Optimizing the Treatment of CLL With Novel Therapies

Oncologist-hematologists discuss the outlook for treating patients with chronic lymphocytic leukemia with newer novel therapies.


William Wierda, MD, PhD: There are a lot of other things to talk about, but I’d like to thank our panelists for their very informative discussions of the data and insightful thoughts around where we’re at with standard of care and development of new treatments and where the field is going and what they’re interested in in terms of new data being presented. Before we conclude, I’d like to go to each of the panelists, and they can give their final thoughts around where they think the unmet needs are and what they’re excited about in terms of their work in clinical research or laboratory research in CLL [chronic lymphocytic leukemia]. We’re going to start with Jackie.

Jacqueline Barrientos, MD, MS: Our field is moving toward combination treatment strategies to minimize the exposure and the length of duration for our patients on trials on these targeted agents. Achieving undetectable MRD [minimal residual disease] should become, at some point, a goal in a young, fit patient. I’m not sure for older patients. Unmet needs in my head remain those patients with high-risk disease, and how do we treat them to the best of our abilities, and patients who are elderly and with comorbidities that cannot tolerate any of these drugs. We should always try for better, safer drugs. Last but not least, I’m very excited about these noncovalent, bound BTK [Bruton tyrosine kinase] inhibitors in development. I can’t wait for these to be approved for our patients who’ve developed a BTK mutation or a PLC-gamma mutation. As Dr Lamanna was saying, the role of CAR [chimeric antigen receptor] T cells will need to be assessed in the future. It seems to be a very successful story for patients who’ve previously relapsed to everything, but we still have to figure out a way to minimize the toxicity.

William Wierda, MD, PhD: Great, thank you.

Catherine Callaghan Coombs, MD: The 2 things that represent big areas of unmet need are 1) Combinations are going to be important for our patients in the future, but the toughest problems are that our patients have been failed by a BTK inhibitor and venetoclax, usually that they get in sequence as opposed to combination. The outcomes for those patients are poor. But there was a subanalysis that Anthony presented of the pirtobrutinib data that shows that that drug is efficacious. In that setting, it’s a huge problem clinically. If we don’t have a trial for those patients, they do very poorly.

I’m also excited about the noncovalent data. The other thing that we need to continue to work on is an effective therapy for Richter transformation. There wasn’t a ton at this ASH [American Society of Hematology Annual Meeting], but at EHA [European Hematology Association Congress], there was a presentation looking at pirtobrutinib. There was a small trial out of [The University of Texas] MD Anderson [Cancer Center] that Dr Nitin Jain led. Looking at new combinations and ways to treat Richter, because that’s just such a horrible complication for our patients and I’d love to see more progress, it will likely involve combination data of a lot of these agents that we’ve been discussing and/or CAR T.

William Wierda, MD, PhD: Great, thank you. Nicole?

Nicole Lamanna, MD: I agree. We obviously need more work in our Richter population. Combinations are, in terms of time, clearly evolving. More patients will be choosing to do that because they get a break from therapy. Although some older, frailer patients might still benefit from some monotherapy and be fine with that.

For our high-risk disease population, I’m looking forward to seeing how these combinations improve over time in terms of their time to next treatment and how salvageability is their disease if they have high-risk features. I’m looking to see evolving data on our high-risk patient population and some of the continued data on the noncovalent. We didn’t even talk about bispecific monoclonal. There are obviously lots of newer agents that hopefully will come into play and will give our patients ample opportunity to salvage them if they fail BTK noncovalent or venetoclax. I’m looking forward to more data.

Deborah M. Stephens, DO: I agree with everything that has been said. Piggybacking on the idea of Richter, we need to make concerted efforts to make sure our trials can enroll the patients who need it. One of the biggest things that’s often required for is for patients’ creatinine clearance to be over 60 mL/min to enroll in a lot of these trials that patients with Richter or multiple refractory disease need. Age is calculated into creatinine clearance. That excludes a lot of patients in their 80s, which is a lot of patients with CLL. We need to make sure we have studies that address these people.

The other thing that I’m very interested in studying is all these great novel agents with good efficacy—time-limited therapies. With the SWOG group, we’re studying early intervention with venetoclax-obinutuzumab therapy for a limited 1-year course in patients newly diagnosed with CLL who are high risk or 17p or have a CLL–IPI [International Prognostic Index] score of 4 or higher. Because it’s time to ask the question, with all these great drugs, will earlier intervention with a lower amount of cancer cells result in better efficacy and potentially less toxicity because there are fewer tumor cells to break down?

William Wierda, MD, PhD: Great, thank you. Anthony?

Anthony Mato, MD, MSCE: These were perfect summaries. There’s very little for me to add, and probably for you too. The only thing is I want to overemphasize my excitement about bispecifics and then comment about Richter. It’s sad, but none of us knows how to design a trial that would lead to an approval for anything in that space. We need to focus more on trying to understand the regulatory pathway to bring good ideas to patients in clinical practice. That’s the biggest unknown in CLL. I’ll pass it to you.

William Wierda, MD, PhD: I agree. Richter is an unmet need. We’re still seeing it in the setting of or in the era of targeted therapy. It reflects the biology of the disease and the genomic instability in CLL cells. I don’t think it’s going to go away. We need treatments. I’ve been most excited about immune-based therapies; the checkpoint inhibitors, cellular therapy. The longest long-term survivors we have from Richter are those who’ve had allogeneic stem cell transplant or patients who are de novo Richter, previously untreated who’ve had standard chemoimmunotherapy. That’s probably a second disease entity and not related to CLL.

I’m also interested and excited in the bispecifics. That’s an area that I’ll be watching closely. The PROTACs [proteolysis-targeting chimerics], or protein degraders, are a very appealing area that may be an area of development of new agents for CLL, degraders of BTK. A number of other targets would be reasonable targets for degradation—BCL-XL, for example, and others. This is also a topic of great interest. We’ll be continuing our work on MRD and designing trials with MRD as an end point.

A lot of exciting things going on. I’ll make 1 appeal to our colleagues in the viewing audience. We have a lot of clinical trials available. We have a lot of opportunities. There’s a great need to refer patients to us. We’re happy to see patients who are refractory. We have trials also for frontline patients, and it’s a way to access drugs that wouldn’t otherwise be paid for or available if they’re given on clinical trial. Please refer patients. There’s a great need for enrollment on studies.

With that, I would like to thank the panel for their participation and excellent discussion and review of the current data. I’d also like to thank our viewing audience for joining us. We hope you found this OncLive® Peer Exchange to be useful and valuable to your treatment of your patients with chronic lymphocytic leukemia. Thank you again.

Transcript edited for clarity.

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