Recent Advances in the Treatment of Chronic Lymphocytic Leukemia - Episode 9

Chemotherapy-Free Regimens as Frontline Therapy in CLL

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Key takeaways of the CLL13 (GAIA) clinical trial based on highlights presented at ASH 2021.

William Wierda, MD, PhD: Nicole, I’m going to give you the task of introducing and reviewing large randomized trials that the German CLL [Chronic Lymphocytic Leukemia] Study Group has been doing, and the first report was this ASH (American Society of Hematology) meeting on the CLL13 trial that was done by the German CLL Study Group. Can you review that and the highlights of what was found with that study?

Nicole Lamanna, MD: This was a nice study, although I wanted 1 more arm.

William Wierda, MD, PhD: Me too.

Nicole Lamanna, MD: You did too, right? Glad I’m not the only 1.

William Wierda, MD, PhD: That [second arm] is in CLL17. It’s coming.

Nicole Lamanna, MD: Excellent. This is looking at fixed duration with venetoclax-based combinations vs chemoimmunotherapy in previously untreated patients with CLL. The combinations were randomized to 4 different arms, so you had either FCR (fludarabine, cyclophosphamide, rituximab) or BR (bendamustine, rituximab) depending upon your age and comorbidities, vs venetoclax-rituximab as an arm vs venetoclax-obinutuzumab as an arm, and then the fourth arm of venetoclax-ibrutinib and obinutuzumab. A nice randomization. The arm that I’m assuming all of you also wanted was monotherapy with a BTK [Bruton tyrosine kinase] inhibitor, correct?

Catherine Callaghan Coombs, MD: I wouldn’t mind I plus V (ibrutinib- venetoclax).

Nicole Lamanna, MD: Or I plus V.

Catherine Callaghan Coombs, MD: Monotherapy, maybe. I’m greedy, but I would take both.

Nicole Lamanna, MD: But a nice, large, randomized study, of course. One of the things was to look at not just response but levels of undetectable MRD (minimal residual disease) between the arms, as well as adverse effects and toxicities over time. And in terms of the undetectable MRD, looking at both peripheral blood and bone marrow, believe it or not, not surprisingly, the arms that had venetoclax with obinutuzumab or venetoclax with ibrutinib and obinutuzumab had a higher level of undetectable MRD in the peripheral blood compared to traditional chemoimmunotherapy, upwards anywhere from 87% to 92% vs 50% in the chemoimmunotherapy arms.

The venetoclax-rituximab vs chemoimmunotherapy were more similar: in the 50% range for peripheral blood undetectable MRD. In the obinutuzumab arms, we saw a difference between that with the combination of venetoclax vs rituximab and venetoclax. Similarly, the adverse events and toxicities between all the treatment arms were much more similar to neutropenia, thrombocytopenia—all the things we see with chemoimmunotherapy. But obviously, with the combinations with the antibodies and venetoclax, cytopenias were also observed. The toxicities and adverse events were more similar in all the treatment arms. There were slightly higher hematologic malignancies in the chemoimmunotherapy arms but nonhematologic malignancies in the other arms; a little bit of [an outlier] in terms of that.

Obviously exciting data….We’re going to need longer follow-up to see how things settle out between the arms, but certainly there’s no doubt that we saw greater depth of undetectable MRD with the obinutuzumab-venetoclax–treated arms compared to chemoimmunotherapy. And we just need to stay tuned for that.

Anthony Mato, MD, MSCE: May I add 1 comment just in terms of arms? Instead of thinking I wanted 1 more arm, I was thinking I wanted 1 less arm. The chemoimmunotherapy arm was—I don’t know—I would have rather seen either of the arms you guys proposed for a 1000-patient study. One of the clever things about CAPTIVATE, [although] I sometimes criticize GLOW or CAPTIVATE, but the CAPTIVATE fixed-duration arm where they bothered to use the CLL, it was the data from CLL10 for FCR as a historical control; I think it was so clever to spare patients the randomization vs FCR. The primary comparison were CR [complete response] rates of FCR with I plus V. If they did that for CAPTIVATE, it would have been wise to do it again to spare patients chemoimmunotherapy in this setting.

Jacqueline Barrientos, MD, MS: I bet you’re not the only 1. You saw that there were patients that decided to get off the trial once they were randomized to chemotherapy.

Anthony Mato, MD, MSCE: Yes, I’m with them. I probably wouldn’t have been on board for that.

Transcript edited for clarity.