Sunday, August 5, 2012

Clonal Evolution in CLL

This article came out about the same time as one from John Byrd's lab.  Both show the same concept and I think it is important.  It highlights the evolutionary capability of CLL over time.  The disease is not the same disease at initial diagnosis and relapse.

You often hear of patients say that when their disease was diagnosed they were 13q but when it came back it may be both 13q and 17p.  Frankly, FISH is only a small portion of the story.  There are a lot of point mutation in key genes such as SF3B1, BIRC3, NOTCH, etc.  For the time being, we don't have an easy way to even test for these abnormalities let alone monitor over time.

I think it is a lot like when you took antibiotics for your sore throat as a child.  You were told to take all your medicine so that the bacteria didn't get resistant.  I think of CLL as the germ that keeps coming back a little smarter than before.

When I did lab work, I was amazed how many CLL cells you could take out of a single tube of a patients blood.  If a patient had a high white blood cell count, you could literally get tens of millions of cancer cells in a single 10mL tube of blood.  In many cases we know that these cancer cells are "genomically unstable" (especially 11q, 17p) which means they are all free to "experiment" with new mutations.  Throw in all the blood, the marrow, the spleen and you have many billions of cells.

Now treat that patient.

Let's say you have effective therapy and get rid of 99.99% of the cells (ie. only one out of 10,000 survive - perhaps we should write another post about minimal residual disease), you may have millions of cells left over that survived because they had the right genetic changes to survive the treatment.  Those are the ones that may then have a competitive advantage and establish themselves as the dominant clone at relapse.

This potentially has broad implications on things such as initial therapy selection, treatment intensity, elimination of minimal residual disease, etc.  I am not sure we have the tools to deploy on broad enough  scale just yet to answer these questions but with genomic sequencing coming online so fast, perhaps that will change soon.