CAR-T Cell Therapies in CLL

Transcript:John Byrd, MD: There are data at this ASH 2016 meeting about the CAR-T cells. There are several nice laboratory papers from the group at the University of Pennsylvania. The results of that look promising, particularly for the patients who have progressed through ibrutinib, where you’re saying, “Well, do I send this 70-year-old to transplant or do I send this patient to CAR-T cells?” Unfortunately, because of all the excitement with these drugs in ALL and lymphoma, the CLL doctors that have these patients are feeling like there’s less access to these trials. Hopefully, the studies are going to open and we’ll be able to move forward with testing these to see if they have the same results.

Krishna V. Komanduri, MD: Also, I think one area where we saw initial remarkable success was actually in the context of low-grade lymphoma in CLL. Cameron Turtle is presenting an abstract at this ASH 2016 meeting that looked at 18 patients with CLL. In fact, 13 of those patients were either intolerant or had failed ibrutinib, and there was about a 77% overall response rate in the overall group. And responses in patients who were on ibrutinib and were either intolerant or failures, it was really about the same.

There are real toxicities with these therapies, and the composition of the cells and the approaches may matter. In that abstract, there were balance C4 and CD8 infusions, and how the cells were expanded, how they’re enriched, this may matter. We also think that there are probably disease-oriented risk factors. We seem to see higher rates of neurotoxicity in the context of ALL than we do in the setting of B-cell lymphoma. So, I actually think that we’re more likely to see, as we’ll talk about later, approval of B-cell lymphomas first. But I agree with you. I’d like to see more research in CLL patients with CAR T-cell therapies.

Michael J. Keating, MB, BS: Perhaps we ought to think seriously about the fact that the other curative therapy is allogeneic stem cell transplant, and that with the mini transplants, you can do it in patients up to [the] mid-70s now. They end up with some chronic GVH (graft-versus-host), but if we used the CAR-T cells, that means all the B cells are gone and they go to have monthly infusions of gamma globulin for the rest of life, etc.

Krishna V. Komanduri, MD: Well, I appreciate you mentioning that, Michael. As an allogeneic transplanter, I rarely now see any patients who actually even referred for CLL, even when they’re young patients who’ve failed multiple lines of therapy. The same is actually true for follicular lymphoma as well, so I think that that is the therapy that I would like people to actually realize—especially when they have younger patients who failed multiple lines of therapy—that that early treatment-related morbidity-mortality is quite low and we clearly can cure patients.

John Byrd, MD: I think one of the nice things of the targeted therapies that we have, like ibrutinib, 85% of them will have a mutation similar to the T315I in CML. We know these therapies are going to fail and you can identify that 9 to 12 months before, so you have the status of MRD (minimal residual disease). They have a small amount of disease, but they’re not in forward relapse, where transplant doesn’t work. And now with the ability to do haploidentical transplants, I’ve been very impressed over the past 1 to 2 years that it’s really not an issue of finding a donor. If somebody has a child and you talk about the generous donor, a child wanting to being able to give back to their parent or something like that, it’s a special thing whether the therapy works or not.

Krishna V. Komanduri, MD: In allogeneic transplantations, we’ve seen convergence of results, really, almost to the point where matched unrelated donor transplants have similar transplant outcomes to sibling transplants, and now we’re seeing this convergence between even cord blood transplants and haploidentical transplants. So, I think it is a great time. And I do think that it’s important, as we think about these novel therapies, that, again, the approach is like how allogeneic transplant still remains for us.

Leo I. Gordon, MD: And I think the idea of whether the CAR-T, for example, is a bridge to transplant or a replacement for transplant, or is transplant a bridge to CAR-T or replacement for CAR-T, is one of the major issues on this.

Krishna V. Komanduri, MD: I agree. Well, this is a really wonderful discussion about CLL.

Transcript Edited for Clarity