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Clonal Heterogeneity In CLL: Part 2

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Take Away Points:

  • CLL evolves drastically over time, but the seeds of the population that leads to resistance and relapse may be present from the very start.
  • There is more to the story than the cancer itself. CLL’s microenvironment and host immune system’s response also evolve.
  • “There has never been a cure in oncology that has not involved a combination”.


Hematology in general and CLL specifically are full of jargon and acronyms that can be both overwhelming and daunting.  With time and experience, you’ll become familiar with the terminology and acronyms.  We will try to explain each medical term the first time it appears in an article, but we will use the true terminology so that you gain comfort and familiarity with the medical terms that you will see in your lab reports and in medical articles. We will also provide a glossary for your reference.

Clonal Evolutional And Its Implications For Therapy:

In the second part of our interview in Greece with Dr. Cathy Wu from Dana Farber we get down to the gritty implications of how the clonal evolutional of our cancer results in relapse and resistance.

This is critical research if we ever going to get to CURE.

Please review Part 1 of this interview first to set the stage. It also includes several journal and abstract references on the topic.

Dr. Wu makes the remarkable statement that the seeds of our resistance are there in some cells from the very onset and lays out the important implications of this finding in curing our cancer.

Her hypothesis is not yet proven.

Let’s use the burgeoning research on the still relatively rare problem of resistance to ibrutinib to illustrate the issues.

In this 2014 NEJM article, Dr. Jennifer Woyach out of OSU discusses the two most common reasons for the development of resistance to ibrutinib, namely the emergence of mutations in either BTK (for more on the particulars of this mutation, please see this 2014 NEJM article by Dr. Furman) or PLCγ2.  Either of these mutations would prevent ibrutinib from fully blocking BCR (B-cell receptor) signaling. And blocking BCR is how we believe that ibrutinib works to control our cancer.

The authors clearly state: “At baseline, no patient had evidence of mutations in either BTK or PLCγ2 on the basis of whole-exome sequencing”.

This seems to contradict Dr. Wu’s assertion that the mutations are there from the get-go.

Could Dr. Woyach’s team have simply missed a tiny sub-clone with numbers too low to detect? Of course that is possible. But another possibility is that the mutations are a novel response to the pressure on the cancer clone from ibrutinib in the context of genomic instability and a reflection of the cancer’s ability to mutate past its control of growth.

At one level, I am not sure it matters that much. Does treatment select out a resistant clone for dominance or does it produce an entirely new clone to evolve past the drugs trying to control it?

I quote Dr. Byrd from a Medscape interview:

About 3% of untreated patients and 20% to 30% of treated patients will have a deletion in 17p or a complex karyotype,”

We know those patients have more genomic instability; that’s probably why they develop these mutations. That’s our hypothesis,”

Either way, ancestral or de novo, we are in trouble when these resistant clones grow.


Either way, both the emerging clinical data (see this abstract from ASH 2014) and our understanding of the genetics are converging to suggest that combination therapies make good sense for those of us with a complex karyotype or other markers that suggest that our cancer is unstable.

Yet another good reason to consider a clinical trial that combines different therapeutic options.

Dr. Wu also gives us a lovely explanation of the difference between epigenetics and genetics, yet another confounding factor in how our CLL might change over time.

And finally she reminds us to stay vigilant. Her advice to us patients: “ Keep your ear to the ground.”

As we said in our welcome video, plan on the fact that changes in how we treat CLL are coming and they will be positive.

Let’s hear from the doctor herself:

As Dr. Wu said: “We live in truly exciting times, yet where we want to go is cure.”

Truer words have never been spoken.

Brian Koffman 3/13/15