Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center; John Byrd, MD, Ohio State University; Michael Keating, MB, BS, University of Texas MD Anderson Cancer Center; John Leonard, MD, New York-Presbyterian Hospital
Krishna V. Komanduri, MD: I want to briefly ask you, are there other promising emerging therapies that we should touch on before moving on?
Leo I. Gordon, MD: Well, I think there are a number of them—ibrutinib, as John mentioned, venetoclax, and the BCL-2 inhibitor, ABT-199. Some of the early data with that are perhaps a little disappointing because, thinking of the mechanism of that, this is the disease that it should have been the most active in, actually, but I think we’re not seeing it nearly as active as we do in CLL. And then, Dr. Neelapu at MD Anderson published a study with the drug, pidilizumab, which was probably the first at the time. We thought it was a PD-1 inhibitor. We did a study in large cell lymphoma, and he did a study in follicular lymphoma with some interesting responses, although we combined it with Rituxan. It turns out that that drug probably doesn’t work. Although we don’t know how it works, it probably doesn’t work as a classical PD-1 inhibitor. And I think it’s been a little disappointing to see some of the others in follicular lymphoma. We want to think that they’re going to be effective, but I’m not sure that we’re seeing some responses, say, that we’re seeing in classical Hodgkin’s lymphoma, for example, or in primary mediastinal B-cell lymphoma. I think those are drugs that I think we are going to be looking at.
We have a presentation and a poster at this meeting with the SYK inhibitor, TAK-659, that’s very interesting in both diffuse large B-cell lymphoma and in follicular lymphoma. We’re seeing very impressive responses with a fairly well-tolerated oral drug. And so, these are things that I think we need to be looking at. We need to be investigating different parts of the B-cell receptor pathway in follicular lymphoma, and I think those are going to make, I’m hoping, inroads in treatment.
John Byrd, MD: It’s enigmatic to me why idelalisib works so well in follicular lymphoma, and it’s clearly a proximal B-cell receptor in the SYK inhibitor. But, yet with ibrutinib, the responses are very different in CLL. It appears to take longer and from some of the early data, it’s much less, and I wonder, does anybody have thoughts of why that is?
John P. Leonard, MD: I don’t have a good answer. It is interesting and I think it’s important for the audience—the subtype specificity. Clearly, we’ve known CLL is different than Mantle cell and follicular, but it’s even getting more nuanced from the standpoint of the other indolent lymphomas. We have data presented at ASH 2016 with ibrutinib in marginal cell lymphoma where roughly half the patients responded, which I think are important data. But, they’re different than the follicular lymphoma data—again different patients, etc.—where the response rates weren’t quite so high. I think it’s important to not really lump all these diseases together, and try to parse out which is really which.
John Byrd, MD: For somebody that’s practicing though, so you go down the pike—because I treat mostly CLL—for Leo and John, where do you cut the line? Because, clearly, some of the patients with ibrutinib have a durable response. The response was, I think, 21%. What’s going to be presented is 21%. So, where do you say it’s not worth doing this versus it’s worth doing it?
John P. Leonard, MD: I think it depends on what your other options are. And I think if a patient hadn’t had idelalisib first and was a candidate, I’d probably try that first. That’s not curing everyone, but there are people doing well clearly. I think it’s certainly something I would pull out in some patients to use just like other settings.
Leo I. Gordon, MD: In terms of mechanism, you think about long responses. Maybe John or Krishna can answer this. The effect of ibrutinib in T cell function, are we maybe seeing some inhibition of Tregs (regulatory T cells)? Is that why we’re seeing responses or is it a direct effect?
Krishna V. Komanduri, MD: That’s a great question. Actually, I think that we don’t have as much data as we need. We’re starting to look at that now. We utilized these drugs like drugs that you wouldn’t expect to work in the context of graft-versus-host disease. We have new data that suggests that MEK inhibitors, for example, can inhibit T cell responses. Nobody would have guessed, and there are now trials of both JAK inhibitors and SYK inhibitors. And, of course, ibrutinib has been tested in the graft-versus-host disease setting with effects in chronic graft-versus-host disease, where B cells play a role. But, that is something, I think, just like as you noted with idelalisib, we have to keep an eye out for. We think of them as off-target effects, but they’re really on-target effects where they’re affecting things like ITK (interleukin-2-inducible T cell kinase) or BTK (Bruton's tyrosine kinase) that also have a role in T cells.