CLL: Going nowhere fast or going fast to nowhere? How Growth Kinetics Apply to Clinical Picture

Understanding the disease

Traditional theory of CLL holds that it is a disease of long lived malignant cells that slowly proliferate.  Of course there can be significant variability from patient to patient.  The idea would suggest that typical 13q/mutated patient with a doubling time of 4 years has a very low proliferative rate.

One of my favorite CLL papers shatters this theory:


In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells

In this paper, researchers had patients drink a daily allocation of deuterium (aka heavy water).  They could then take the malignant cells and measure how much deuterium was incorporated into their DNA and from there calculate a "birth rate" and upon cessation of deuterium a "death rate" of the population of CLL cells.

In summary, they found that CLL is much more like a stationary treadmill than a slow walk.  In other words, there is a significant and balanced birth and death of CLL cells that can be as high as 3% of the total population of cells per day.  Progression occurs when there is an imbalance between a higher birth rate and a lower death rate.  Occasionally you will see patients WBC fall quite a bit.  This is an imbalance where death rate exceeds birth rate.  At 3%, you could envision virtually the entire population of cancer cells "turning over" in a period of several months.

This is important because we know that CLL is a disease in which the original clone begets several sub-clones.  If a sub-clone gains a growth or survival advantage, in this model, it is a lot easier for that clone to become dominant.  This is why it is important to recheck FISH when disease relapses after therapy - if you kill off the easy disease, you may be left with more resistant disease.  This is why you see a higher rate of 11q, 17p at relapse than original presentation.  This is also why a disease that remains "stable" for quite some time can suddenly become more "active."

In my own way of thinking, it is why I am trying to move the field away from traditional fludarabine / bendamustine based regimens in front line treatment.  I worry that we are selecting for resistance in the same way we remember being told to take all our antibiotics when we were kids with a sore throat because we didn't want the bacteria to become resistant.

Sadly, there is a tremendous under appreciation of how to use FISH out there with many docs.  It is not used as frequently as it should be.  It is not a static measurement for a patient - if it can change, and that change influences your therapy, you should be getting it rechecked at major clinical turning points.