Optimizing the Frontline Management of High-Risk CLL

Anna Schuh, MD, PhD: The definition of high-risk CLL [chronic lymphocytic leukemia] hasn’t changed in the year of targeted therapies. Of course, the overall survival of patients with high-risk CLL has improved compared with the era when we had just chemoimmunotherapy, but the definition of high risk hasn’t changed. Patients with TP53 abnormalities, whether they’re exon deletions or mutations. We know a lot more know about the features because we know that the majority of patients with deletions also have a mutation on the other allele. There are also patients without deletions but with mutations—not in significant numbers, and we know therefore that to identify patients with high-risk CLL, we have to do the sequencing and not just do the FISH [fluorescence in situ hybridization].

If you want to drop 1 of those tests, you drop the FISH. You don’t drop the sequencing. You’ll pick up about 8% to 12% of patients in the front line who’ve got high-risk CLL from the outset. That number can go up to 40% in subsequent relapses so it’s not in significant numbers of patients. I wouldn’t say that patients with unmutated CLL who are wild type for TP53 are high risk, but they clearly do worse than patients with hypermutated CLL.

We’ve known for a long time across any disease that age and comorbidities are high-risk features. When you’re looking at studies in patients with or without comorbidities, the progression-free survival of those patients reflects the simple fact that they’re older, and more frail is much worse with exactly the same regimen. When you’re looking at the doublets, like the venetoclax-obinutuzumab doublet studies—I’m remembering those because they were more recently published—CAPTIVATE, and GLOW, you can see that the progression-free survival isn’t necessarily the same and the MRD [minimal residual disease] levels clearly aren’t the same in the 2 studies. The regimen is the same, but it’s not the same study group.

Paolo Ghia, MD, PhD: The definition of high-risk disease is interchangeable. We might include in that patient with patients with mutating immunoglobin genes and deletion 17p, patients with deletion 11q. I tend to consider the very high-risk patients, those who have TP53 abnormalities, either deletion 17p and/or mutation in the TP53 gene. Here, we made a lot of progress with the novel therapies because we know that these patients were refractory or responded poorly to immunochemotherapy. Their overall survival was very short in the era of immunochemotherapy. With the novel therapies, we really revolutionized their existence and their outcome with the BTK [Bruton tyrosine kinase] inhibiter patients, for whom we have longer follow-up and more studies. And we have a phase 2 study from the NIH [National Institute of Health] that shows that up to 6 years, 61% of patients with TP53 aberration, if treated in the first line, aren’t yet progressing; they’re still responding. This makes it comparable with all other patients without TP53 aberration.

Similarly, that has been also shown in another study run at The University of Texas MD Anderson Cancer Center, and the follow-up have been really short. At 5 years, 66% of patients were responding, that’s quite comparable. In general, BTK inhibition seems to be very favorable for the patients, alluding to the fact that the continued expression on the clone is probably needed in this disease, in this high-risk disease. Even if you don’t achieve complete responses, even if you don’t achieve deep responses, they’d be better for many years.

The same thing has been hinted also by the second-generation BTK inhibitor acalabrutinib in the elevated treatment-naïve study, in which an older patient has been randomized to acalabrutinib alone or acalabrutinib plus obinutuzumab in combination and compared with obinutuzumab. In this study, also patients with TP53 aberration were enrolled. Indeed, these patients benefited from the use of acalabrutinib alone or acalabrutinib combination with obinutuzumab with the same efficacy as all other patients—75%, 3 of 4 patients were still responding after 4 years of follow-up.

Finally, we have also the possibility of using venetoclax in patients with TP53 aberration. We know this is an approved therapy, it’s a continuous therapy. In the CLL14 study, the drug has been combined to obinutuzumab in a fixed-duration strategy for 12 cycles. That appears to be less effective, so patients already reached a median progression-free survival of around 4 years. There is a statistically significant difference with patients who don’t carry TP53 aberration. We still have to see longer follow-up to see if these patients can be re-treated with the same venetoclax-based treatment, so that would prolong their progression-free survival overall. That might extend the outcome of the patient before switching to another class of drug.

John C. Byrd, MD: We’re left seeing patients with a moving target for both risk and comorbidities. The moving target, say, for disease risk, the 4 criteria reported by Dr Anna, are helpful. There are other things in small patient groups that we use, to incorporate: Are we going to use 1 therapy over another. Or are we going to try to get a person to a combination study. Do they have tetraploid? Do they have an uncommon mutation that might predict that a BTK inhibitor or venetoclax by itself is going to not work as well. That factors in, particularly in younger patients. For older patients who have comorbidities, I believe a couple of things that end up being really important, including the need for anticoagulation, particularly with warfarin. One would want to stay away from BTK inhibitors there, and that’s plus-venetoclax combination in the forefront.

If somebody has a history of atrial fibrillation, there are a lot of cardiovascular issues with the 2 studies on acalabrutinib and zanubrutinib—randomized studies showing less cardiotoxicity compared with ibrutinib. And now that we have a mechanism that’s been published, that ibrutinib probably inhibits 1 of the Src kinases, whereas acalabrutinib and zanubrutinib don’t. You can recapitulate cardiac toxicity and mouse, which 1 would want to stay away from. If you’re going to use a BTK inhibitor and somebody who has a lot of cardiovascular things, using a second-generation molecule such as zanubrutinib or acalabrutinib would for sure be my choice.

A lot of people are on proton pump inhibitors, and acalabrutinib is really affected by that. One wouldn’t want to use acalabrutinib in a patient who’s on a proton pump inhibitor. Zanubrutinib moved into the NCCN [National Cancer Comprehensive Network] Guidelines as an acceptable therapy. That’s where I’d consider using it. A lot of comorbidities affect choice. The last thing is, for that really frail 80- to 90-year-old patient, I’d stay away from the venetoclax because of the complexity. Even with a BTK inhibitor by itself, whether it’s ibrutinib, acalabrutinib, or zanubrutinib, sometimes patients will fall apart with a full dose. Even though I don’t like to underdose people, sometimes I’ll start with half a dosage: 100 mg a day of acalabrutinib or 150 mg of zanubrutinib per day. Then I’ll increase the dose after 2 or 4 weeks when I’m sure they’re tolerating it. Because those 85-, 90-, 95-year-old patients can sometimes fall apart, even with a therapy that you think is going to be really easy to give.

Transcript Edited for Clarity