Novel Combinations in Development for CLL


Nicole Lamanna, MD: Let’s talk about some of the data that were presented at ASH [the American Society of Hematology 2019 annual meeting] with the combinations in our multiply relapsed patients. The triplets, the acalabrutinib, obinutuzumab, venetoclax or even more, the umbralisib data. In that setting, if they’re not going to go to CAR [chimeric antigen receptor] T-cell therapy or maybe if they’re young and fit to eventually go to an allogeneic transplant, what do you think about that data that we saw at ASH?

Jan Burger, MD, PhD: It’s a bit different patient population though. These combination trials didn’t allow BTK [Bruton tyrosine kinase] inhibitor-resistant patients.

Javier A. Pinilla-Ibarz, MD, PhD: It’s more frontline.

Jan Burger, MD, PhD: If we go into the double or triple combinations, oftentimes what is used is BTK inhibitor [BTKi], venetoclax, CD20 antibody, all the double combinations of ibrutinib or another BTK inhibitor with venetoclax. The goal there is to get patients into deep remissions. Durability of these remissions is unclear at this point. What’s not defined either is what is the best population of patients to go into. I doubt these combinations are going to rescue or salvage patients who have problems with BTK inhibitors and are starting to get resistant. That’s an open-ended question, but I think at the meeting there was a lot of emphasis on these multiple combination trials, a lot of interest in that. In the discussions, what I also heard is are there alternatives to that? Should we also develop alternative strategies to sequence drugs and maybe start with a BTK inhibitor, alternate to a BCL2 [B-cell lymphoma 2 protein] antagonist, and later come back with a kinase inhibitor, which could be PI3 kinase inhibitor or BTK inhibitor? There was also I think a lot of discussion about limited-duration triplet.

Nicole Lamanna, MD: Even though, these are probably rarer patients, but for our patients who have failed BTKi and venetoclax, we should talk a little bit about immune therapy in CAR T-cells. Anyone of you want to take a stab at some of the data that got presented?

Javier A. Pinilla-Ibarz, MD, PhD: I think this is an important study from the point of view that it will address an unmet need in a relatively small population that most of the time tend to be younger, although we know that we can really do CAR T-cell therapy in an older population, and definitely it’s something that is going to be pursued. It’s very interesting that as you may know, in the initial cohort we thought ibrutinib, but the subsequent cohort is the one that they are currently growing is with the addition of ibrutinib that seems to has beneficial effect, based on previous study. The more I discuss with these patients, it continues to be a very small proportion of patients, the ones who are candidates for these cellular therapies. Most of them, the ones who fail BCR [B-cell receptor], or BTK, or BCL2, they may have a very short life with a PI3K.

Definitely in the younger population with high-risk features, the ones who can really benefit, I think the question is are those kind of new therapies or CAR T going to completely wipe out the allogeneic bone marrow transplant? Because we still recognize, the EBMT [European Society for Blood and Marrow Transplantation] recognizes, after 2 failures, those patients are young, they should be considered for an allogeneic BMT [bone marrow transplant].

The question is how many can go there, how many can be in a good remission to go there, that I think is the problem. Maybe we’re going to go back to the story of the ALL [acute lymphocytic leukemia] where we know that very likely CAR T-cell therapies don’t have durability. We don’t know in CLL [chronic lymphocytic leukemia], but maybe it’s another step forward to bring some of these younger population to a stem cell transplant, or see how durable are these responses. But for now it still is, in my opinion, early data and it still needs to mature.

Richard R. Furman, MD: We did hear, at one session today, discussion as to the environmental defects that might actually impair the CAR T-cell function. I think this is a very interesting area, and we’ve known for years that CLL patients can come up with the most interesting infections that are often mediated by T-cell defects. Two questions come to mind. At one point in the future, we may know how we can fix that issue and make the CAR T-cells more efficacious.

The other question is whether there’s a role for CAR T-cells in consolidation. Maybe if we give patients some therapy to debulk them, get the immune system back to health, that then may allow us at that point to use CAR T-cells effectively. When we look at the bispecific antibodies, the CD19, CD3 ones in particular, the dose escalations through the lymphoma cohorts have been much easier than in the CLL cohort. The T-cells, they’re so different in CLL patients that we still have a lot to learn.

Nicole Lamanna, MD: So the role for CAR T-cell currently, besides on clinical trial?

Richard R. Furman, MD: I only reserve it for patients who have really run out of other options.

Farrukh Awan, MD: I think we also have to realize that the CAR T trials that are ongoing right now, they are also for patients who’ve failed both BCL2 and BTK. The vast majority of patients who are enrolled on these trials are patients who have seen chemoimmunotherapy and do really have super aggressive disease. We have all seen those patients who have failed venetoclax as second-line or salvage therapy. And you cannot go on without measurable disease. If you’re in a complete remission [CR], you cannot get a CAR T, so you need to have measurable disease before you can get on to those clinical trials.

You’re selecting out a patient population that is expected to do really poorly, and that’s why I agree completely that maybe we should use it in the consolidation setting in the patient with the true high-risk features and documented progression on a BTK inhibitor before they get into a MRD [minimal residual disease]-negative CR. Maybe we can use venetoclax as salvage. The second issue is that we know that the T-cells are anergic in patients with CLL, so maybe joining or combining the peri-CAR T harvesting, reinfusion with an immune stimulating drug of some sort, possibly a BTK inhibitor, possibly something else.

I think that is probably the strategy that can be employed to augment it. Then with the new products that are coming out, hopefully the cytokine release and the neurotoxicity, all of the adverse effects would be much easier to manage, and possibly do this as an outpatient. I think that’s really the future. I think CAR T-cell therapy is very promising. I still feel we have a long way to go in doing it optimally across all disease indication. I think CLL is still a very unique disease group, but we’re still very excited because we have seen long-term remissions in patients with heavily refractory diseases.

Javier A. Pinilla-Ibarz, MD, PhD: I want to add that there’s a trial coming for CLL CAR T. It’s going to incorporate specific arms where the patients can be treated with ibrutinib, high-risk patients with the goal to produce further response, really addressing the question that maybe we should explore the possibility to produce deeper responses, immunological deeper responses, in a population of patients who in the long run we know that targeted therapies may not be the best way to go.

Transcript Edited for Clarity

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