Thursday, April 12, 2012

Clonal Complexity and Prognosis

Nothing in CLL is simple. Or easy to understand. Or consistent.

And it turns out that the greater the complexity, the poorer the prognosis.

It appears that FISH is just the tip of the iceberg. FISH probes only what is programmed to probe. Very focused, very limited.

Massive whole gene sequencing (sponsored by grants from the National Human Genome Research Institute, National Cancer Institute, the Blavatnik Family Foundation, and National Institutes of Health) has discovered much more complexity . There are 9 mutated genes in 5 core signaling pathways namely: DNA damage repair and cell-cycle control (these are our old friends, TP53 or del 17p and ATM or del 11q), Notch signaling (newly discovered FBXW7, and the better known NOTCH1), inflammatory pathways (MYD88, DDX3X, MAPK1), and RNA splicing/processing (two new players, SF3B1, DDX3X).

What is important is that for the first time ever more than half of these of these were discovered in CLL.

In the CLL patients studied, SFB31 was the second most frequently mutated gene occurring in surprisingly high 15%. SFB31 mutations was primarily associated with del 11q (that includes me) cancer already known to have a poor prognosis. This same mutation in SFB31 is founded in myelodysplastic syndromes that is a well recognized and rightly feared complication of CLL and its treatment.

Just the presence of the SFB31 mutation in CLL is an independent predictor of poor prognosis. Just what we need: Another risk factor to worry about. You don't want a bad spliceosome messing up your RNA.

Here is a link to the article in NEJM . This same material has presented at ASH 2011.

I bring it up now, not to add more reasons to worry, but to point to the progress being made in understanding the complexities of the disease.

Remember that PCI-32765 (ibritinib) is a targeted therapy that works in blunting of some of the pro-survival or anti-apoptotic crosstalk done by the BCR or B cell receptor between the cancer clone and its micro-enviroment . This drug and its ilk were not possible without the help of the basic science that elucidated these pathways, their importance, and their possible aberrations.

The good news is that these new mutations are strong clues as to how the cancer develops and what might be new vulnerabilities to be exploited in emerging targeted pharmaceuticals.

I am still clearing up a backlog of news from ASH and important journals and will be bringing you more videos and news soon. There is so much new in CLL that it is near impossible to stay current and not feel overwhelmed. I will try to continue to clarify some of what I believe is the critical new stuff.

My treatment at OSU has taken more out of me than I anticipated, slowing me down, but I hope to up and more energetic and if the stars line up, bring you want I think will be even better news from ASCO.

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Anonymous Anonymous said...

Fascinating and frightening stuff. To know everything, or be on "need to know" basis? I don't know.

I am wondering, and you may not wish to say, if this more detailed testing is related to your personal "bad news" you've mentioned and were discussing w Dr. Byrd yesterday. Whether yes or no, I found the overall tone of your post quite positive in terms of more and more means to deal with iffy prognoses.

Thanks again for all the info, and I hope the discussion w Dr. Byrd did yield good individual results for you as well as so much info for all of us.


April 12, 2012 at 4:16 PM  
Blogger Unknown said...

Brian, Thank you so much for keeping all us CLLers informed, you're doing a great job. It is very exciting about the new discoveries. I'm sorry you're having trouble with your treatments. I wish you the best. Dave Tipton 68; dxed 2001; FCR 2004; relapsed 2007; ITP 2007; Rituxan signle agent since 2010, currently wait for something better

April 12, 2012 at 4:39 PM  
Anonymous Anonymous said...

Thanks for the update Brian. Hope your energy levels return soon. Be well. Cheers, Deborah

April 13, 2012 at 3:29 AM  
Anonymous Anonymous said...

Thanks for your updates, Brian. Best regards, Alison.

April 13, 2012 at 7:00 PM  
Anonymous Anonymous said...

Your posts and information is always greatly appreciated.


April 15, 2012 at 7:20 AM  
Anonymous Anonymous said...

As always, thanks for you posts. It's hard to believe they would design this study for only 17p deletes. I have to think that's their error in the wording. Or, it's a rather cruel gift .. 50% will get a drug that seems to work for 17p- and the others .. well, they'll get something that may work for a while but ...

All the best, Lynn

April 18, 2012 at 12:41 PM  

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