Evolving Role of Anti-CD20 Therapy in Chronic Lymphocytic Leukemia

Expert perspectives on the novel use of ant-CD20 therapy as first-line or combination treatment in chronic lymphocytic leukemia.


Sonali M. Smith, MD: [This has been] a great discussion. There are so many data out there. We’ve focused on the BTK [Bruton tyrosine kinase] inhibitors, venetoclax, and some of the combinations. In the beginning, we also talked a little about the anti-CD20 monoclonal antibodies. I’m going to ask Susan to come back to that and review some data on fixed-duration venetoclax-based regimens with anti-CD20. What are the clinical implications in the frontline setting?

Susan M. O’Brien, MD: The 1 that we have approved is venetoclax with obinutuzumab as a 1-year time-limited therapy in the frontline setting. That has produced very high rates of MRD [minimal residual disease] undetectability. Last year at the European Hematology Association [Congress], we got a 5-year update. We’re starting to see a longer-term follow-up. It’s very important to note that there still was no median progression-free survival [PFS] with venetoclax-obinutuzumab. Remember, that’s 4 years off therapy because everybody comes off at 1 year.

What’s interesting is there are differences depending on the subsets. One difference is based on the IGHV mutation status. [Compared with] the BTK inhibitors, IGHV mutation status doesn’t make much difference in terms of outcome. Here, it made a big difference because in the patients who were IGHV unmutated, the median progression-free survival was reached, and it was about 5 years. That’s still pretty darn good, especially if you consider that’s 4 years off treatment. Potentially, you can go back and reuse the treatment because you’re not driving a resistant clone. The point is that that was much shorter than in the mutated population. At 5 years, it’s still over 80%, so that group is doing phenomenally well with only 1 year of therapy.

The other group who don’t fare quite as well are patients with 17p deletion, where median progression-free survival was about 4 years. If 10 years ago we were thinking about a treatment that produced a median PFS of 4 years in a 17p patient, we would’ve been jumping up and down. But that’s significantly shorter than the rest of the patients in that trial. Nevertheless, these are phenomenal data with only 1 year of treatment.

Another trial that we have some data from that was also updated this year is a larger, more complicated trial. It’s the CLL13 trial, also referred to as the GAIA trial. This is a trial of almost 1000 patients with 4 arms. One arm is chemoimmunotherapy, either BR [bendamustine, rituximab] or FCR [fludarabine, cyclophosphamide, rituximab]. That depends on age. The second arm was venetoclax and rituximab, but not like we think about it in MURANO. In other words, in this VR [venetoclax, rituximab] regimen, venetoclax is given for only 1 year with the rituximab up front. It’s analogous to VenG [venetoclax, obinutuzumab], except that the antibody is different. We have VenR [venetoclax, rituximab], and then we have VenG standard 1 year. The only difference between those 2 regimens is the antibody. Then we have the combination regimen, which is ibrutinib, venetoclax, and obinutuzumab. Here, we’re also taking the 2 small molecules but adding an antibody—which we haven’t talked about—to that combination. That was the only 1 that wasn’t necessarily fixed duration because the patients were still MRD detectable. After 12 months, they could continue on ibrutinib.

The findings are quite interesting. The first thing I’ll point out is that VenO [venetoclax, obinutuzumab] and VenR [venetoclax, rituximab] are totally different in outcome, both in MRD undetectability and PFS; it’s much better for VenO [venetoclax, obinutuzumab]. The only difference between those 2 regimens is the antibody. That speaks to what an incredibly potent antibody obinutuzumab is. VenR [venetoclax, rituximab] didn’t produce much better MRD undetectability than chemotherapy. Chemoimmunotherapy produces reasonable rates of MRD undetectability. Either VenG [venetoclax, obinutuzumab] or the triple combo IV [ibrutinib, venetoclax] plus antibody produced much higher rates of MRD undetectability and much better PFS.

What’s interesting is on the follow-up of about 3 years, VenG [venetoclax, obinutuzumab]—where we have only 1 small molecule—and IV-G [ibrutinib, venetoclax, obinutuzumab] look very much the same. It’s interesting to know which of those will win in the end. Of course, that’s a little different from the I [ibrutinib] plus V [venetoclax] combinations because we have an antibody. Maybe we’ll talk a little more about that. It raises an interesting question: if you’re getting such great levels of MRD undetectability with I plus V [venetoclax], is antibody going to add? Do you need the antibody? That’s an open question.

Sonali M. Smith, MD: You alluded to doublets and triplets. The antibody question is fascinating. There was a 4-year follow-up for triplet data with obinutuzumab, ibrutinib, and venetoclax presented at ASCO [American Society of Clinical Oncology Annual Meeting]. Could you comment on that?

Susan M. O’Brien, MD: The issue is that when we talk about these combos—doublets or triplets—we’re up around 70%, 80% MRD undetectability. If we’re going to know whether the antibody adds anything or I [ibrutinib] adds to VenG [venetoclax, obinutuzumab], then you have to have a huge, randomized trial because the bar is so high. One way we might be able to look at that moving forward, to give us a quicker answer, is to look at deeper levels of MRD undetectability: 104is the gold standard, but we can measure deeper levels. We can measure 105 and 106. If you have 2 regimens that both produce 80% MRD undetectability at 104 and then you measure 106, and 1 is 70% and 1 is 20%, I might not have the PFS yet, but I’m going to put my money on the 1 that has 70% on MRD undetectability at the deeper level. We need to start looking in these important clinical trials at deeper levels of MRD undetectability if we’re going to get a hint at whether you need doublets or triplets.

Transcript edited for clarity.

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