Nicole Lamanna, MD: Now for some of the fun stuff—in 2020, frontline therapy of CLL [chronic lymphocytic leukemia]. That’s what we’re going to talk about now. What do you think is standard frontline therapy in your opinion,? And then we’ll get into some of the research, some of the studies that have been done.

Jan Burger, MD, PhD: The field has dramatically shifted obviously in the last 10 years, as we’ve gone from chemoimmunotherapy to novel targeted agents. We first need to say that we are we talking about the United States, because the situation is different compared with most other countries. Here in the United States, the standard treatment is with novel agents and then the ones that are available: the BTK inhibitors, ibrutinib, and the latest addition just a few weeks ago with the approval of acalabrutinib, a second-generation BTK inhibitor. And we also have the possibility of using venetoclax alone or in combination with a CD20 antibody.

All these are for frontline therapy, and that’s gradually but increasingly replacing chemoimmunotherapy, based on a wave of randomized studies, which showed consistently that patients treated with the new agents have better outcome in terms of survival. It’s a positive development for patients.

The question that’s going to keep us busy is, how do we sequence these? How do we pick the best one? In this time and day, ibrutinib has been around the longest and has a very good track record and many patients are doing well on it. But this is something we can improve on. The hope is that maybe newer BTK inhibitors might have differential adverse-effect profiles that may favor them over time.

Venetoclax has this ability to induce somewhat deeper remissions, at least early on in bone marrow, in blood and that might be an advantage. It’s also a limited-duration treatment, but it’s not so widely used for frontline treatment because of concern of tumor lysis, so you need to monitor them closely.

The other problem I see with this agent is that if patients are treated with it and then eventually relapse, we’re not sure which salvage therapy to use.

Nicole Lamanna, MD: Let’s first talk about some of the data that led up to BTKs being the leader or standard of care now in CLL. Let’s first talk about the FCR [fludarabine, cyclophosphamide, rituximab] data versus ibrutinib rituximab data. Farrukh, do you want to talk about that randomized study?

Farrukh Awan, MD: Sure. I think that and also the companion study, the ALLIANCE trial, and the ECOG trials recently reported and updated at ASH [the American Society of Hematology Annual Meeting & Exposition]. Both those studies are seen as the same. I think the ibrutinib combination arms tend to do better compared with chemoimmunotherapy. Toxicity with the FCR [fludarabine, cyclophosphamide, rituximab] was higher as far as hematologic toxicities are concerned, and those are expected results—where there is still some argument or discussion, I should say.

Nicole Lamanna, MD: As a little smile leaks out. He sits next to…

Farrukh Awan, MD: Let me be clear.

Nicole Lamanna, MD: Yeah, fair enough.

Farrukh Awan, MD: The group who still believe in the role of chemoimmunotherapy, there still hasn’t been a clear-cut advantage established by the use of ibrutinib in combination with rituximab, or FCR [fludarabine, cyclophosphamide, rituximab] in patients who are mutated for IGHV. That’s really the only cohort where there’s still any debate in our minds, I would imagine. Because in that cohort, we have demonstrated, and there are multiple data in the past that have shown that that’s a very select group of patients who can experience prolonged remission after only 6 cycles of therapy. I think there is an argument that can still be made. But for a young, fit, and otherwise healthy person, chemoimmunotherapy might still have a limited role.

However, I will argue that those patients tend to do better regardless of what treatment they get. I think that’s 1 argument against using FCR [fludarabine, cyclophosphamide, rituximab]. The other argument against using FCR [fludarabine, cyclophosphamide, rituximab] chemoimmunotherapy is that the second new malignancy risk still needs to be elucidated and kept in mind; you have a long enough survival span in those patients that you have enough time to develop those malignancies. For all other cohorts you still have it very well established that ibrutinib or ibrutinib combinations tend to be better compared with chemoimmunotherapy.

That question has been addressed in my mind. Having said that, committing somebody to lifelong therapy, what will happen with these kinase inhibitors or novel therapies 5 years or 10 years down the road? We have 5-year data. We have 7-year-data. What will happen after 15 years? What kind of delayed adverse events we will see? All these questions have not been answered. There are still some possibilities of how we can limit these therapies. There are a lot of questions that need to be addressed. Can we continue this thing for life? What about compliance issues? What about the cost issues?

Even though, yes, the data [show] that ibrutinib was better and that ibrutinib combinations were better than FCR [fludarabine, cyclophosphamide, rituximab], we still don’t have enough of a follow-up to conclusively say that chemotherapy is absolutely the right choice. There is still a sliver—there’s still a slight opening in the door.

Nicole Lamanna, MD: We’re not going to leave you hanging there. Don’t worry. This is a good discussion, and we’ll get to some of the newer data that are here at ASH this year. But in that context, given the ECOG data and the ALLIANCE data and the frequency of chemoimmunotherapy that we see in the United States, given those data, what do you want to say?

Richard R. Furman, MD: It is important to keep in mind that we can always talk about longer-term follow-up. We do say that now we have the 12.0, 8-year progression-free survival data for FCR [fludarabine, cyclophosphamide, rituximab], and at some point we’ll have the 20-year follow-up data for FCR [fludarabine, cyclophosphamide, rituximab]. Just because we have longer data for a particular agent, it’s important that we not let that keep us from taking advantage of the newer agents. Our current data with ibrutinib at 7 years is certainly sufficient to allow us to make some basic conclusions about its long-term tolerability and safety.

The thing I worry about most when I look at these patients who are young and fit and getting treated with chemoimmunotherapy is that we know that there’s a baseline incidence of MDS [myelodysplastic syndromes] and AML [acute myeloid leukemia] in the population when they turn 80 years old. We’re beginning to learn a lot about clonal hematopoiesis and its ability to indicate future risk for AML and MDS. I worry about the 50-year-old who, because of all the new agents, has the potential to make it to 80. We don’t know what 30 years of fludarabine-based chemotherapy could do to a long-term outcome of that patient.

From my perspective it’s about what toxicities are going to be irrevocable. Certainly if someone’s having malaise or if they’re having joint aches and you were to stop the drug and the joint aches go away, that’s fine. If someone develops something like MDS or AML, that’s something that can’t be remediated by discontinuing the therapy. I really have a greater caution toward avoiding those sorts of toxicities that are really going to be impossible to come back from.

The question about duration of therapy is 1 we’re going to learn lot about in the future. I don’t think right now that any of these agents will need to be lifelong. I think we’ll see, at some point in the future, what would be served for a sufficient duration.

Ultimately the combinations of BCR antagonists and BCL2 inhibitors will be able to get people into very deep remissions very quickly and shorten the need for continuous therapy. That might be ultimately what really is the comparator for a fludarabine, cyclophosphamide, and rituximab induction therapy.

Nicole Lamanna, MD: OK, so we’ll get there.

Transcript Edited for Clarity