Clinical Cases in Chronic Lymphocytic Leukemia - Episode 17

Case 4: Resistance to Ibrutinib in CLL

January 28, 2020


Anthony Mato, MD, MSCE:That was an interesting case you presented. I was happy to see that they repeated the FISH [fluorescence in situ hybridization] analysis, so I think that is an important practice to do after a significant period of time has gone by. The major question is why this favorable-risk patient developed progression of disease, and I guess I’m calling this clinical resistance to a BTK [Bruton tyrosine kinase] inhibitor. I think the intent of the work-up was to try to document molecular resistance. I was wondering if you can speak to that and tell us a little about what we might find in the setting of progression from a molecular perspective for patients who were treated with ibrutinib.

Nupam A. Patel, MD:With patients who have been treated with ibrutinib, you can definitely find resistance within theBTKgene itself. Ibrutinib, when it normally binds—it actually binds within this ATP-binding pocket to an exposed cysteine. You develop mutations that confer resistance, which change the cysteine to a different amino acid, and therefore ibrutinib can no longer bind. That’s 1 mechanism. What you can find is mutations further down in the pathway, specifically in phospholipase C-gamma-2 [PLCG2]. Sequencing of both of these genes is pretty much essential to document that you have resistance inherent to those.

Anthony Mato, MD, MSCE:I also think it was interesting that it was done in the context of progression. I’m curious from your practice: a) Do you have the ability to do this type of testing? And then b) Do you do it in the setting of progression, or is there any value into doing it earlier on prior to clinical progression?

Sameer A. Parikh, MBBS:That’s a very important question. In our lab, we do not have the ability to do this particular testing. We can do it on a research basis, but we do not have a CLIA [Clinical Laboratory Improvement Amendments]—certified lab that can give us a result that can go into the patient’s clinical record. We do use outside vendors where we get this testing done. There are data to suggest that in many patients who have been on ibrutinib as a single agent for many years, these resistance mutations actually develop early on before clinical relapse occurs.

Anthony Mato, MD, MSCE:How early, would you say?

Sameer A. Parikh, MBBS:In the data that were presented, it appears that anywhere from a median of 9 to 12 months prior to clinical relapse. Although we do sequence some of our high-risk patients, particularly patients who have deletion 17p or maybe aTP53mutation to look for early evidence of relapse. Here is a prime example of a patient who did not meet any of the “high-risk” criteria yet developed clinical relapse.

Anthony Mato, MD, MSCE:I guess we saw the NGS [next-generation sequencing] performed after the fact, so we don’t know if it was...

Sameer A. Parikh, MBBS:That is true. I think the other thing to point out that is important is that when a patient who has been on ibrutinib—and I couldn’t tell how long this patient was on, maybe for a year or 2—and has progressive disease, it’s important to make sure that this patient has not developed a Richter transformation. I’m assuming that was thought of and that they did an LDH [lactate dehydrogenase] and potentially did a lymph node biopsy to make sure there was no Richter transformation.

Anthony Mato, MD, MSCE:Had imaging as well.

Sameer A. Parikh, MBBS:And had imaging as well, because data suggest that if a patient has early progression of disease on ibrutinib, particularly in the first 12 months, it’s more likely to be a Richter transformation as opposed to true CLL [chronic lymphocytic leukemia] progression.

Anthony Mato, MD, MSCE:I completely agree.

Transcript edited for clarity.