Choosing the Appropriate Treatment Strategy in CLL

Richard R. Furman, MD: Let me ask you a follow-up question. Now that we’ve talked about all these new BTK [Bruton tyrosine kinase] inhibitors, we have the PI3 kinase inhibitors, BCL2 inhibitors, doublets, and also triplets. We have many approaches. What factors might you consider in deciding between a single agent, doublet, or a triplet for your individual patient?

Nitin Jain, MD: In terms of a single agent, we’re talking about a single-agent BTK inhibitor, which means a continuous daily, indefinite therapy for patients. It’s a very effective approach. Patients generally don’t want to do that approach of taking something for the rest of their lives, though some might be OK with that. To me, an ideal scenario would be a time-limited therapy approach, whether it’s a doublet or a triplet, given for a duration of 6 months to 1 year. And then being able to stop therapy, have a treatment-free interval, and potentially reintroduce the same therapy again at the time of relapse.

I don’t know if doublet is going to be better than the triplet. The data at ASH [American Society of Hematology Annual Meeting] with the randomized CLL13 study, which is already public, shows that ven-G [venetoclax, obinutuzumab] had the same MRD [minimal residual disease] rate as venetoclax-ibrutinib plus obinutuzumab. The doublet was equal to the triplet for MRD rates at 1 year. We’ll have to see how the PFS [progression-free survival] pans out at a later stage. With the triplets—the BCL2, BTK plus CD20 antibody—I don’t know whether you need all 3 for the best efficacy or a doublet approach, whether venetoclax-obinutuzumab, venetoclax-ibrutinib, or venetoclax-acalabrutinib would suffice. Because with a doublet, you’re getting 70% to 80% MRD negativity, and it’s difficult to improve upon that, at least when you’re already getting such high MRD negativity with doublets to move to the triplet approach. I don’t know. The data with triplet is interesting and intriguing. We have to see that manifest in a longer PFS compared with a doublet approach.

Richard R. Furman, MD: Are there patients in whom you don’t want to use fixed-duration therapy?

Nitin Jain, MD: Right now, with the venetoclax-obinutuzumab approach in patients with deletion 17p or TP53, based on what we know from the CLL14 study, if you stop the therapy in those patients at 1 year, their disease tends to come back sooner. So venetoclax-obinutuzumab for 1 year might not be the best option. Can you use venetoclax-ibrutinib for that patient population? That’s an intriguing question. There are only limited data with that regard. We’ll present some data at that ASH meeting, but that needs to be studied further, whether you can use this doublet approach of a BTK plus venetoclax or a time-limited approach for this patient population. Until we have those data, to me a continuous daily BTK inhibitor is probably the best approach for patients with deletion 17p or TP53.

Richard R. Furman, MD: Do you see any populations that might benefit from a 24- vs a 12-month treatment course of venetoclax?

Nitin Jain, MD: In the frontline setting?

Richard R. Furman, MD: Yes.

Nitin Jain, MD: At least in the venetoclax-ibrutinib data—not the venetoclax-obinutuzumab data—what we’ve seen in the study we did is that with patients who were MRD-positive at the 1-year mark with venetoclax-ibrutinib, when we continued the therapy for the second year, half the patients were able to become MRD-negative. There were some incremental improvement in MRD during the second year of therapy. Whether that will eventually lead to improved PFS, I don’t know. If you’re MRD-negative at 1 year, it’s probably safe to stop. If you’re MRD-positive and you have deletion 17p or TP53, that group of patients may benefit from a second year. But that’s something we truly don’t have the data for.

Richard R. Furman, MD: Just to clarify, your patients who continued on were on ibrutinib-venetoclax, not just venetoclax alone, correct?

Nitin Jain, MD: Correct. Both were continued.

Transcript Edited for Clarity