Repeat Prognostic Testing in CLL


Drs Alexey Danilov and Anthony Mato recommend when hematologists and oncologists should consider repeat molecular testing for patients with chronic lymphocytic leukemia.

Anthony Mato, MD, MSCE: We talked a lot about what we do at diagnosis and prior to initial therapy. What’s your take on repeating prognostic testing? And I’ll throw a new question in there. What are your thoughts about performing markers of resistance for people who are on targeted therapies, particularly the BTK [Bruton tyrosine kinase] inhibitors? Is that becoming part of your practice or is that still experimental in your opinion?

Alexey Danilov, MD, PhD: In terms of repeating testing prior to therapy, I’d do it depending on how much time has passed since the initial testing. As we discussed, IGHV mutational status doesn’t change, so I don’t repeat it. However, there is clonal evolution even when treatment isn’t present. It can be of linear nature where clones expand at the same rate, or it can be of nonlinear nature where, for example, a subclone which harbors a deletion 17p abnormality expands over time. This typically happens over months to years. I have an arbitrary cutoff in my mind that if this FISH [fluorescence in situ hybridization] karyotyping was performed 2 years or longer ago, then I repeat it. If it was performed as recently as 6 to 12 months ago, then I won’t do it. Two years is my arbitrary cutoff where I try to repeat this prognostic testing.

If the clinical situation changes, like if somebody behaved in a really indolent manner and suddenly develops rapid lymphocyte doubling time or they have rapidly progressive lymphadenopathy, and their initial testing was some benign abnormality such as deletion 13q, I would perform repeat testing to look for more negative for other abnormalities at that point, whether it’s complex karyotype or deletion 11q that I suspect. Do you do it in a similar way?

Anthony Mato, MD, MSCE: Yes, except my cutoff is a little different. For me, it’s about 6 months. If their testing hasn’t been repeated within 6 months, oftentimes I’ll repeat it. But both of us are enrolling many patients on clinical trials, so even if it was performed 31 days ago, most of the time I’m repeating all of these prognostic tests. It’s a good example and maybe leads us to another segment. There are definitely differences in the way we approach patients on trials vs those in clinical practice, or the so-called real-world setting. Do you find in your referral base that patients who aren’t on trials are coming with all of the appropriate prognostic testing, or are you having to add to it or start them on testing?

Alexey Danilov, MD, PhD: I’d say it’s roughly 50-50. Anthony, you published really important information about testing in the community where I believe you found that testing for IGHV mutations is typically in the low teens. That’s what I see. And testing for FISH abnormalities, you found about 40% or 50%, and that’s also what I see for patients coming from the community. It’s better now than it was 5 or 7 years ago, maybe thanks to your education efforts. It’s better, but that’s what I typically see. By far, not every patient gets tested. It’s particularly disconcerting sometimes if the patient has already been through multiple lines of therapy and we still don’t know the disease genetics. I will reinforce the point that you can maybe justify not testing at diagnosis. However, testing is very important prior to therapy.

The other question you asked was about testing for novel mutations which can underlie resistance to targeted therapies. In the process of therapy, I haven’t instituted it for the majority of my patients. I have done it in situations where patients have progressed through multiple therapies, have high-risk disease genetically with complex karyotype and TP53 aberration, and are on a BTK inhibitor, such as ibrutinib [Imbruvica] or acalabrutinib [Calquence]. I’m beginning to think of the next step, knowing that this won’t hold them for many years.

For these patients, I started sometimes checking BTK mutation status, but I don’t do it for everybody. As you know, the outcomes of ibrutinib therapy are excellent and many patients—particularly previously untreated—remain on the drug for many years. So far, I haven’t instituted this testing for everyone who’s on a targeted agent. Also, I have to double-check if BCL2 mutational status is available as part of our panel. The last time I checked, it still wasn’t part of the panel, the G101V mutation or others. I don’t think we’ve done that, so that still would be part of whole exome sequencing. What about you, Anthony? Have you started using this test more often?

Anthony Mato, MD, MSCE: I’d love to say I’ve made a firm decision, but honestly, the next-generation sequencing panel at MSK [Memorial Sloan Kettering Cancer Center] is pretty much one size fits all, so if you send it, you get everything. Whether I want to consciously check it or not, if I have a patient progressing on a BTK inhibitor, I get it. It’s the same with the BCL2 and PLCG2 mutations. We’re gathering a wealth of information, oftentimes not using that information at this point in time. But for us, we have a 400-plus mutation panel, and those mutations are included.

Alexey Danilov, MD, PhD: It’s a similar situation here at City of Hope, where we have a hematologic malignancies panel that’s very comprehensive and gives a lot of information, but it wouldn’t necessarily be targeted to patients with CLL [chronic lymphocytic leukemia].

Transcript edited for clarity.

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