American Society of Hematology (ASH) 2016: Dr. Adrian Wiestner on Failure of ibrutinib in chronic lymphocytic leukemia

In my interview from ASH 2016 in San Diego, Dr. Adrian Wiestner of the National Institutes of Health talks about the patients who fail ibrutinib due to disease progression.

Our interview covers important considerations for all patients when planning chronic lymphocytic leukemia treatment.

Take Away Points:

• Responses to single agent ibrutinib in CLL have been surprisingly robust and durable.
• Early relapses, usually within the 1st year, on ibrutinib are often Richter’s Transformation (RT). This is a more aggressive lymphoma that may have been there already and only becomes apparent when CLL has been treated.
• RT carries a poor prognosis, but new treatments using checkpoint inhibitors (PD-1 inhibitors) or CAR-T (chimeric antigen receptor- T- cells) are promising new options in clinical trials.
• Later relapses of CLL are often related to a mutation where ibrutinib binds (C481), rendering it much less potent.
  • It is unclear as to whether this is a new mutation that develops under the therapeutic pressures of ibrutinib or is one that was present before at levels too low to detect. Emerging evidence suggests the latter.
  • This is a slower moving relapse than with RT and gives the doctor and patient time to consider their next move.
• Combination therapies may not be necessary for all patients, but rather a sequential use of drugs may make more sense for some patients.

Here is an article from ASCO 2017 on Richter’s Transformation after novel agents:

Richter’s syndrome (RS) in patients with chronic lymphocytic leukemia (CLL) on novel agent therapy.

Here are two abstracts offering information on checkpoint blockade for RT:

PD-1 Blockade with Pembrolizumab (MK-3475) in Relapsed/Refractory CLL Including Richter Transformation: An Early Efficacy Report from a Phase 2 Trial (MC1485)

Nivolumab Combined with Ibrutinib for CLL and Richter Transformation: A Phase II Trial

Here is my interview with Dr. Wiestner:

Lingering Questions:

How to best use these drugs is not a trivial or strictly academic pursuit.

In Dr. Byrd’s Cake of Cure, he points out that while we don’t know the right mix to cure our chronic lymphocytic leukemia, we are getting closer.

I tend to believe that we should carpet bomb the CLL with a cocktail of multiple novel agents so that not one errant cell survives.

But is that even possible? And what if a few of the nastiest cells survive with all their natural checks and balances wiped out in the attack?

Does sequential therapy offer a chance at a longer life as Dr. Wiestner suggests?

These are questions only more research will answer.