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.

More Good News- Update on My Lab, CT Scans, and General CLL (chronic lymphocytic leukemia) Status

My blog has veered far away from the simple telling of my story to more telling of our stories with much B roll.

I am making plans to maybe bifurcate its content in the future, but for now it will continue its happy and diverse life as a personal health blog, a home for research news and video and audio interviews with leading researchers, and a whole bunch of personal analysis and advocacy on what it all means.

I am back from Ohio State where I am still seeing the research team every 3 months and getting CT scans every six months for my clinical trial on ibrutinib. I have riffed on this being too much radiation before in this prior post that includes links to some of the basic research of radiation exposure and its risks, but Dr. Byrd argues that the few relapses he sees on ibrutinib show up first in the nodes, so he wants to monitor me with the scans.

True enough. When I relapsed post failed hematopoeitic stem cell transplant in 2008, the nodes were my canary in the coal mine showing slight growth months before my lymphocyte counts started to move up and my platelets down.

So twice a year CTs are still the plot line for my clinical trial at OSU.

Since diagnosed in 2005, I have probably had about two dozen CT scans!

Add to that the equivalent of the 20 chest X-rays annually I get from flying over 100,000 miles a year, and my risk of secondary cancer is significant. This link with a NASA produced video tells the air travel part of the story.

If you really want to worry, take a look at this article from Medscape on CT scans in NHL.

But this post is not about the danger of CT scans, but about what my last one showed and happily that was stable disease.

I still have enlarged lymph nodes but they have changed little since October of 2012, or for the last 20 of my total of 25 plus months on ibrutinib. My largest sentinel gut node near my liver was about 10 cm at its peak, 7.3 x 3.3 cm just before starting ibrutinib, 4.4 x 0.7 cm in October, 2012 after about 6 months on the medication, then it shrunk to its shortest 3.9 x 0.7 three months later and when last measured on June 30, 2014 was 4.4 x 0.4 which actually represents its lowest volume. It has been fluctuating and when you account for the difficulty of measuring mobile objects in the mesentery and near the liver, is mostly stable since its dramatic shrinking in the first 6 months of therapy. Its a long hot dog shaped node instead of the more common bean shape. The same early dramatic shrinking in the first six months and slight ups and downs since has been the tale for my other smaller sentinel nodes on the scans.

So I have pretty stable disease.

What does this mean to still have enlarged nodes and a touch of CLL in my blood (see this prior post from last April on my flow cytometry report to understand more about my numbers and disease burden)?

The CLL does not proliferate in our blood, so the disease in our nodes and bone marrow are the source of all our problems and I will ignore the blood for now.

There is good reason to believe that these enlarged nodes are still full of CLL, but that it is not proliferating, thanks to the signal blocking from ibrutinib preventing it from getting the messages from its nurse like cells and others to be fruitful and multiply. So chock full of CLL, but it's dormant.

The other more positive interpretation is that these enlarged nodes are just the scarred down skeletons of the cancerous nodes they once were, and there is no residual disease to be found. Unfortunately, I am skeptical of this more PolyAnna hypothesis, and short of a biopsy which is not going to happen, there is not way to know for sure.

So what to do to avoid waking the Kraken?

Hope my genomic instability as evidenced by my 17p and 11q deletions and my complex karyotype will continue to behave with the ibrutinib aboard and not mutate so that my magical bullet no longer covalently binds BTK and blocks its activity?

Knock down the residual disease by adding a second or even a third agent?

Be reactive or proactive?

That is the question du jour faced by many of us now and more in the future whose CLL is controlled but it is not gone now with the new medications such as ibrutinib and idelalisib.

I have probed this recurring and unanswered question in more detail a prior post, and will soon be updating my thoughts on how to avoid being left stranded on third base and not getting home to a cure.

The rest of my news is also good.

My blood counts are boring and despite dropping my cyclosporin to a token dose of only 25 mgs once a day and stretching my 40 grams of IVIG infusions to every 7-8 weeks, my ITP also remains dormant. I think the possible immune stabilizing activity of ibrutinib and my low disease burden may be the factors  that have given me this long ride with high normal platelet counts. I have not been anemic for many months now and my neutrophils and the rest of the CBC are all copasetic. My blood chemistries are in the normal range and only my very low immunoglobulins, namely IGA, IGM, and IGG give proof to that fact that I still have a B cell leukemia, albeit a very sleepy and well behaved one.

More personal clinical and general CLL news soon, nearly all of it good.

I will be posting some of my interviews from ASCO 2014, plus sharing some exciting advocacy news. Busy times.

iwCLL 2013: Day One

So far iwCLL 2013 has been a very cutting edge and bench science driven conference. Great stuff, but not easy stuff to digest.

Tomorrow that changes with more "clinical" presentations.

I need to sleep and not blog, but expect video interviews when I get home from three of the speakers today: George Calin on micro-RNA, Juan Castro on the micro-environment, and Jan Burger on a review of all the mid morning presentations.

This is important stuff we patients need to understand and the doctors that I interviewed do a great job of making it accessible. This is the basic science that molds the future of therapy that they are discussing.

Spent hours reviewing the many excellent poster presentations.

One tidbit: Notch1 and 11q del may be mutually exclusive. Who knew?

My brain is exploding. So much new information.

I will try to hold your hand as I share over the next several weeks all that I have discovered here in Cologne on day one.

Met many old friends and made some new ones. Working hard on some patient advocacy plans with some of the people here. Stay tuned.

Tomorrow looks to be just as busy or busier with at least three interviews lined up, but everything changes at the last minute.

But my son and I will make the time to get out of the conference center and see the famous cathedral before we leave. That is a must. It is only a short walk (in the rain) from our hotel.

But first I must sleep.

Why I am keen on PCI-32765

This very nice blog post deals with the business as much as the scientific aspects of the enthusiasm about Bruton's Tyrosine Kinase (BTK) Inhibitors, specifically PCI-32765 in CLL and other B cell lymphomas.

It is a nice simple introduction to how the BTK inhibitors work and outlines the little but promising data presented at ASH 2011. The blog does not mention the 89% progression free survival in CLL.

I suspect we still don't have the whole story. In fact, I am sure we don't.

What do you think?

Am I and many others over excited about this little pill when the evidence is still pretty sparse?

Probably, but there doesn't seems to be much downside, and the other options of doing nothing or using an established therapy sure have their own very real problems.

And I can always move onto those options later if PCI-32765 doesn't work out. Moving in the other direction is not a likely option.

I am not going there. I have every reason to believe that I will be part of the vast group of dramatic responders, especially since my disease is so concentrated in my nodes and my 11q deletion has pretty much done everything by the book so far, which means my clone should melt away in this trial.

Can't wait to get started.

I see Dr. Kipps in three days to go over my bone marrow biopsy and get his final blessing on my plans.

Live from ASH ( Even Quicker interlude)

Looks as if the 11 q deletion is a much more complicated story than just ATM deletion.

This is good news and is one tiny step on the road to personalized therapy. More to come. Off to chat with Dr. Adrian Wiestner from the NIH.

Constant Comment

You must read the eloquent and heartfelt comments on my last post.

Please remember to email me at bkoffmanMD@gmail.com if you want me to respond.

To my friend who is a fellow amputee, having, like me, lost his 11 q arm (chromosome) in the CLL mine fields, and who also has growing nodes, let me suggest that there may be ways to flush out the cancer cells from where the sweet "nurse cells" are keeping them safe from all the poison arrows we can hurdle in their direction.  With AMD 310, or Cytoxan or GM-CSF we may be able evict those no goods that just want to live forever in a nice warm gut node while eating us out of house and home. With coaxing, we might get them out into the blood stream where they must take their medicine like a cell with no resuscitation from their posse. Out in the open, they will be dropping quicker than the value of a share in Madoff's hedge fund.  

I think MDACC has a study using GM-CSF  and R.  I am planning to research it.