Recent Advances in the Treatment of Chronic Lymphocytic Leukemia - Episode 7

Fixed-Duration Therapy in Frontline CLL: Venetoclax Plus Obinutuzumab

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The rationale for investigating the fixed-duration, all-oral combination regimen of venetoclax with obinutuzumab as treatment for chronic lymphocytic leukemia.

William Wierda, MD, PhD: If we’re talking about fixed-duration therapy, the other alternative standard of care would be venetoclax plus obinutuzumab. I wonder if anybody is willing to comment on their choice between these 2 and what might drive how to choose between these 2 regimens, assuming that they’ll both be available as standard treatment for first line. Anybody willing to share?

Anthony Mato, MD, MSCE: I’m happy to stake an opinion to start the debate. If both are approved, I’ll still lean toward using venetoclax-obinutuzumab. The rationale is that the safety profile is better in a similar patient population between GLOW and CLL14. That would be 1. The second is that MRD [minimal residual disease] rates are comparable or more favorable for the venetoclax-obinutuzumab combination. Third, we have so much data for use of a BTK [Bruton tyrosine kinase] inhibitor following venetoclax that show that not only is venetoclax-obinutuzumab quite effective, but the median isn’t reached. Also, venetoclax re-treatment is a viable strategy. On top of that, BTK inhibitors like acalabrutinib would be a great choice based on the data we’ve seen updated in the relapsed/refractory setting. From a sequencing perspective in a noncurative strategy, where palliation obviously is the approach, you can get a lot more miles out of venetoclax-obinutuzumab and probably a safer regimen. I’m not convinced that I+V [ibrutinib, venetoclax] is safe in an older-patient population. That’s 1 side of the coin. Maybe someone else feels different.

Catherine Callaghan Coombs, MD: I’ll throw in my 2 cents. I agree with what Anthony said. I may have some temptation to use I+V [ibrutinib, venetoclax] if it is approved in some scenarios, specifically a younger, fitter patient who’s desiring an all-oral regimen. That would be 1 advantage. During the COVID-19 pandemic, all these agents affect immunity, but the CD20s are the hardest on impairing vaccine response and annihilating one’s ability to make meaningful antibodies. That’s 1 attractive view, but I use a lot of venetoclax-obinutuzumab. It is safe and has a lot of experience with older patients. I do have concerns with BTK inhibition in cardiac toxicity. But for patients who are young and fit, the cardiac toxicities are much lower in younger-patient populations. To me ,that wouldn’t be as much of a concern, and it has the advantage of being an all-oral regimen.

Deborah M. Stephens, DO: The only thing that would sway me fully to use it in a combination up front is if we see that certain patients are cured or at least functionally cured. I haven’t seen data to support that this combination is curing people. Of course, if you could give something up front and cure the patient, and they don’t have to worry about CLL [chronic lymphocytic leukemia] ever again, then that’s 1 thing. But it seems like the sequential, powerhouse drugs in this space are the BCL2 inhibitors like venetoclax and the BTK inhibitors. In a setting of not being able to cure the patient, we want to give them the longest time possible, and using them sequentially makes a lot of sense in this population.

William Wierda, MD, PhD: When the word cure comes up, I reflect on the FCR [fludarabine, cyclophosphamide, rituximab] data and how long it was before we were able to appreciate a plateau on the PFS [progression-free survival] curve. That was more than 10 years. We started the FCR [fludarabine, cyclophosphamide, rituximab] trials in 1998, 1999, and it wasn’t until nearly 2010 that we and also the German CLL study group realized that there was plateau. It may be awhile before we get the data that show a cure fraction. I’m optimistic that there probably is 1. I’ll be looking closely at the time to MRD relapse as an early indicator because we do tend to see an association of features correlating across the time to event. If we’re talking about time to MRD relapse, time to progression, time to next treatment, etc., they all correlate. Time to MRD relapse is meaningful.

Transcript edited for clarity.