Global Approaches to the Frontline Management of CLL

Paolo Ghia, MD, PhD: When I consider first-line treatment for patients with TP53 aberration in the deletion 17p or TP53 mutations, I don’t consider age as effective to decide therapy, because I feel much safer, in populations of both old and young patients, using BTK [Bruton tyrosine kinase] inhibition continuous treatment. It’s the only 1 that has proven to be effective, even after 6 years with 61% of patients still responding despite having BTK treatment or not.

BTK inhibition therapy shows long-term follow-up. The control of the disease is up to 61% of the patients who will be responding after 6 years of treatment, despite carrying TP53 mutation and BTK inhibitors. The continuous therapy is indeed well tolerated in both the young and the older. Of course, in the young population, there’s probably a higher concern of the continuous therapy because they’re not used to taking drugs, and they’re also concerned about the long-term consequences. For this population, we’re still struggling to have a better treatment and the combination treatment that we’ll be seeing soon. For example, BTK inhibitors and BCL2 inhibitors might be a strategy, providing important responses but with the time limit.

When we move to the rest of the population, those without deletion 17p and TP53 mutation, which are the vast majority of patients, regardless of the age, I prefer to stratify my patients based on the genetic feature of the immunoglobulin gene mutation status. For a patient with mutated immunoglobulin genes, there is evidence that time-limited reconfiguration is very beneficial. Of course, we know that these are younger patients, who can still benefit from rituximab for 6 cycles. Though I’m a little against using immunotherapy in younger patients, even if mutated in IgG, because I’m afraid of the long-term consequences: continuous risk of infection for 1 or 2 years after the end of treatment, the occurrence of acute leukemia, or the occurrence of MDS [myelodysplastic syndrome].

In terms of time-limited treatment, fixed-duration treatment, now we have available the combination between venetoclax and obinutuzumab that had been shown to be very effective in the mutated patients and older patients. Of course, we can extrapolate data. Though the study was enrolling only older patients or older patients with comorbidities, we can extrapolate the data to the young patients, thinking that this population could also benefit from this type of explanation. For unmutated patients, who are a high-risk population, they tend to progress a little earlier. When we look at the treatment of fixed-duration therapies, I still prefer at least for a few years—until we don’t have a longer follow-up with other treatments, and we don’t see the re-treatment, for example—after we need venetoclax and obinutuzumab. I still prefer to treat this patient, regardless of age, with the continuous BTK inhibition.

John C. Byrd, MD: Young patients who present with deletion 17p are the patients you worry about the most, because those patients have at least 1 risk factor for progression, and they’re going to live a long time. There are limited data outside the monotherapy studies with ibrutinib and zanubrutinib and acalabrutinib across these studies. This would suggest that this group of patients has a higher risk over time of relapsing than patients who don’t have this. And they’re going to be at risk for relapsing over a longer period.

Your other choices are going to be venetoclax-obinutuzumab. The German CLL [chronic lymphocytic leukemia] studied venetoclax-obinutuzumab for a year vs chlorambucil obinutuzumab. Venetoclax-obinutuzumab performed much better than chemotherapy-immunotherapy. The curves of that study for 17p were much worse than any of the BTK inhibitor studies. For a younger person with 17p, I tend to use a BTK inhibitor with a CD20 antibody. More than likely I would use 1 of the second-generation molecule acalabrutinib, because in a younger person it’s going to have less hypertension.

There’s a relapse study that compared acalabrutinib with ibrutinib, and they saw less hypertension, less atrial fibrillation, and fewer adverse events. One would be able to keep them on therapy for longer. I tend to use obinutuzumab with that, particularly in this patient group, because the acalabrutinib-obinutuzumab study that was done, the ELEVATE TN treatment-naïve study, showed a progression-free survival advantage with the addition of obinutuzumab and not a lot of added toxicity. This is a higher-risk group. For those with non-17p, I would say the same. I tend to favor a BTK inhibitor often as a second generation, acalabrutinib or zanubrutinib, with more data with acalabrutinib plus or minus obinutuzumab.

I generally don’t use venetoclax in the up-front setting or venetoclax-obinutuzumab unless there’s a relative contraindication to BTK inhibitors, because venetoclax-obinutuzumab is only 1 randomized study supporting its use in this setting. Of all the phase 3 studies, this was the only 1 that showed a big progression-free survival advantage over chemotherapy-immunotherapy. But the overall survival, although it wasn’t statistically different, favored the control chemotherapy-immunotherapy arm. I would use venetoclax-obinutuzumab only if somebody would require warfarin long term. They had a mechanical valve, let’s say, or some reason that they needed to be on warfarin because you can’t really give irreversible BTK inhibitors safe in that setting.

My approach for older or frail patients in this group, whether or not they have deletion 17p, is a second-generation BTK inhibitor, more than likely in the same pattern as in younger patients. If they’re profoundly old, in their 80s, I might do monotherapy. For a younger person possibly adding obinutuzumab just based upon the data from the ELEVATE TN treatment-naïve study. I always have a discussion with patients about which BTK inhibitor we choose. Two studies with second-generation BTK inhibitors show fewer adverse events and at least equivalent results. I tend to use these in those settings unless patients had the need for a proton pump inhibitor, then acalabrutinib can’t be used. I probably would use zanubrutinib or ibrutinib there.

Finally, the group of patients who are IGVH mutated, and who fall in that age group of 65 or 70 or less, still represent the most challenging patient that I’ll have the longest discussion with. That group of patients can potentially be cured with FCR [fludarabine, cyclophosphamide, rituximab]. There are nice data from Michael Keating’s studies with FCR [fludarabine, cyclophosphamide, rituximab] that show event-free survival of about 60% to 70% in that group at 14-plus years. It’s a long discussion with patients because they also have the risk of secondary leukemia and other things. When you have that discussion, most patients who I see still end up going on to a targeted drug, but that IGVH-mutated group under age 70 good has performance status. FCR [fludarabine, cyclophosphamide, rituximab] is an acceptable therapy. Chemotherapy-targeted immunotherapy is also acceptable. The only thing that’s not acceptable in that group that’s IGVH mutated is that bendamustine-rituximab is not equivalent to FCR [fludarabine, cyclophosphamide, rituximab].

Anna Schuh, MD, PhD: In young patients, if we’re going on the available evidence from randomized controlled studies in the frontline setting, we must go with the ECOG study that compared FCR [fludarabine, cyclophosphamide, rituximab] against continuous ibrutinib because that’s the available evidence we have. For that reason, in young patients we would probably prefer to give a BTK inhibitor continuously. The question then is, does the TP53 status make a difference? I don’t think it does. The question is whether 1 would consider fixed-duration therapy in a patient with wild-type TP53, in particular obviously venetoclax-obinutuzumab. There’s no evidence. CLL14 looked only at patients with a CIRS [Cumulative Illness Rating Scale] of over 6, but there’s no reason to believe why a patient with standard-risk CLL who is fit and young shouldn’t benefit from venetoclax-obinutuzumab. In my practice, we’ll discuss ibrutinib in standard-risk patients who are fit and in a fixed-duration venetoclax-obinutuzumab. In patients with TP53 deletions, I’ll also discuss both regimens, but it might be advantageous for them to go on to a continuous regimen because the outcome of patients with TP53 mutations in the fixed-duration regimen isn’t very satisfying. Although the counterargument is that you can re-treat, give them a treatment break, and then you re-treat with the same fixed-duration regimen. In the United Kingdom, that’s not available to us. We have that option once, and we can’t really re-treat. That’s why I advise them to go on continuous therapy.

For patients with comorbidities and frailer patients, the majority of the randomized evidence was generated for the targeted agents, both continuous and fixed duration. What I do now in this setting, when I treat with acalabrutinib as the first-line agent—based on the evidence from ELEVATE TN—is go with the ELEVATE TN study or the CLL14 study for fixed-duration treatment. The same rules apply to TP53. I tell patients go onto continuous treatment with TP53 if you have a TP53 mutation. For standard risk, the fixed-duration regimen is very adequate. It’s clearly something preferred by many patients, to have a break after 12 months from treatment. During the pandemic, we’ve been prescribing acalabrutinib more as a second-generation, well-tolerated BTK inhibitor compared with venetoclax-obinutuzumab because the obinutuzumab is an intravenous agent. It’s using up a lot of chair time. It’s an anti-CD20 antibody, so there’s a lot of anxiety around antibodies in the pandemic. We’ve avoided giving antibodies, and therefore we in the United Kingdom opt more for continuous therapy.

Transcript Edited for Clarity