Prognostic Testing and Chemoimmunotherapy Use in CLL

Alexey Danilov, MD, PhD: We keep talking about chemoimmunotherapy as a frontline treatment approach for a fraction of patients with CLL [chronic lymphocytic leukemia], particularly a regimen that combines fludarabine, cyclophosphamide, and rituximab. I have to admit that I don’t use FCR [fludarabine, cyclophosphamide, rituximab] frequently. It has been quite some time since I last used it, but if someone plans to start chemotherapy, that’s where prognostic testing is particularly important to identify patients who are candidates—and more frequently not candidates—for chemoimmunotherapy. That’s where the role of the next-generation sequencing panel and IGHV testing is particularly important. Anthony, how frequently do you test for IGHV?

Anthony Mato, MD, MSCE: Because it doesn’t change, I’m just testing it once. If I tested it at diagnosis for patients, then I never repeat it. How about you?

Alexey Danilov, MD, PhD: I only test once as well. It never changes. If this information is available from a referring doctor, I use that information. But do you test it in every patient, just like other tests?

Anthony Mato, MD, MSCE: I test it for a few different reasons. No. 1, I occasionally find discordant results, particularly if patients are on the borderline. No. 2, the outside testing at our institution is useless to me from the perspective of MRD [minimal residual disease] testing later on, so we need to sequence internally to be able to use that later as a fingerprint for next-generation sequencing and MRD testing. The third is that—this might be a good point of conversation—even the targeted therapies probably have differences in efficacy for IGHV-mutated vs unmutated patients. Even though I’m not ready to declare which therapy I’d use for mutated vs unmutated, we’re heading in that direction, so the information will be useful for selection of therapy, even outside patients considering chemoimmunotherapy. I completely agree with you. Next-generation sequencing is critical because it often provides additional information and support to not give a patient a regimen like FCR [fludarabine, cyclophosphamide, rituximab].

Alexey Danilov, MD, PhD: Have you used FCR [fludarabine, cyclophosphamide, rituximab] in the past 3 to 5 years? Who would be the patient that you’d use it on?

Anthony Mato, MD, MSCE: On average, I’ve used it once per year for the last couple of years, not counting the COVID-19 year that just passed. It’s part of the conversation for the IGHV-mutated, TP53-intact young patient population, with young meaning younger than age 65 who don’t have any major comorbidities. Those are the patients we offer it to and discuss with. That’s based on the long-term follow-up data from The University of Texas MD Anderson Cancer Center and the German CLL study group.

What I’m waiting on is the next update of the ECOG-E1912 study. If those curves for IGHV-mutated disease further separate, favoring the ibrutinib therapy, then that’s going to support abandoning chemoimmunotherapy altogether, even though there’s that theoretical cure fraction. You said you’re not using it at all. You specified FCR [fludarabine, cyclophosphamide, rituximab]. What about bendamustine as a first therapy? Are you using that?

Alexey Danilov, MD, PhD: I stopped using bendamustine several years ago as well, mainly because of the data that came out from the Alliance study that randomized ibrutinib with or without rituximab against bendamustine-rituximab in older patients with CLL. Even though the overall survival hasn’t been superior, the progression-free survival for ibrutinib was better. There are some additional concerns with bendamustine, of course. It’s a noncurative regimen. The attractiveness of the bendamustine regimen is in its time-limited therapy approach. However, with the introduction of venetoclax, which has shown advantage over chemoimmunotherapy in the CLL14 trial, there’s less rationale to use bendamustine.

I’m also worried about clonal evolution with any chemotherapy that we use, particularly in older patients who sometimes have background CHIP [clonal hematopoiesis of indeterminate potential] or clonal hematopoiesis abnormalities. I worry about the risks of emergence of myelodysplastic syndromes or AML [acute myeloid leukemia] over time. That’s potentially another reason next-generation sequencing is helpful, particularly if it’s done on the bone marrow and there’s a significant fraction of myeloid cells to sequence. That’s where we can also detect some of these CHIPs, which will further inform therapy.

Transcript edited for clarity.