Frontline Treatment Options in CLL

Nicole Lamanna, MD: A question that comes up all the time is a BTK [Bruton tyrosine kinase] inhibitor plus or minus a monoclonal antibody. We’ve seen mixed data that in some of the studies, adding rituximab to ibrutinib didn’t really look like it enhanced anything to ibrutinib monotherapy. We’ve had data looking at acalabrutinib and obinutuzumab, and that looked as though there may be more enhancement in that. Of course, there are no head-to-head data. but certainly I think 1 option is that many of us will use BTK monotherapy; however, I do think there might be some subtle times where using a CD20 monoclonal antibody could have advantages: If somebody has autoimmune cytopenias that are really prevalent initially upon starting therapy, and you want to calm that process down and add in the BTK. There are different ways where monoclonal antibodies are still very useful on our patients, but we don’t have conclusive data that adding a CD20 monoclonal antibody necessarily to a BTK inhibitor has improved survival or progression-free survival greater than just a BTK inhibitor alone. That’s something to consider.

When talking about comorbidities of our patients, like cardiac issues with our BTK inhibitors, obviously the second-generation BTK inhibitors such as acalabrutinib and zanubrutinib are being studied, and there are more when you’re thinking about anticoagulation and antiplatelet agents. Obviously, head-to-head data are still pending, meaning these studies are enrolled. One is closed to accrual, and that’s the ibrutinib versus acalabrutinib in high-risk, relapsed patients with CLL [chronic lymphocytic leukemia]. Data are still pending about second-generation BTK inhibitors decreasing frequency of adverse events, such as the cardiac issues, bleeding issues, and hypertension. We have lots of data on acalabrutinib, not head-to-head but suggesting that the adverse events may be less than ibrutinib. The head-to-head data are really what we’re all looking for, to really see if there’s decreased frequency.

If you’re considering a BTK inhibitor with your patient and you’re worried about some of these issues, many folks are prescribing the second-generation BTK inhibitors over ibrutinib. Again, I’m waiting for the head-to-head data to see because now you have more than 1 BTK inhibitor that you can choose for your patients.

When we’re talking about the venetoclax-obinutuzumab combination, it’s risk stratifying your patients to see if they have low, moderate, or high risk for tumor lysis and taking strategic measures to mitigate for tumor lysis syndrome. Certainly, if you have an older patient, maybe some borderline renal insufficiency and maybe moderate or high risk, hospitalization is something to consider because you really want to monitor for tumor lysis and protect those individuals because it’s very treatable.

Those individuals are going to require treatments to monitor for uric acid and electrolyte abnormalities more frequently than patients who are not getting a venetoclax-based combination. You’ve got to take that into consideration. The advantage of that is that there’s a time-limited duration of therapy for using venetoclax-obinutuzumab. Those discussions need to be held with your patients, and the comorbidities need to be taken into consideration.

In terms of chemoimmunotherapy in the frontline setting for patients, we still discuss the data that have come out from The University of Texas MD Anderson Cancer Center and others looking at that long-term tale of patients with the 13q deletion, who are mutated, with favorable disease characteristics, who may be in remission long term after chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. That’s still a discussion in that patient population. Many patients have clearly moved away from outright chemoimmunotherapy given the adverse-effect profile that we’ve seen with chemoimmunotherapy, but it’s still a discussion in that unique subgroup of patients who have favorable disease. I don’t necessarily throw that entirely out of the water, but most of my patients don’t choose to receive chemoimmunotherapy very frequently anymore given all these new agents that we have. We see less use of chemoimmunotherapy in our CLL patient population.

With regard to our high-risk patients as discussed previously, like the 17p, TP53, complex karyotype, although unmutated—they’re higher risk than the mutated, but your choices are a little broader. When we talk about the 17p or TP53 patients, the longest data we have are with BTK inhibitors. For up-front, untreated patients, I still favor a BTK, but there are very good data for venetoclax. The question many of us are still grappling with is because the venetoclax-based combinations are time-limited duration, in those high-risk patients such as the 17p or TP53, such as venetoclax-obinutuzumab, the duration of therapy is 12 months, are we comfortable stopping at 12 months for those patients? That’s where we’re still looking for longer follow-up and longer data. I still preferentially will put my 17p/TP53 patients on a BTK inhibitor up front and continue for monotherapy. But it doesn’t mean that the venetoclax-obinutuzumab combination wouldn’t be adequate, because we obviously have very good data that that drug works very well in these high-risk patients. The stopping versus continuation of venetoclax, for example, is something that we don’t have enough follow-up on those high-risk individuals. Are you comfortable taking those patients off after the end of their time-limited duration, whether that’s in front line or if you’re doing this with venetoclax–rituximab in relapse à la the MURANO study? Are you stopping at 2 years of therapy? I tend to keep my patient on chronic therapy if they’re high risk in that sense, but the data are still pending.

Transcript Edited for Clarity