Chronic Lymphocytic Leukemia: Emerging Therapeutic Targets

An in-depth review of novel therapeutic targets making their way into clinical trials for patients with chronic lymphocytic leukemia.


Sonali M. Smith, MD: These agents do stop working. We have to remember CLL [chronic lymphocytic leukemia] remains an incurable disease. That’s a perfect segue to ask Sameer to comment on emerging therapies, such as cellular therapy. Could you comment on CAR [chimeric antigen receptor] T-cell [therapy]?

Sameer A. Parikh, MD: I think we are very fortunate to have all the treatment options we’ve just discussed, but unfortunately, many patients despite all of these treatments will continue to experience disease progression. I think CAR T therapy or cellular therapy remains an option. I’ll just remind everyone that the first published report of CAR T therapy and its efficacy was in CLL, and there were recent reports that those CAR T cells were found in a patient who was in remission 10 years out. I think that speaks to the power of this treatment. Now, unlike other leukemias and lymphomas where this treatment has been approved, unfortunately as yet in larger cohorts of patients, we haven’t seen the same response rate and therefore it’s not yet approved for CLL. But I think in many studies this is being done, where patients who have had progression of disease on ibrutinib or other covalent BTK [Bruton tyrosine kinase] inhibitors and venetoclax, CAR T therapy has been used, in particular, liso-cel [lisocabtagene maraleucel].

In one study, which is a phase 1 study, where about 25 patients with progressive CLL were treated, the complete response rate was about 50%. These were durable. I think one of the challenges with the use of cellular therapy, CAR T therapy, was the observation of cytokine release syndrome [CRS]. I think that has now been successfully treated. There are now newer and second-generation trials with CAR T therapy that have combined CAR T with ibrutinib. These trials are all in progress. Let’s hope that with these newer approaches, cellular therapy and CAR T will be better tolerated, and there will be better outcomes in this group of patients.

Sonali M. Smith, MD: I definitely think there’s a lot of excitement about CAR T, but there are other classes of agents also emerging, and this includes bispecific antibodies, ROR1 [receptor tyrosine kinase-like orphan receptor 1] antibodies, and even a class called BTK degraders. Since you were talking about CAR T, as a next step, out of those 3 classes, is there any one in particular you’re excited about?

Sameer A. Parikh, MD: I think the next class of agents might depend on what a patient has previously received. The BTK degraders are oral pills, and so those are easier for patients to take. Bispecific antibodies of course will have some similar adverse effects like CAR T therapies would, including CRS, etc. I think what may end up happening is patients, if they have progressive disease, may go from one type of treatment approach to another. I think the data are very premature for us to know confidently what should be the right approach or what should be the right sequence. But I’m excited to see that thankfully there are many other treatment options being considered and trials are being run to treat our patients.

Sonali M. Smith, MD: Nicole, what do you think? What are you excited about?

Nicole Lamanna, MD: It’s really nice to have some newer agents to look forward to because as we mentioned during this session, obviously there are patients who are relapsing post-covalent and noncovalent BTK inhibitors, and of course, post-venetoclax as well. We need to have newer therapies for patients to go forward. I think the BTK degraders are going to be exciting to look at. They’re also oral. Certainly, I think that’s a great option, potentially for patients who have wild-type or BTK-resistant mutations. That’s an option. But I’m also excited to see the bispecifics as well. I think that will also be important for T-cell activation. I think there are roles for many of these newer agents in development for our patients who are multiply relapsed and maybe cannot go onto CAR T, for example.

Sonali M. Smith, MD: Susan, speaking of bispecifics, there was a press release on one of them. Do you want to comment on that?

Susan M. O’Brien, MD: I found that very interesting for 2 reasons, No. 1, I knew nothing about the target. It turns out the drug is called LAVA-051, and the target is an antigen called CD1d, which is apparently present on almost all hematologic malignancies. In this first-in-man trial, they’re focusing right now on patients with CLL and myeloma, but also plan to expand to AML [acute myeloid leukemia]. It would be a trial that would have both lymphoid and myeloid malignancies. The other interesting thing about it is that rather than being a pure standard T-cell bispecific, the other target is delta-gamma T cells and NK [natural killer] cells. Speaking of, as Sameer mentioned, some of the cytokine release that we typically see with almost any bispecific, there is a feeling, and I don’t think there are any data yet, that by targeting NK cells or some of these other cells, you can still get very excellent antitumor activity, but you’re less likely to have cytokine release. That might be very promising, although right now I would say that’s somewhat hypothetical and maybe remains to be seen. But it’s an interesting molecule from both perspectives.

Sonali M. Smith, MD: In the last few minutes I’m going to ask Ryan and then John. Maybe Ryan, can you touch a bit on ROR1 antibodies, and then I’ll let John pick whatever you’re most excited about as we go forward,

Ryan W. Jacobs, MD: I think along the lines of BTK degraders as we talked about, we’re always looking for the next target that we can potentially move to because we don’t seem to be curing the disease. And especially for the young patients who are going to need multiple treatments, finding a new target like ROR1 is exciting. Hopefully, that can ultimately unfold into a new easily administered, well-tolerated option for our patients with CLL.

John N. Allan, MD: I think there are a lot of exciting compounds, as we’ve all just spoken about. One of the more exciting things maybe at this year’s ASH [American Society of Hematology annual meeting] that we’re seeing is a new class of drugs, these protein degraders. I think those are really exciting because they’re addressing resistance to covalent-bound inhibitors and basically can knock out B-cell receptor signaling. We’re starting to see the safety and now even efficacy of these agents. There are several of them in development, and I think that’s a burgeoning field of inhibiting downstream pathways of B-cell receptors.

Transcript edited for clarity.

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