Critical insights on leukaemia and lymphoma from ASH 2013

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Published: 2 Feb 2014
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Prof Robin Foa, Dr Simon Rule, Dr Clemens Wendtner

Prof Robin Foa, Dr Simon Rule and Dr Clemens Wendtner discuss the main highlights presented from the ASH 2013 meeting.

The participants discuss recent treatment advances in CLL and MCL and how this could impact on future treatment practices.

The Multiple Myeloma Debates

Critical insights on leukaemia and lymphoma from ASH 2013

Copenhagen, Denmark

RF: Prof Robin Foa – “Sapienza” University, Rome, Italy
SR: Dr Simon Rule – Derriford Hospital, Plymouth, UK
CW: Dr Clemens Wendtner – Schwabing Hospital, Munich, Germany

RF: We’re here in Copenhagen for a European meeting aimed at discussing some of the highlights of the recent congress of the American Society for Haematology held in New Orleans. The purpose is to see what has emerged in particular in haematological malignancies and to see how this could translate into a different approach to the clinical management of patients with the diseases. So we have the fortune of having some colleagues and friends here; I would like to introduce them: Clemens Wendtner from Munich and Simon Rule from Plymouth, UK and Germany. I would take advantage of them being here and thank them for being available to ask them what they think has emerged in two particular diseases which are extremely important. One is chronic lymphocytic leukaemia and the other is mantle cell lymphoma. So, Clemens, would you give us maybe a short update of what you think are the key points that have emerged and how this could possibly translate in different clinical management of CLL patients?

CW: Right. First of all I think ASH 2013 was a little bit of a CLL firework; we have seen many abstracts, new things, phase III trials. The first point I would like to make, we have seen some convincing data that we can achieve very nice remissions, also in the elderly CLL patients, this is the majority of CLL patients, using a chemo backbone, chlorambucil, plus anti-CD20 antibodies. We have seen different phase III trials using ofatumumab, for example, using rituximab, using obinutuzumab; the most convincing data for myself, although I’m a little bit biased because I was part of this trial, was the combination of chlorambucil plus obinutuzumab, it’s a new type II anti-CD20 antibody. This will probably become the new standard in the elderly ones.

Besides this I think we have seen many data, including phase III data, using new tyrosine kinase inhibitors even in a disease like CLL; this is new. We have seen data using a PI3 kinase delta inhibitor called idelalisib. We have seen data using a BTK inhibitor called ibrutinib and we have seen data using a BCL2 inhibitor called ABT-109. So we are approaching maybe an area where we will not use chemotherapy anymore so we are coming very close to a chemo-free approach.

RF: So you’re thinking, if I may make a comment, that it’s probably a turning point, this, because we’ve been obviously managing CLL for years with chemo and you think that probably opening a new era where we hope, like for other conditions, that we might go towards chemo-free.

CW: Absolutely. I think chemo is still a point in the very young and fit ones but this is a minority. There we’re aiming for MRD negative disease so you really have to hit hard, including chemotherapy, but in the elderly ones the majority of CLL patients so the median  age is above 70, you have to think about this, chemo-free is the new way to go and this includes antibodies and signalling inhibitors called tyrosine kinase inhibitors.

RF: And that will be the change. Simon, do you think we’re in a similar area for mantle cell lymphoma too? That emerged again at ASH although data came earlier on mantle cell.

SR: Yes, I think we’re at exactly the same place in mantle cell lymphoma. ASH this year was all about CLL; there was very little on mantle cell actually. Just before ASH happened ibrutinib got a licence through the FDA so it’s clearly going to be a very important drug in mantle cell lymphoma. There wasn’t a lot at ASH but, again, there was data in some of these newer agents, another BTK inhibitor, there was data in ABT-199; so very similar drugs, oral, very active, modest toxicity which is going to certainly lend them to being incorporated into novel chemo-free regimens. There was data adding drugs into established chemotherapy regimens; I was struck by the addition of Velcade to bendamustine/rituximab with some dexamethasone, clearly a very active regimen in older patients. There was data on lenalidomide/rituximab which has become very trendy, if you like, in indolent lymphomas. Very early that data, whether that’s going to be as good as chemotherapy based treatments, we’ll see, but I think we’re in a very similar place to CLL, very similar.

RF: It comes to my mind, in the old days, old – even up to today, I always used to say that key pointers to make a differential diagnosis in diseases. It’s just come into my mind, thinking about the BTK inhibitors, that maybe…

SR: Maybe it doesn’t matter.

RF: Well maybe it matters less nowadays. This is ironic, as I always tell everybody that we have to be very precise. Think of leukemic mantle cell lymphoma which is an entity in between classic nodal mantle cell and CLL, I always say, or we always say, you have to be very precise, it’s not a CLL. But if the BTK inhibitors are equally effective in CLL and in mantle cell, they’ll be, I imagine, equally effective in leukemic mantle cell or mantle cell in leukemic phase although I don’t know if we have any data in that specific area.

SR: We don’t. Those patients tend to have a more indolent biology than the classic nodal but I would imagine perhaps that group would be better off with the BTK inhibitors.

RF: Yes, maybe we should do a study on that, that comes to my mind now. Anything else that struck you in particular?

SR: No. These trials are on-going and what you saw with CLL this year you’re going to see in the lymphomas in the next couple of years. They’re very similar trials being designed; they’re very similar approaches being looked at. The interesting thing will be when we finally do head to head trials of non-chemo versus chemo approaches because the challenge there is what endpoints are you going to use because you may not get… The responses with chemoimmunotherapy are very good; when you start using chemo-free regimens they might be equally as good but actually much better tolerated. So we need non-inferiority, quality of life designed studies. That’s a whole different paradigm to improving response, improving response, improving remission, not just duration but depth of remission which is what’s been the driver for years and years and years. I think we’ll have to go from there to being very much more patient-focussed.

RF: Again that becomes a bit provocative because we always used to say that ideally we’d like a patient to become MRD negative, minimal residual disease negative, which means a lot of treatment, obviously. Maybe, again maybe not for all patients, but a very high risk patient, at least in CLL, probably needs aggressive treatment. But for others it might be different; if you can control the disease, chronicise it for years and years and patients live well with less toxicity, I think any of us would be really happy with that as physicians and certainly patients would be happy with that.

If I may add one point on this because I think this goes into obviously the area of defining disease where biology applied MRD, whatever. Something that is emerging is development of new technologies because new drugs come from new technologies too, we have all these personalised medicines that we use for different diseases in haematology and even the BTK inhibitors because they’re targeting the B-cell receptor which plays, obviously, a major role in the disease. What we are seeing is now that you can use technology to stratify patients even more and one thing that came out at ASH was, and I think it’s very interesting, in CLL was the fact that you can identify a sub-group of CLL patients and in fact have a minute p53 sub-clone which I think is very interesting because so far we know that in CLL the sub-group of patients who actually does worse is the group that have lots of p53 disruption. We always say that those patients should be treated in a different way, they don’t usually respond to conventional treatment, we have to go to different treatment and if they’re young enough we try to offer them a chance because that’s the only way we can try to salvage them because their progression free and overall survival rates are extremely poor. The data by ultra-deep sequencing shows that you can pick up minute sub-clones of p53, there was an oral presentation at ASH, even to an extent of 1% to a proportion as about almost 6% of patient diagnosis and these are patients who would not have been recognised because they are under the limit of detection of conventional Sanger sequencing which is roughly 20%. Now the important point is not to find it but to show that that appears to correlate again with bad prognosis. So, in fact, broadening the sub-group of CLL patients with a very poor prognostic likelihood based on deep sequencing and that adds up, prior to treatment, of almost 15% of cases which is not a small proportion. So I think technology will develop, I think we’ll see more of that in the future and I think it’s extremely interesting, particularly now that we have new drugs. We’ll have to see the new drugs, how effective they are in a p53 disruptor because there’s great hope for that. I think we’ll have to see that even further.

SR: I think that’s increasingly more important because these new drugs do work very effectively in that situation and these are expensive drugs so you want to be using them in the best place rather than exposing them to expensive chemotherapy which isn’t going to work.

CW: And you might also have to redo these kinds of analyses in the area of new drugs because the prognostic impact of p53 might then change when you have these new drugs available. But we have to clearly analyse this within controlled trials, we have to have very long observation times and things like that.

RF: It’s almost biology applied to clinical trials. That is the message coming out, there’s always more if you’re sub-dividing groups and sub-analysis. So it’s been a positive ASH meeting, I think important clues have come out. I think one clue that we always say is that all these conclusions come from clinical trials. We always say, because one of the endpoints of this meeting in Copenhagen is how would these inputs or outputs from the congress actually impact the clinical daily activity, and we always say that this might take a bit more time. They have to be confirmed in a large clinical trial so we always insist that patients should go on clinical trials because if we do studies quickly then we can get responses that then can actually impact on a daily activity.

So, thank you very much for being here tonight for the filming for ecancer. Thank you very much and see you next time.

SR: Thank you.

CW: Thanks.