JG: Hello, I’m John Gribben from the Bart’s Cancer Institute in London. Welcome to the twelfth International Workshop in Non-Hodgkin’s Lymphoma here in Scottsdale, Arizona. The temperature today was cooler, I think it only reached 100o today, so much cooler than our previous days. We’re here with some experts and some committee members from the workshop to be discussing the highlights from day 2. I think we’ll all agree that it was a very successful workshop over the last few days. So, Wyndham, what do you take as the highlights from what you heard about today?

WW: One of the things that we did differently this time was we had some non-lymphoma specialists come in. Specifically we had three international experts in multiple myeloma and they spoke about multiple myeloma within the context of how it might apply to lymphoid tumours. I found it to be a very fascinating discussion because we talked about how does resistance to drugs emerge. There has been this idea that somehow cells develop a resistant phenotype and what they showed, and what I think many of us have thought for many years, is that there are, in fact, many, many different sub-clones by the time cancers reach a large enough state that they actually cause problems. What they found was that as they treated the patients with different types of drugs they found that there was emergence of very small clones from the very start that really became the dominant clone that in fact had a pre-existent resistance phenotype. And when the patient eventually died that was the dominant clone. They also found that as part of this a number of things occur. They talked about how MEK activation was perhaps an event that occurs that allows the cell to become more aggressive, to become more independent. I think all of this has great impact and significance for lymphoid tumours as well, probably more likely low grade tumours but, nonetheless, I found that entire paradigm to be very interesting and it really points out how useful it is to bring different disciplines into a workshop such as this.

JG: Yes, I agree with you. You’re right, they didn’t really say anything so different but somehow a fresh approach to how they’ve looked at a similar problem just made us think a little bit differently about our own disease.

WW: Absolutely.

JG: So, Anton, what was the highlight for you today?

AH: Well, the new smart molecules are close to my heart and I would like to refer to the studies, the PI3 kinase inhibitor - you presented that. It struck me there are quite a number of patients, more than 100 patients, the Australian study, that’s a significant response rate although it appears to be mainly partial remissions, that’s one of the issues that is at stake with only, I think, 5% CRs. So what you reach at the end with this single oral drug is patients in PR, they stay in PR for some time, but we are not going to win the war with a single drug like this, of course. That’s one thing, so we need to look, and that’s the next step, maybe for the next workshop, to come up with intelligent combinations to really get rid of the tumour load and get it to minimal residual disease and even better. Another thing is that these drugs are not without toxicity; that’s a different sort of spectrum of toxicities, different from the conventional chemotherapy induced toxicity like alopecia and nausea and vomiting and those sorts of things, but in particular diarrhoea which is maybe a problem to several patients with an unknown etiology so far and in most of the cases manageable. Also granulocytopenia, there is something happening in the bone marrow, so this is not without side effects. But the good thing is that this is, well, we call it all targeted therapy and now that we know more about the biology of the lymphoma cells in this case we can more specifically hit, let’s say, the proliferation pathway and block that and get to these results.

JG: Hopefully we can learn a lot from what’s already come from the clinical trials; we can find who are the patients who are going to respond best to it and, just as importantly, who are the patients who may not be good candidates for these types of approaches so that we can not just use a tailored therapy but tailor that therapy for the individual patients that need the treatment.

AH: Yes.

JG: So, Michael, what did you take as the highlight from today?

MP: For me the highlight today was David Maloney’s report on their study with CARS, that means chimeric antigen-receptor T-cells. I was always very sceptical about the issues of CARS but he brought it onto a more scientific ground. First of all I was surprised that it takes one week or two weeks until you have the patient’s own T-cells prepared in such a way that they attack the tumour. What’s fascinating is that a small number of T-cells can really kill billions and trillions of tumour cells once they have the right antibody, let’s say, transplanted onto the T-cells. Moreover, David Maloney showed that in contrast to the other approaches which used peripheral mononuclear cells, they could show that by really defining the T-cell, or the CD8 cell, in a specific type of differentiation the central memory cells were the T-cells which were the most effective. He also showed that if you combine, then, the transduced central memory CD8 cells together with a limited number of CD4 cells then the effect is even stronger. Of course, this new approach is not without side effects and I think the most scaring, or frightening, side effects, both for the patient and for the doctors, are the CNS side effects which reminded me very much of the side effects that we have observed with the bi-specific, so-called, T-engaging antibodies, also CD19 and CD3 where, at least in the lymphoma patients that I have been treating, was really a frightening experience. The patient had problems to speak; the patient couldn’t write anymore and in some patients the side effects were so severe that the differential diagnosis was apoplexy. I think we still have to learn how to cope with these side effects but, for me, the CARS, that’s the most potent immunotherapy I’ve ever experienced.

JG: I think there are several surprises to me. I think you’re right, what’s very clear is that programme is making huge advances by the amount of pre-clinical work that went in to defining how they want us to do these cells, what was the spacer, what was the co-symmetry molecule, what T-cells they went into. But for me also the surprising feature has been the spectrum of diseases that respond well. I did not expect when these T-cells were in their infancy that it would be very aggressive acute lymphoblastic leukaemia and refractory diffuse large B-cell lymphomas that would see responses.

MP: Down to CLL.

JG: I expected it to be in the more slow-growing, more indolent lymphomas that we would see the best response. That’s not to say that we’re not seeing good responses in those other histologies but we’re seeing it right across the spectrum and I think that’s really exciting.

MP: Yes, that they can control the fast-growing tumours like ALL, it’s really surprising.

JG: Particularly when we think that ALL has been not the disease in which we’ve really thought there’s a strong graft versus leukaemia effect with allogeneic stem cell transplants. To find that there’s such exquisite targets of autologous cells just goes to show how strong a patient’s own immune system against a cancer can be when we arm it in the right way.

MP: But again I think also the bi-specific antibody CD3, CD19, worked excellent in ALL, maybe even better than the diffuse large B-cell lymphoma, well the phase II studies are going on, we will know soon. But I think it’s fascinating that these CARS seem to be another dimension compared to the bi-specific T-cell engagements.

JG: I had thought maybe the acute lymphoblastic leukaemias were responding because of where the cells were and not in large nodal masses but David showed examples today of a patient with lymphoma with very large masses responding incredibly quickly to the CAR T-cells. So one of the questions that we’ve feared before about whether these CAR T-cells will be able to home into lymph nodes doesn’t seem to be being holding up so far.

MP: No, not so far but there’s not much known about the fate, especially after the infusion of the CAR cells. For some days they go down and you don’t find them and then usually after one week they just pop up in millions of numbers of proliferating T-cells.

JG: I guess there are two other issues, one is that because it’s exciting technology those papers tend to get published, when they are published, with very, very short follow-ups so we never really get a chance to see how durable the responses are. Nor do you sometimes get a sense of what the long-term toxicities are. We see a lot about what the acute infusional related toxicities are but very little less about the fact that normal B-cells are also targets of this response, loss of antibodies, and the potential for infectious complications down the way and turning these people into individuals who aren’t able to make antibodies could really be a problem for us later on.

MP: It could be a problem but so far infectious complications were not the major issue, as I understood David Maloney. Even though it’s really surprising that as long as the CARs against CD19 work, you don’t have peripheral B lymphocytes detectable.

MC: Just to comment on that also, it’s interesting that a lot of these patients do get chemotherapy, Cytoxan and/or fludarabine, but do they really need chemotherapy before they get the CAR T-cells? I think that’s a very interesting thing that’s not answered yet.

JG: Absolutely and, of course, the rationale is to try to both create some immunological space and particularly a lot of people think about taking out T regulatory cells which are often very sensitive to those particular types of chemotherapy to allow expansion of those new T-cells. But the question is, as we’ve evolved new technologies to develop more effective CARs do we still need that? I don’t think we know the answer to that yet.

MC: And the only other observation that I made also is the ability, even in a patient heavily pre-treated with chemotherapy, still have the ability that these CAR T-cells are immunogenic and still can mount a response against the CAR T-cell in some patients which I thought was very interesting.

JG: So, apart from the CAR T-cells, what for you was the highlight of what we experienced today? Apart from your own presentation.

MC: Apart from my own presentation in proteasome inhibition which I thought was very interesting, the next generation proteasome carfilzomib. Of interest, we’ve studied that in the laboratory; it appears to have at least in different cell lines, in lymphoma cell lines as well as in primary patient specimens, we found that it has more potency than bortezomib in our own experiments, even at a log-fold difference, a log-fold less, has at least a similar killing capacity. In addition to that we’re aware from the studies mostly in myeloma that the patients actually have less in the way of neurotoxicity. Therefore, those can probably be pushed higher and right now we’re doing a carfilzomib plus RICE combination trial in patients that are transplant ineligible or relapsed refractory large cell lymphoma study just getting RICE. We’re understanding that from the CORAL data that these patients need something else and we’ve been able to demonstrate that the combination of carfilzomib with the same agents, chemotherapeutic agents, show additive not synergistic activity. The hope is that we’ll be able to do some reversal of the chemo-resistance using a phase I then leading to a phase II study in the combination. In addition to that we heard more today on IMiDs, immunomodulatory drugs, with respect Andy Zelenetz talked about lenalidomide in not only single agent but in combination therapy. We’re aware that it was approved as a single agent with respect to mantle cell lymphoma not that long ago. I think what was interesting also is that where these are going to play out with respect to single or combination therapies there’s also data, as we heard from the R-squared lenalidomide plus rituximab combinations with respect to not only in relapsed mantle cell but in up-front mantle cell lymphoma as well as the data from Nathan Fowler as well as from the CALGB as well as a very large randomised phase III study looking at this R-squared combination in follicular, it’s very exciting in the up-front setting. So I think that that and then one last one that actually is a really exciting agent but we’re moving with caution because of initial toxicity which actually is probably mostly an anti-tumour effect is the ABT-199 which is a Bcl-2 inhibitor. We know how powerful it is that the Bcl-2 over-expression in any tumour and in particular lymphoid malignancies actually always carries with it a bad prognostic type of factor. Now we have the ability, purely against Bcl-2 in the past, ABT-263 also had activity against Bcl-xL and we saw the thrombocytopenia. Even though we saw activity we’re always concerned by combining it with chemotherapeutic agents that would also induce thrombocytopenia and/or maybe have dramatic… we could have life threatening bleeding if we use those combinations. That issue is not an issue with ABT-199, it’s purely selected for Bcl-2. The problem, however, at this point is it was so good, initial trials demonstrated that by using it to perhaps… and it’s not always dose effect, and patients who are sensitive can develop tumour lysis syndrome. However, in experienced hands tumour lysis syndrome  and now changing the dose and the schedule and maybe monitoring the patients much more closely, those types of issues hopefully will not be a major concern in future. As we learn how to give it better I think it’s going to be a real deal changer; it’s going to be a major addition to our armamentarium, as we’re saying with other agents. I’m very excited looking at what’s going to happen with ABT-199.

JG: Yes, I completely agree with you. Even though the company themselves were very concerned by the tumour lysis syndrome, I think most trained oncologists would view tumour lysis as a sign of the activity of the drug and therefore that we just have to learn how to handle the drug better. Certainly that seems to be the case from the more recent clinical trial data that we’re seeing and certainly from my own experience of patients that we’ve got on the drug, that this graded approach seems to be able to overcome the major issues without impacting on the efficacy. It is fascinating, though, that the disease in which Bcl-2 has been the paradigm, that is a follicular lymphoma with a 14/18 translocation with very high levels of Bcl-2, seems to be the disease in which maybe we’re seeing perhaps the least signal. Just, I guess, emphasising the importance of not just Bcl-2 but the other family members of Bcl-2 in terms of the balance that’s going on. So anything surprising about the results that you saw today in terms of follicular versus non-follicular in that setting? Or you knew all that already?

WW: I wouldn’t say knew it already. I know that when we did the original phase I/II of 263 the activity in follicular seemed to be somewhat less. I think what’s unknown so far, and we have a great interest in this, where ABT-199 will fit into with large cell. There has been an emergence of interest in over-expression of Bcl-2 within large cell lymphoma being associated with a poor outcome and so it’s a logical extension to think about combining a drug like this with conventional chemotherapy and seeing if we can improve the prognosis of the high Bcl-2 which is also associated, when combined with high MEK, seems to portend a poor outcome.

JG: I just want to pick up on something you were mentioning earlier, that is the big phase III randomised clinical trial of lenalidomide and rituximab, the so-called R-squared regimen, compared to chemotherapy. That trial has accrued incredibly well, both in the US and in Europe, I guess perhaps highlighting the interest that patients have towards what’s been termed a chemo-free approach. Now we’ll come on to that issue in a moment because we had a very lively debate about the notion of chemo-free. I guess what we are seeing is lots of our patients like the notion that we’re moving away from conventional chemotherapies on to more novel agents. What it’s also showing is that in the right disease setting some of these agents are able to be very effective. So we did see very promising phase II results coming out from the Mayo and from MD Anderson; it’s in the CALGB and LISA trial right now. If the results from this are indeed positive could you see that we would be moving away from conventional CHOP-like regimens as the backbone for how we would treat follicular lymphoma patients up front?

WW: I think we’re already moving away from it. Bendamustine plus rituximab is already replacing in many people’s minds CHOP. People don’t like CHOP because adriamycin is associated with hair loss, with nausea, with very low white counts, of course bendamustine has low white counts. But I think it’s very important to recognise that we’re really moving away from a conventional cytotoxic and not moving away from chemotherapy. At the end of the day it’s about therapeutic index; it’s about getting the most effective therapy with the least amount of toxicity to the extent that R-squared will give that to you in follicular lymphoma over bendamustine, rituximab or R-CHOP, I would say that’s great. But we all know that around 5-6% of follicular lymphomas associated with transformation to a large cell and at least, to the extent that lenalidomide has been tested as a single agent in relapsed large cell, you’re just simply not going to see the same kind of long-term control. So I think the jury is out. I think it’s a very exciting regimen, I suspect it will be a positive trial in so far as at least as good and for the right selected patients it probably will be a very good option for them.

AH: To add to that I agree with you that the R-squared treatment might be the optimal initial treatment to keep the patient away as long as possible from the more conventional cytotoxic approaches. But the patient is not going to be cured by this regimen so everybody will go through the second, the third, the forth, the fifth line and there comes bendamustine, there comes CHOP at the end.

MC: But the only concern is what is the best sequence and how do we avoid cross-resistance and we don’t know that answer, that’s the problem.

JG: So the whole last debate that we were having, and spirited it was indeed, was this notion of chemo-free which I think is a very attractive sounding thing for our patients. But what we came away with was that we found it very difficult to define what was chemotherapy versus what wasn’t and the notion, perhaps, that it was dangerous for our patients to think of chemo-free versus chemotherapy when in fact what they ought to be thinking about was the optimal treatment approach for their disease at that stage. So what would be your message for patients coming looking for chemo-free approaches?

WW: My message would be that these drugs are chemotherapy, they’re just not a conventional cytotoxic and that it’s all about the best product, the best endpoint with the least amount of toxicity. In fact, that may be achieved with chemotherapy plus some of these newer drugs with the chemotherapy given for a very few cycles. That may be far less toxic and more effective than giving R-squared for six, seven, eight, nine months. So I just think that we have to keep an open mind. I also think that we should also think about the fact that many conventional chemotherapy agents are actually herbal medicines, they’re actual natural products and we all know that we like to take herbal medicine.

MC: Especially from the Netherlands, from Amsterdam.

WW: Absolutely. We won’t go there in the US!

MC: That’s true.

WW: Many chemotherapy agents are from plants and they’re completely herbal so we should think about it like that.

JG: OK, so I think we can wrap up there and say we all agree that the right combination is the best agents that we have available for our patients. So what we’ve heard is another very successful day at the International Workshop for NHL with many of the world’s experts in this disease coming together, discussing the latest findings. I think all of us finding it very exciting to be basing our treatments upon a better understanding of the science and the biology of the disease and that that’s what we’re looking to build rational approaches from going forwards. So we all look forward to next year’s meeting back in Europe and thank you very much.