL had grown beyond the capacity of this meager blog.

That will be a major part of the mission of the nonprofit CLL Society Inc., to inform and support both the newbie and the cognoscenti of the CLL community through a new dedicated and more robust CLL specific website.

Please complete our survey to let us know what are your unmet needs by clicking this link: https://cllsociety.questionpro.com. It closes at the end of the week.

And thanks so much to the many of you that have already finished the survey and a big thanks to those of you that have generously supported us already with a tax deductible donation. It will all be used to extend and deepen our reach with more knowledge and support.

                                            

iwCLL 2013: Dr. Jeff Sharman Discusses the Practicalities of the New Prognostic Factors

In this short but rather technical discussion of the new diagnostic tests that is a follow-up to part one of my interview from iwCLL 2013 in Cologne, Germany, Dr. Sharman shares what he actually tests for in a patient who is considering therapy.

I started by challenging him that we have heard of these novel disease markers such as BIRC3, Notch 1 and SF3B1, but they are not discussed much outside of academic research, and even then, they are not tested for in most trials

Most of these new prognostic markers have just not yet made it from the research studies into the hematologist's office.

One important point that I want to linger on for a moment is the difference between a prognostic and a predictive marker.

Though the terms are often used rather loosely, and many markers are clearly both, there is a difference.

A predictive marker tells us patients how likely we are to respond to a particular therapy. A 17p or BIR3 or CYP2B6*6 warns us that our chance of a response to FC is markedly diminished.

Mutation status prognosticates how likely we are to need therapy and die too soon from our disease. Remember that all prognostic markers are prognostic for groups, not for individuals

While there is frequent overlap, it is a helpful distinction to keep in mind when considering our  workup in advance of therapy. Obviously a marker that predicts that we won't do well with traditional chemo-immunotherapy carries with a bad prognosis if that is the only therapy our docs could offer.

But as you have heard over and over again, that dangerous bottleneck is rapidly expanding with the new treatments coming into use. Accordingly, the distinction becomes increasingly important and predictive tests may soon help guide choice of our therapy.

Here is Dr. Sharman:



One more sad note: I just found out that another CLL warrior lost the fight. George Martinez, whom I met and connected with in Columbus, Ohio, a fellow charter member of Team I (ibrutinib) who like me, flew to Ohio from his home in SoCal to join Byrdland, came to that drug after being badly beaten up by his CLL, its treatment, and multiple horrific infections.

I will miss his kind, funny, warm and generous ways.

We need to be looking at more than kicking the cancer down the road. We need to looking at reconstituting our immunity and preserving our marrow.

I hate this disease and want to see it vanquished!

Rest in peace, George.