SR: Hello, welcome to ecancer.tv. We’re here at ASH 2014 in San Francisco and I’m joined by three very esteemed colleagues who are going to give you their brief highlights of what they’ve seen in the last couple of days. So I’m going to start with Gert Ossenkoppele from the Netherlands, who is an AML expert. What have you seen that’s struck you in the last couple of days?
GO: This was really a very exciting ASH for those who are interested in acute myeloid leukaemia. All rooms were overcrowded and that was a long time ago that that occurs for AML sessions. That was mainly due to the fact that the genomic landscape of AML is unravelled very much and we can now detect some driver mutations and with the driver mutations we have also new targets for treatment. Many new drugs are developed to hit that target and an exciting example is, for example, the IDH1 and IDH2 inhibitors that showed really activity in those IDH1 and IDH2 mutated acute myeloid leukaemias, resulting in complete remissions in very heavily pre-treated patients with monotherapy. So that’s rather new and that’s only one example of one of the exciting drugs, there are more. For example, there was in the plenary session was the addition of sorafenib to a standard treatment that’s showing in a randomised phase III study an advantage in relapse free survival and also in overall survival. Also that was amazing for me. A lot of other new drugs are coming up now and are tested now, for example DOT1-Like inhibitors that show very promising efficacy in heavily pre-treated AML again. And I can name a lot of other new drugs and they have to be proven in randomised studies in upcoming years, but at least we now have new drugs for AML and, as you know, we treat already for 30-40 years the AML patients with the 3 7 regimen and didn’t improve much on that. So that’s, for me, the most striking in this ASH.
Another aspect, if you allow me, is that for the elderly AML also some advantages. It’s now possible… it was always difficult to decide which patient is fit enough to receive chemotherapy and it has been shown that a simple geriatric assessment could really distinguish between fit and unfit patients so the fit can then achieve intensive chemotherapy and the unfit less intensive chemotherapy. With that you can also see which patients could go for very intensive treatment in allogeneic stem cell transplantation. That’s the other exciting thing, is that it has been shown in two presentations this ASH, and by the HOVAN group that allogenic stem cell transplantation for the elderly patient is a feasible option now but, besides that, it delivers also an overall survival advantage. So those were, for me, the most exciting things at ASH.
SR: Just to comment on that, so the elderly AML patients generally do pretty poorly unless you can treat them relatively intensively. Do you think these newer drugs, then, are likely to come into play there? Because that’s very, very much the unmet need, isn’t it?
GO: Yes, and the unmet need is especially in the elderly. AML is, of course, an elderly disease in the elderly and it looks that, for example, also in the elderly you have IDH1 and IDH2 mutated patients and probably they will also benefit from these new drugs, yes.
SR: Exciting times.
GO: Yes.
SR: Antonio Palumbo from Italy, myeloma – what has struck you the last couple of days?
AP: Well we saw, I would say, three presentations that were probably the most interesting. One is certainly the study comparing lenalidomide dexamethasone as a control versus a three drug combination including the second generation proteasome inhibitor carfilzomib. This study probably set a new standard in the treatment of relapsed refractory myeloma. You can consider that today the expectation of remission duration is around one year in relapsed refractory disease and the study showed a progression free survival of 27 months. So we are now moving from one year remission duration to two years remission duration and certainly this was the most important event for myeloma coming from ASH.
The second one is certainly coming from the CD38 antibody. We have been so jealous of you lymphoma guys and wanted to have our R-CHOP. The great expectation today is to have a sort of R-CHOP for myeloma and the CD38 is the antigen number one to hit in this disease. They presented early data on phase I/II studies combining lenalidomide and dexamethasone with CD38. We have now two compounds: one from Janssen, the daratumumab compound, and the other from Sanofi, the SAR compound. The interesting data, I would say, in relapsed refractory myeloma, they were able to show a VGPR rate up to 60%. So that was the other important issue.
The third is coming also for a novel agent that will probably come and become important for myeloma. We may have an oral proteasome inhibitor, ixazomib, and they have been using as a continuous treatment after induction for myeloma patients. The two novelties are, one, the opportunity to have an oral proteasome inhibitor and second they were able to show an increase in response, an upgrade of response in more than 50% of patients during maintenance and continuous treatment. So this, I would say, would be the major finding, at least I could see, at this ASH.
SR: So, exciting times and new drugs. We had this conversation last time you and I met – if you put these newer drugs together, again do you think the potential to challenge transplant? Is that going to happen again, do you think?
AP: The transplant is still there, we had an educational and our French colleague was absolutely positive and I agree with him – the transplant is still absolutely a must for the younger patient today. Tomorrow I don’t know, but today, even with the second generation proteasome inhibitor, I think the transplant should be part of the induction treatment.
SR: Peter Hillman, professor from Leeds, a good friend of mine. CLL, Pete, what have we learnt in the last couple of days?
PH: I think the main story has really been in the therapy of CLL and we’ve had really three main themes. One has been the clarification of chemo-immunotherapy and there’s always been the question mark of is FCR or bendamustine rituximab the most appropriate therapy. We had the update of the German CLL10 trial which really shows clearly that FCR gives better responses and with the price of some extra toxicity. I think it remains the gold standard for patients who are fit. There is some discussion about the 65 year old and plus patients who are fit and whether bendamustine rituximab could be useful for that group of patients but we don’t really have the data yet to show that. And alongside that in patients who achieve MRD negative remissions have a better outcome, that was clearly shown. And then maintenance with rituximab and ofatumumab, with two randomised phase III trials which suggests in an early follow-up that progression free survival is prolonged with either rituximab or ofatumumab from the Austrian and the HOVAN groups. They’re quite short follow-up and we really need to see a longer follow-up, more overall survival data, before we can really change the treatment but they are phase III trials.
And the second big story has been the further clarification of some of the small molecules, so the B-cell receptor antagonists, particularly the PI3 kinase delta, idelalisib, plus rituximab trial and ibrutinib BTK inhibitors. So we’ve seen clarification of the two randomised phase III trials and for idelalisib 116 which has shown, now, data beyond the year which was… we saw it earlier on at last year’s ASH where it was a very short follow-up, again an overall survival advantage, a clear advantage for the poorest patients, for the 17p 11q deleted patients, and no difference between those patients and those without high risk in the relapsed refractory setting with idelalisib. Again, ibrutinib we’ve seen the further clarification of the RESONATE trial now out to beyond the year, again a survival advantage for single agent ibrutinib. And Susan O’Brien presented the first data in Holland (?) 44 patients with 17p deleted CLL, specifically with ibrutinib. A short follow-up but very good responses, much better than we’ve seen with chemo-immunotherapy.
I think the third major story is around the combination of these molecules, particularly ABT-199 which is the Bcl2 inhibitor which we’ve seen for the first time at ASH the combination with rituximab. In that phase I/phase II trial which Andrew Roberts presented we’re seeing very high CR rates, actually, for relapsed refractory disease and 13 out of 55 patients achieved MRD negative remissions. One of the most exciting aspects of that is that five of those patients stopped therapy when they were MRD negative and remain in remission, in fact some of them longer than they were on the ABT-199 treatment. So I think we’re now moving towards an era where we can use combinations of therapies to achieve very deep remissions and stop treatment, which is going to be important for the indolent lymphomas and CLL with these novel agents.
SR: Yes, that was dramatic, wasn’t it? I guess that’s the challenge – putting the best combination together and then stopping and then seeing what happens from a financial toxicity more than anything else.
PH: As well we don’t want patients to remain on treatment, patients don’t want to remain on treatment, if they don’t need to and we know from the chemotherapy era and transplant protocols over years that achieving minimal residual disease negative remission is associated with a much better outcome. This is the first evidence that we can achieve it with small molecules and no chemotherapy and that we can stop it and they still remain in remission. So that has to be our aim of therapy and I think that links nicely really to the indolent lymphomas and mantle cell lymphoma where similar approaches and similar drugs are being used.
SR: Absolutely. I’ve just come here from a session listening to Michael Wang present the data on ibrutinib plus rituximab in relapsed mantle cell lymphoma. Very interesting, the high response rates, high CR rate. In fact it’s very important, the CR rate, almost 40% which is twice what you get with ibrutinib as a single agent, so these concerns about rituximab and ibrutinib being antagonistic clearly isn’t the case. So that’s exciting and very modest toxicity. One thing he showed which I hadn’t seen before was that those with the high Ki-67 didn’t seem to respond as well as those with the low Ki-67. So there’s something about those proliferative patients that don’t do as well. Having said that, when you relapse with ibrutinib you tend to be more proliferative so maybe it’s the same pathways that are being exposed there. We’ve also just seen lenalidomide plus rituximab front-line, again very high response rates but it was labelled as a non-cytotoxic approach and yet 50% of patients had grade 3/4 neutropenia. So just because things aren’t chemotherapy doesn’t mean they don’t come with toxicity.
And I guess the thing that is probably going to impact the quickest is we saw a presentation earlier about rituximab maintenance post-autograft, a randomised trial showing a benefit. So maintenance post-autograft is exactly the same as maintenance post-chemotherapy in older patients, so a recurring theme. But yes, it’s going to be very similar. We’re going to be putting novel combinations together and then the challenge is how we do that and for how long we do that and I’m not sure how we manage that. MRD, I guess, is the key here.
PH: I think so and it may be different between certainly mantle cell and CLL because of the proliferative rate of mantle cell. But likewise in CLL we’re seeing that these molecules that target B-cell receptors singly and in proliferation seem to have a quicker effect in patients who have got very proliferative disease which is similar to what you’re seeing in mantle.
SR: So very exciting times, novel agents coming to the fore led very much historically with myeloma. We’ve seen huge advances latterly in CLL and mantle cell and other lymphomas and now, very exciting, in AML. I think the disease probably held back a little bit compared to the other haematological malignancies but it’s exciting times and the next year or so we’re going to see some great advances. Thank you very much.
