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Unmet Needs Addressed by BTKis


Brian Koffman, MD, reviews how Bruton tyrosine kinase inhibitors are addressing unmet needs in chronic lymphocytic leukemia, mantle cell lymphoma, and small lymphocytic lymphoma, and what unmet needs remain.

Ryan Haumschild, PharmD, MS, MBA: I want to bring up some of the unmet needs that exist. We talked about this a little bit earlier, but how do you think BTK [Bruton tyrosine kinase] inhibitors are addressing the unmet needs in CLL [chronic lymphocytic leukemia], MCL [mantle cell lymphoma], and SLL [small lymphocytic lymphoma]? What are the unmet needs that remain within these diseases?

Brian Koffman, MD: There were a million breakthroughs with BTK [inhibitors]. I am particularly lucky and got into a phase 1 trial of PCI-32765 [ibrutinib] before it even had a name, it just had a number. And for a patient like me, who had 17p deletion, 11q, complex karyotype, NOTCH1, I could go on and on; I failed the bone marrow transplant, because that’s what you had when you had those kinds of risk factors 15 or 16 years ago. There was nothing there. So for these high-risk patients, with 17p deletion particularly, this was like a beam of light. This was like heaven sent to have an option because there were no options that worked. There was nothing that was shown to prolong life at that time. That was the incredible unmet need for these high-risk patients.

But we still have these other unmet needs, circling back to where we were before, all these therapies were still palliative. And though they’re quite durable, eventually most patients relapse on BTK inhibitors. At some point they do, or they become intolerant. We need to be looking at second-line therapies, and we have pretty good second-line therapies with venetoclax, but we need to be looking at third-line therapies and other available options. Data suggest that double-exposed patients, patients who’ve been through both classes of drugs, again, have overall survival data that are just miserable. It’s measured in months in some studies.

Roy Beveridge, MD: When we looked at data for patients with relapsed CLL, it was a little depressing, because what we found was repeated use of Rituxan [rituximab]. Then when we looked at how people were thinking, if we could interpret what the electronic health record was saying, we found that the world is different than what you had said, when you mentioned that CLL doctors think this way. I will tell you that most patients with CLL, in my experience, are not treated by CLL physicians, they’re treated by general medical oncologists and hematologists. When we look at their interpretation of risks, in terms of the interpretation of the CLL panel, they don’t always get it right. I think one of the things we should mention in terms of what would be great, would be the education of more people who take care of this disease because they’re not as knowledgeable as some of the discussion that has occurred here. Until that occurs, you’re going to have a lot of strange therapies. In the payer world, you can see what everyone’s had for the last 5 or 7 years no matter where they’ve gone. And it’s very disconcerting sometimes, in terms of the choices that were made.

Ryan Haumschild, PharmD, MS, MBA: Hopefully with all this innovation that’s occurring, we’ll start to get more of that standardization of treatment and care. Especially with some of these agents that I think can be taken at home, have a good response rate for a lot of patients, and provide further hope. Before we move on, Dr Koffman, is there anything else you wanted to add?

Brian Koffman, MD: I think one of the critical pieces you just touched on is the testing before treatment. And what we see in study after study, and you talked about real-world data. The real-world data show that it’s not happening before the first treatment, and it’s happening even less after a second treatment. We know that CLL evolves, and it always evolves in a bad direction. Even though a drug might have been a good choice the first time, it may not be a good choice the second time. So we’re vigorous in education, about having the patient get tested before treatment. Then it breaks my heart to see somebody, as you said, somebody gets tested and still gets the wrong therapy. This is a huge issue that we see. People are getting cytotoxic therapies, which is damaging their bone marrow and damaging their immune system.

Roy Beveridge, MD: Like extra doses of fludarabine.

Brian Koffman, MD: Right.

Callie Coombs, MD: I’d love to contribute because I think you brought up so many good points, as did you. First, I would like to say, I think community oncologists have an extraordinarily hard job that I don’t think I would be smart enough to do, to know so many details about every single cancer type. So I do not mean to criticize them. However, when looking at real-world data, we have seen patterns that are not in line with what the CLL community would think is appropriate. I think a focus certainly should be on outreach and making ourselves more accessible, given that these are rare cancers for the community doctor. But again, they’re not doing anything wrong, I think they just have a really tough job, and some patients truly don’t have access to tertiary care centers, particularly rural patients. I know there have been efforts to be able to offer more patients these connections with CLL specialists, and I think that’s so valuable. I believe that’s something the CLL Society has done.

Brian Koffman, MD: We do 2 things. First, we have this wristband, which I don’t know if you can see, but it says, “Test before treat.” And on the flip side, it says, “If you’re TP53, if you’re unmutated IgVH, or if you’re 17p deleted, that equals no chemotherapy.” We give these to patients, and we have a sheet with the studies that we have them hand to their hematologist or oncologist. Because they’re busy, and they don’t see a lot of CLL, and try to help your hematologist or oncologist do that.

The second thing we do at the CLL Society is offer a free consultation with key opinion leaders and top CLL researchers at the major institutes. This is a consultation, it’s telehealth; we were doing this way before telehealth due to COVID-19 and all that. It’s a half an hour consult, where they review the electronic medical records, and then they get a report that they take to their local hematologist. Sometimes that’s to say, “You should do IgVH mutation status before you start this patient on treatment.” And the results we’ve gotten from the community hematologists are, “Thank goodness. I got this doctor from Dana-Farber Cancer Institute, I got this doctor from MD Anderson Cancer Center to look at my patient for free, and you gave me this advice. This is great, and I learned something.” This has been incredible. Because studies have shown that people who get either expert care at a tertiary center or doctors who follow the guidelines, those patients tend to do better than patients with doctors who don’t have those options. I understand, it’s like a sigh of relief, “Oh, it’s a patient with CLL; I can just relax on this one.” I get it. But from the patient’s point of view, we know that it has a negative impact if they’re not getting the appropriate testing, and not following up on that testing properly, and then the appropriate therapies.

Roy Beveridge, MD: Callie, I’m a proud community oncologist. I practiced for 20 years. I’m not bashing community oncology at all. What I’m saying is that CLL is fundamentally a different disease now than it was 10 or 15 years ago. It’s much more complicated.

Callie Coombs, MD: I would love to preface that I wasn’t suggesting you were. I wanted to make it known my statement was not insulting them either because it’s so hard, and I can’t imagine what that would be like. But I think it’s easy to say when you’re laser-focused on CLL. I just wanted to say that as a general statement.

Roy Beveridge, MD: I know. But I think what we’re finding is, with the complexity, what you’re hearing, what I said earlier, is that having some alignment with key opinion leaders in terms of, “This would be first-line therapy, this would be second-line therapy, this would be third-line therapy,” makes it easier not just for the payers, who I want to make life easier for. But also it’s going to help the community oncologists if we can demystify a lot of the choices and the lines of choices that we have at this point.

Transcript edited for clarity.

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