 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.

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.

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.

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.

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?

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.

 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 

 to be useful and valuable to your treatment of your patients with chronic lymphocytic leukemia. Thank you again.

Videos

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

Optimizing the Treatment of CLL With Novel Therapies

 Let’s turn to CAR [chimeric antigen receptor] T-cell therapy. Nicole, we have CAR T-cell therapy available for other B-cell malignancies. There isn’t anything approved for CLL [chronic lymphocytic leukemia]. Can you summarize where we’re at with that modality and where you think it’s going in the future for CLL.

There were several presentations, of course. CAR T cell has been evolving over the years because it’s approved for…multiple relapsed DLBCL [diffuse large B-cell lymphoma] patients and obviously for acute lymphoblastic leukemia. But in CLL, it hasn’t been approved, and there’s a plethora of agents. Many studies that have shown the clinical efficacy of CAR, but when we weigh some of the toxicity issues, we’re choosing between PI3 kinase inhibitors. Where would this fall for CLL? In which line of therapy will it evolve as well? There were a couple of presentations, with 1 looking at the third-generation CD20 CAR T cells with both 4-1BB and CD28 costimulatory domains, hoping to decrease some of the CRS [cytokine release syndrome] and the neurotoxicity. In patients with lymphoma as well as a cohort of patients with CLL, the responses are quite dramatic. The overall response is somewhere around 80% and CR [complete response] somewhere between 40% and 50%. They reported no neurotoxicity and low CRS rates. As the evolution of CARs trying to minimize toxicity, there’s activity both in the lymphoma subsets and clearly in patients with CLL as well. 

There was another abstract looking at AUTO1, a fast off-rate CD19 CAR in patients with CLL, in terms of reducing the immunotoxicity and improving engraftment of CAR T cells in our CLL population. Similarly, multiple types of patients, including lymphoma and CLL, were treated. There were responses seen, although early numbers were small. Neurotoxicity seems very minimal and the CRS was grade 1, grade 2. There was improvement of some of the toxicity profile of the concern of the CAR T cells, given the cytokine release syndrome, the neurotoxicity issues, and tumor lysis. Certainly, we’re improving the toxicity profile of CAR T. There are responses seen in some of our patients with relapsed CLL.

But where do we fit CAR T? I’d like to throw that out to everybody. Given the types of therapies that we have between the BTK [Bruton tyrosine kinase] inhibitors, venetoclax, the noncovalent BTK inhibitors, we typically will relegate them—right or wrong, because they do have efficacy—to our multiple relapsed younger, fitter, high-risk patient population for CAR T cell as these other therapies evolve and take up this space.

There was also an abstract looking at real-world data and at the incidence of adverse events with CAR T cells and hospitalizations in patients who received CAR T cells within that first year. And 44% were hospitalized because of some adverse event, usually infection or myelosuppression related. It’s something to keep in mind, and we’ll need more. Clearly, we’re up on the adverse-effect profile, but where to fit that in the paradigm of treatment, given all our options, is going to be tricky.

 I agree. For me it depends on the durability of those responses. Do we see a plateau on the progression-free survival curve? I’ve had patients I treated with CAR T who had failed everything, and they’ve gone. I saw a lady last week who went a year ago to CAR T-cell therapy and is MRD [minimal residual disease] negative in remission still. It will find a place. It does depend, in part, on the durability of the remissions and the percentage of patients who have a very durable remission.

Take-home messages from ASH 2021 regarding the role of CAR T-cell therapies in chronic lymphocytic leukemia.

CAR T-Cell Therapies in CLL

Jacqueline Claudia Barrientos, MD, MS, associate professor, Karches Center for Oncology Research, Feinstein Institutes for Medical Research, associate professor, Division of Hematology and Medical Oncology, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, discusses the shift away from chemoimmunotherapy in chronic lymphocytic leukemia (CLL).

Historically, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) was the standard of care treatment for fit patients with CLL who did not have significant comorbidities, says Barrientos. FCR was used in patients with mutated 

 who did not harbor 17p or 11q deletions because they were able to derive long-term responses from the fixed-duration therapy, Barrientos adds. 

However, chemoimmunotherapy was associated with severe infections that required hospitalization, as well as severe myelosuppression, says Barrientos. As such, chemoimmunotherapy was not optimal for many elderly patients with CLL, and the field has shifted to utilize less toxic regimens, concludes Barrientos. 

Jacqueline Claudia Barrientos, MD, MS, discusses the shift away from chemoimmunotherapy in chronic lymphocytic leukemia. 



Dr. Barrientos on the Shift Away From Chemoimmunotherapy in CLL 

Jacqueline C. Barrientos, MD, MS, associate professor, The Feinstein Institute for Medical Research, Northwell Health, discusses remaining challenges in the treatment of patients with chronic lymphocytic leukemia (CLL).

Researchers do not have much data on sequencing strategies. For example, it is still unclear if a patient who has been exposed to venetoclax (Venclexta) can be salvaged with ibrutinib (Imbruvica) or idelalisib (Zydelig). Another challenge is determining optimal combinations, Barrientos says. If a patient is treated with venetoclax plus ibrutinib in the frontline setting, what is best to use in the second-line setting? PI3K-delta inhibition and CAR T-cell therapy, among other strategies, have potential. Recent progress has allowed physicians to shy away from chemotherapy, but it remains unclear what to do when patients become refractory to novel agents, says Barrientos.

Another challenge is the duration of therapy. TKI therapy is continued until a patient develops disease progression or a treatment-limiting toxicity. This is particularly hard for a young, fit patient who may be on therapy indefinitely. Ongoing trials are looking at combination strategies to define time-limited therapy, says Barrientos.

Jacqueline C. Barrientos, MD, associate professor, The Feinstein Institute for Medical Research, Northwell Health, discusses remaining challenges in the treatment of patients with chronic lymphocytic leukemia.

Jacqueline C. Barrientos, MD, MS

Articles

Optimizing the Treatment of CLL With Novel Therapies

CAR T-Cell Therapies in CLL

Dr. Barrientos on the Shift Away From Chemoimmunotherapy in CLL

Dr. Barrientos on Remaining Challenges in CLL