Sequencing Algorithms for Umbralisib-Based Therapy in MZL and FL

Anthony Mato, MD, MSCE: The other thing that is important for us to do is talk hypothetically about 6 months into the future. What are our sequencing algorithms for individual drugs? For example, if I see a new patient with follicular lymphoma, I might have an algorithm where I’m going to do chemoimmunotherapy with maintenance as my front line, R-squared [rituximab and lenalidomide] as my second line of therapy, and then a PI3K inhibitor as my third line of choice. Is that similar to what your algorithm would be? How would you incorporate umbralisib or other drugs?

Lori A. Leslie, MD: I don’t think we’ve mentioned the third-line setting yet. We have CAR [chimeric antigen receptor] T-cell therapy available as well for follicular lymphoma, and that’s just this month. That has significantly complicated what to do in the third-line setting for CAR T-cell–eligible patients. PI3K, CAR T-cell therapy, and tazemetostat are options there. With my clinical trial experience with umbralisib, compared to my personal experience with the other PI3Ks so far, I’m eager to use that in clinical practice as standard of care. I’m hopeful that the toxicity management might be a little more streamlined. Maybe that’s because I’ve had a lot of experience with the drug compared to some of the other PI3Ks, which I do once here or once there, but not as high volume.

Anthony Mato, MD, MSCE: What about marginal zone lymphoma? Let’s stick to nodal disease because extranodal is a bit of land mine to try to come up with a sequencing algorithm. If you had to make a generalized case for regimens and lines of therapies in nodal disease, how do you fit in umbralisib?

Lori A. Leslie, MD: Frontline treatment is probably still chemoimmunotherapy for the majority of patients. It’s increasingly complex in the second line. Whether I would pick umbralisib, R-squared [rituximab and lenalidomide], or ibrutinib depends.

Anthony Mato, MD, MSCE: How do you make that choice? I’m curious.

Lori A. Leslie, MD: I haven’t had to do that yet, but a lot of times I’ll look at the patients’ comorbidities. The R-squared [rituximab and lenalidomide] regimen is a year, while both PI3K and ibrutinib would be longer term. That’s at least with the understanding that if a patient has had 2 prior lines, clinical trial options include things like CAR T-cell therapy, but that’s not approved in patients with marginal zone lymphoma. I do molecular testing on patients just because we have access to that and I’m more curious to see if that can help us choose. What are your thoughts on deciding between those 3 targeted options?

Anthony Mato, MD, MSCE: It’s a very tough choice. Knowing the patient, their comorbidities, and their other issues help weigh the decision for me. If I had someone with poorly controlled AF [atrial fibrillation], that helps knock out the BTK inhibitor choice. If I had somebody with liver disease from autoimmune hepatitis or active Crohn disease, I would probably avoid a class that could cause liver disease or colitis. If I had significant CHF [congestive heart failure] or cardiopulmonary disease, I may not be jumping to some of these classes. Knowing patients’ comorbidities matters. Explaining the schedule to patients really matters. Younger patients probably want the fixed-duration approach that you mentioned earlier with the IMiD [immunomodulatory imide drug] vs a long-term commitment for a continuous therapy under a treat-to-progression approach. It’s complicated. What you and I are highlighting without saying it directly is that we don’t have direct comparisons of the most clinically relevant agents to help guide the decision-making. We don’t have trials that look at sequencing questions. That leaves us in no man’s land where we’re weighing individual trials and comparing them with each other. Is that a fair assessment for everyday existence in practice?

Lori A. Leslie, MD: Very well said. I agree completely.

Transcript Edited for Clarity