Very bad and irrelevant news: Ibrutinib (PCI-32765)

Soon after I first arrived here, I hinted at some bad news that I needed some time to digest.


As circumstances developed, I didn't see Dr. Byrd for several weeks to get the proper perspective and then I had to digest what he said.


The good thing about CLL is even with bad news, you almost always have time to analyze your circumstances, adjust to the new realities, under react, and move forward. 


I also wanted to wait to share with you until I had more distant from the shock


Let me set up the story.


Just before I came to see Dr. Bryd at OSU to assess whether I was a good candidate for his trial, I had a bone marrow biopsy with Dr. Kipps to show that I  had recovered my CD20+ after all my rituximab, an inclusion requirement for the clinical trial with ofatumumab and ibritinib and to assess my status.


That bone marrow biopsy done two months early showed slightly less than 10% CLL (with CD 20 positivity), and my old friend 11q deletion back in 11.5% of the the cells analyzed. The marrow was pretty healthy. No big surprises.


I tried to talk them out of another biopsy at OSU, but they insisted. 


It told a different story.


They use mitogens or stimulants that makes cells divide and thus make it easier for the pathologist to find genetic abnormalities.


And they sure did.


The FISH testing found over 50% of my cells as being 11q deleted.


For the first time 13q14.3 (D13S319) and l-3q34 (LAMP) were both positive.


And:


17p1-31 (TP53) which should be 0-6% of the background population was positive at 7.3%. Not a strong signal, but not a signal I wanted to see at all.


And worse yet, the cytogenetic studies showed that I had not one but two evil clones with "complex karyotypes" that confirmed the FISH findings and re-enforced my bad prognostics and suggested likely resistance to most therapy.


My cancer apparently consisted of two clonal populations, both nasty and both pretty bizarre. Bizarre is bad. Bizarre is aggressive and unresponsive. 


This was very dark news indeed. 17p deletion is usually a clarion call for a transplant. Nothing else reliably stops its often furious and fast fatal march. Complex cytogenetics may make any decision, transplant or other therapy more problematic. Clonal evolution is itself a very poor prognostic indicator. Zap 70 +,  unmutated, CD38+.  I had just about every bad omen.


Things were not looking good.


Now before I proceed, I must point out that comparing the sudden change to a much more aggressive and hard to treat cancer in the 60 days between Kipps' and Byrd's biopsies is not fair because the two labs were using very different techniques.


The mitogens employed by the team at OSU are used precisely because they powerfully stimulate cell division, and thus can demonstrate and some would say artificially inflate genetic abnormalities.


The two methods are looking at very different raw material. Comparing apples and rabbits. Static and active. Most research and data you see in the journals and at conferences still asses their findings the way Kipps' lab did with the static FISH studies. That is the existing standard when a paper says that 20% of the patients were risk risk 17p or 11q. 


So there may be much less change in the 60 days than the numbers suggest.


But the realist in me, says it is still some kind of devolution.


And Dr. Byrd said that these low level findings may not be accurate, as the 17p is the most difficult probe to nail against the background noise. It may mean nothing. It may be a false positive.


The skeptic in me says it must mean something.


Moreover, Dr. Byrd (and Dr. Keating agreed) reassuringly stated that he has seen these low levels of 17p disappear. 


The worrier in me wonders if they are really gone or just hiding? 


But what makes all this speculation and grim foreshadowing and ruminating moot and irrelevant is that I am responding to the ibrutinib.


The proof is in the pudding.


It's working. 


IT'S WORKING!


Some data generally suggests that, at least at first, low levels of 17p del are not as a important factor in response to most therapies as are high levels.


Most importantly, as I have posted before, there is little difference in the response to ibrutinib of 17p deleted patents compared to this with those with more favorable FISH. The depth or durability of the drug's activity seem blind to 17p deletion status. And there are theoretical reasons to believe that being the usual lousy ZAP70 + as I am might be actually be an advantage as PCI-32765 blocks B cell signaling and ZAP70 is all about signaling.


It is all irrelevant as long as the pills work their magic. So far, so good.


What it does tell me, is that it was one of my more prescient and fortuitous moves to push to get into this trial when I did. It's closed now.


If I had not, I would not  had a second biopsy and would not have known of my clonal evolution and the sinister loss of a 17p. 


When it came time (sooner rather than later)  that I needed treatment, my options would have been very limited as most therapies are inactive or pretty toxic or both when you don't have a working P53 pathway (usually found on my missing 17p) to tell the cells to die. Making matter worse, many trials with ibrutinib or other tyrosine kinase inhibitors would exclude me because of my prior transplant.


Of course, there still exists a few scary "what ifs" and "what nexts". Planning for them has become much more difficult and constricted. But that can wait.

Right now, the overwhelming sense I have moment to moment and week to week is just I how fortunate I am to have made the jump to Columbus, Ohio when I did.


I am very lucky and very blessed and very thankful to be here. Now.