Management of Chronic Lymphocytic Leukemia in 2020 - Episode 2

Mutation Status Throughout the CLL Clinical Course


William Wierda, MD, PhD: Can you speak to, Carolyn was mentioning mutation status, 17p deletion, TP53 mutation status. I know that the IGVH mutation status is thought not to change through the clinical course, but perhaps can you touch a little bit on how the cytogenetics and the chromosome abnormalities and mutation status of other genes may change through the course of the disease.

Stephen Opat, MBBS: CLL [chronic lymphocytic leukemia] is a genetically unstable disease. And if you compare the genetic landscape of the disease early, before patients present at the time of treatment with relapsed disease, it tends to be an accumulation of mutations. Most of them are adversely prognostic, the worst of which is 17p loss and TP53 mutations. And those abnormalities portend refractoriness to chemotherapy-based regimens. I think it’s important not only to test at baseline but to test it later in the course of the disease.

William Wierda, MD, PhD: Particularly when patients need a change of therapies, it’s important to check. Maybe, Jacqueline, you can comment on other gene mutations. We’ve had data now for several years with regard to other genes that are mutated in CLL, but it doesn’t seem like any of the other ones have come forth in clinical practice. Are there any that are on your radar screen, so to speak? Are there any others that might eventually be important?

Jacqueline Barrientos, MD: I found it interesting that there were some reports presented with the venetoclax data of genomic changes that BRAF was one of the prognostic markers that may have an effect on the outcomes of patients treated with venetoclax. And I would like to see more data based on that because up until now we haven’t seen that as a prognostic marker for our patients treated with other agents.

Stephen Opat, MBBS: Can I add? The other one I think is important to venetoclax is NOTCH1, and NOTCH1 mutations. There’s a signal that they tend to have less durable response to time limited therapy. So that’s something that we’re certainly looking at testing in the frontline.

Shuo Ma, MD, PhD: And also, some indication that the patient with a NOTCH1 mutation might have a higher risk of Richter transformation.

Carolyn Owen, MD: It’s important also, as you say, validate all these tests before they start being used in routine practice. The more we talk about tests, the more people want to do them. But if the tests have no predictive value and you wouldn’t switch your therapy for it, then there’s a cost and implications. I think that these are all very interesting research ideas, but we shouldn’t feel bad, at least in centers where those tests aren’t available, I don’t think those patients are being underserviced.

Jacqueline Barrientos, MD: Yes, and also it may lead to more anxiety on the part of the patient if they are found to have one of these markers and we don’t know what to make of it.

Transcript Edited for Clarity