Now, I would like to introduce your meeting host, Haliah Baker.

S1: Welcome. My name is Haliah Baker with Aptitude Health, and I'm happy to welcome you to tonight's
core chronic lymphocytic leukemia program with Dr. Ian Flynn.

The first part of the meeting will include a presentation on CLL, led by Dr. Ian Flynn, followed by a
discussion where we want to encourage everyone attending to openly engage in conversation and
discuss your treatment approaches and experiences in your practice.

With that, I'd like to introduce our speaker tonight, Dr. Ian Flynn. Dr. Flynn is director of lymphoma
research at the Sarah Cannon Research Institute. In this role, he oversees lymphoma research
throughout Sarah Cannon and its affiliates. Dr. Flynn also serves as the director for the Sarah Cannon
Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center.

Dr. Flynn's research focuses on the development of new therapies for patients with lymphoma and
chronic lymphocytic leukemia. This research includes first-in-human to phase three trials with novel
approaches, such as immune-effective cell therapies, inhibitors of the B-cell receptor pathway, and BCL2
inhibitors, amongst others. His research has been widely published in journals such as The New England
Journal of Medicine, The Lancet, and the Journal of Clinical Oncology and Blood.

With that, Dr. Flynn, the floor is all yours to present the core program.

S2:
Great, thanks. How are you? So nice to be with you this evening. It sounds like we've got a good group.

It's gonna start off with just a brief—here's, uh, the agenda for this evening. So, I think we've just gone
through most of the introductions. We’ll go through just the management options in CLL, with really a
focus on BTK inhibitors this evening, and then about a half an hour of discussion. I really hope that it's an
interactive session and that, you know, just please interrupt me as we go along if you have any
questions. But there’ll be plenty of time at the end for discussion as well.

So again, this is going to really be a focus predominantly on BTK inhibitors in CLL. And so, I think, you
know, probably everyone here this evening realizes there are now three FDA-approved covalent
tyrosine kinase inhibitors for a variety of lymphomas, including mantle cell lymphoma.

There are two that are approved for chronic lymphocytic leukemia, and then finally, Zanubrutinib will
get FDA approval in the not-too-distant future for CLL as well.

You know, when Ibrutinib was first developed, first approved, I mean, this seemed like a groundbreaking
drug. It changed the natural history of CLL, and I remember at the time thinking, Wow, who would want
to compete with this drug?

It really has very little in the way of side effects—certainly fewer side effects compared to the key
immunotherapy we were using at the time. But as we've come to know, and as this drug has moved
further and further towards the frontline and natural history of this disease, there are some adverse
events. And it's probably not due to its inhibition of BTK itself—it's probably its inhibition of some of the
off-target kinases.
And so, here on this slide, you can see the kinome, right? And so, there's a graphical and then numerical
display—the kinome—and then the big, round dots represent the intensity and off-target inhibition of
some of these kinases.

On the left, you can see, you know, what this represents. Of course, there's BTK, TEC, ITK, and so forth.
And again, it's probably inhibition of these off-target kinases that is causing some of the adverse events.

So, there are now a couple of so-called second-generation BTK inhibitors. The first was Acalabrutinib.
We can see from its kinome, it’s clearly cleaner compared to Ibrutinib. And then Zanubrutinib as well,
which is the most recent BTK inhibitor to be approved, and it also is a much cleaner—

So that's my quick overview of BTK inhibitors. I think we have—Now, we’d really like to open this up for
discussion, and we're really hoping we'll get great participation here. I have a few questions just to lead
off, and I think Dr. Chang is going to help us guide the discussion here as well.

But I'd really like to know: what is your general approach to treating CLL in the first line, and what
factors influence your choice? Comorbidities, disease factors, cytogenetics—are there financial barriers?
I mean, maybe you could just walk us through, and I'd like to hear from several people about what that
looks like and how you approach this.

S3:
Yeah, good point. And I think that's a very good first question.

Sidney or Dr. Stoll, do you want to comment on what kind of influences you when you have a CLL patient
in the first line? What makes you choose one BTK or another treatment over the other? And do these
factors affect your thinking on that?

S4: Yeah, I mean, I do look at performance status when, you know, in general, thinking about what to
choose. A few years ago, we—I—used to go with chemotherapy options, like chemoimmunotherapy
options, such as Arbenda. However, I've sort of gone away from that recently, so I'm pretty much using a
BTK in the first line for everybody at this point.

I have probably the most experience with Ibrutinib, so I've been using that, but the data with the new
ones are quite intriguing—especially with fewer side effects, less bleeding, and less atrial fibrillation. So,
I might be inclined to actually try either Acalabrutinib or Zanubrutinib in the first-line setting.

S3: And have you had any issues in terms of financial reimbursement? I mean, we're all part of kind of
the same geographical region, with Southern California insurance, HMO-type systems. Have you seen
any issues getting approval for BTK inhibitors, or have the insurance companies pushed back on giving
you an alternative or anything like that?

S4: So far, I haven't had any major issues. Once I recommend it, usually, we get the drug fairly quickly—
within about a week or two. So, thank goodness, I haven't had any major problems getting the BTKs.

S3: Excellent. Dr. Kim, Rachel, have you had the same experience as Sidney? You know, from your
approach to treating CLL in the first line?
S5: Yeah. I would also agree that my experience with Ibrutinib is probably kind of more robust than with
the newer agents. And I still, for certain patients who are younger and don't want to be on indefinite
BTK therapy, will give them and discuss the option of chemoimmunotherapy.

But for the most part, I think I have been using more of the BTK inhibitors frontline—obviously
considering comorbidities, cardiac risk factors, and then, in particular, patients who are on, you know,
other anticoagulants. That's also an increased bleeding risk. I think those are things that I consider, and
so the newer agents with less bleeding risk are definitely a big consideration.

S2: And just to follow up on that—so, if you had someone who wanted, you know, a fixed-duration
therapy, do you use Venetoclax-based therapy, or are you still using immunotherapy, or is that—

S5: Yeah, I think I mostly discuss their options, and I've done both, depending on what their preferences
are and what their comorbidities-