Novel Therapies for Relapsed/Refractory CLL

Nicole Lamanna, MD: We’re always looking for other therapies in our relapsed CLL [chronic lymphocytic leukemia] patients, and it would be neglectful not to mention CAR [chimeric antigen receptor] T-cell therapy and, of course, allogeneic stem cell transplantation. Of course, allogeneic stem cell transplantation has also decreased in our CLL population remarkably over the years because of the advent of novel agents. Those were typically the patients who had high-risk disease, 17p, TP53, complex karyotypes, and failed chemoimmunotherapy or other therapies, or those who may have transformed. We would be taking those young, fit, high-risk patients to transplantation, but they were still a minority of patients that we were seeing.

We’ve made a lot of strides in CAR T-cell therapy. You see improvements in the response and efficacy but also a decrease in the adverse-effect profile of CAR T-cell therapy. It’s a modality that’s including more clinical trials. It’s obviously approved in our relapsed diffuse large cell patients as well as ALL [acute lymphocytic leukemia], but ongoing clinical trials in CLL look very promising. Of course, whether we use that modality after many subsequent lines of therapy is always an argument. If you save things like transplant and CAR T-cell until the patient is refractory, those are harder patients to salvage with these types of modalities. Clearly, depending how that data go, if the efficacy and the adverse-effect profile continues to improve, clearly there’s a potential that those modalities, or CAR T cells, might move up. It typically tends to be patients who are multiple relapsed, where we’re still using CAR T cell. Again, transplant seems to be further pushed down the line given the plethora of combinations and these novel agents that are approaching. As I said, there are many second-generation and other BTK [Bruton tyrosine kinase] inhibitors that we’re evaluating to salvage our patients; these modalities tend to be pushed off further.

We’re looking at other B-cell receptor pathway agents that are being studied, and there are lots of novel agents in the B-cell receptor pathway that we’re looking at as well. There are a ton of new agents, like CDK9 inhibitors, and there are a ton of new agents that are in phase 1 and phase 2 trials that are constantly being evaluated for CLL and refractory CLL patients.

In terms of groundbreaking transformation of CLL therapies, the BTK inhibitors and venetoclax-based treatments really have changed how we approach our CLL patients. They’ve improved the overall survival and the progression-free survival of our patients. There have been dramatic improvements to the therapy of our patients. These are going to be the mainstays of our treatments. Monotherapy versus combination therapy are still being worked out, but clearly these are drugs that are here to stay.

Hopefully we’ll find newer therapies to salvage even those players who have relapsed after BTKs or after venetoclax-based combinations because we’ll always be looking for newer therapies that are curative. Hopefully 1 of these will be a curative therapy for all. Given that the disease is so complex—and it’s probably not 1 disease; there are multiple subtypes—it may not necessarily be 1 agent by itself. It might be a combination of agents that will achieve such a cure or certainly a long disease-free survival, as did in that subgroup of those 13q-mutated patients. Some of them have gone over 20 years without needing therapy. That would be the best thing that we could do for all our patients with CLL.

Stay tuned. There are lots of clinical trials, lots of exciting things, but we still have a lot to learn from the agents that are even approved. If we can decrease the adverse effects of those agents for our patients so nobody has a problem, that would be best for all.

Transcript Edited for Clarity