EHA 2015
EHA 2015: Reviewing the treatment landscapes of CLL, MCL, and MM
Prof John Gribben – Barts Cancer Institute, London, UK
Prof Marivi Mateos – University Hospital of Salamanca, Salamanca, Spain
Prof Umberto Vitolo – Città della Salute e della Scienza, Turin, Italy
Prof Paolo Ghia – Università Vita-Salute San Raffaele, Milan, Italy
JG: Hello, I’m John Gribben from Barts Cancer Institute in London. Welcome to a very hot and steamy Vienna where we’re here for the European Haematology Association meeting. I’m joined by a very esteemed international panel of experts to review the highlights of the meeting. So if we introduce ourselves, Umberto?
UV: I’m Umberto Vitolo from Haematology, University Hospital, Città della Salute e della Scienza, Torino, Italy.
MM: My name is Maria Victoria Mateos and I work as a haematologist at the University Hospital of Salamanca in Spain.
PG: I’m Paolo Ghia from Milano, Italy, working at Università San Raffaele in Milan.
JG: OK, so what we have is a panel of experts in lymphoma, myeloma, CLL, covering the spectrum of the haematological malignancies that we’ve been seeing in the meeting. So tell me, Umberto, what have you seen so far at the meeting that has struck you as exciting this year?
UV: Well there are many topics for lymphoma in this meeting, also more topics will be next week because there is the International Malignant Lymphoma conference in Lugarno. But, anyhow, there were a couple of interesting presentations in mantle cell lymphoma yesterday that covered the use of novel drugs. In this case there was a first presentation made by our group in which we presented the result in younger patients with high dose chemotherapy, autologous stem cell transplantation followed by maintenance with lenalidomide compared versus observation. The results so far are preliminary so we had only the results for the first part of the study but it’s interesting to note that the complete remission was quite high after high dose AraC, about 77%, along with MRD negativity. But with additional autologous stem cell transplantation it doesn’t seem to increase so much, only a few points more after high dose chemotherapy. So I think this opens a window regarding if we can spare high dose chemotherapy maybe autologous stem cell transplant in these patients, maybe with additional novel drugs like lenalidomide in the maintenance or ibrutinib in combination with chemotherapy. There are some ongoing studies, ongoing trials, that are aimed at this point, just adding novel drugs to a chemotherapy backbone plus, of course, anti-CD20 antibodies in order to spur a more aggressive treatment than usually is required for the treatment of mantle cell lymphoma.
JG: Are these minimal residual disease endpoint studies or have they built assessment of MRD into the design of the study?
UV: Yes, MRD was a secondary endpoint of the study but it was assessed after each step of the treatment, after the first, of course, is over R-CHOP, standard R-CHOP and then after high dose chemotherapy with Ara-C before autologous stem cell transplant and during the maintenance. The data so far we have in quantitative CR was 70% MRD negativity before autologous stem cell transplant and after autologous stem cell transplant 72%. So it doesn’t seem too…
JG: It doesn’t seem to add so much for the toxicity.
UV: And we’ll see in the future during the maintenance period.
JG: So watch this space for the follow-up of this study is basically where we are at this point.
UV: The maintenance is planned for two years and I hope that we have the data on maintenance next year, next year of course.
JG: OK. And in terms of myeloma lots of new drugs emerging in this field. Of course, for those of us who aren’t myeloma experts look at it and think how on earth do you start deciding which of these so many new agents appearing are going to be the ones going forward? So what’s your view of where the field is going, based upon what we’ve heard here?
MM: Absolutely, novel agents are coming for all haematological diseases and also for myeloma. From this European Haematology Association meeting I would like to highlight novel agents, second generation proteasome inhibitors and carfilzomib has demonstrated in a large randomised trial to be superior to bortezomib plus dexamethasone with a significant benefit in terms of overall response rate, complete remission rate and also duplication of the median progression free survival.
JG: With less toxicity or is the toxicity similar?
MM: Toxicity is different because carfilzomib has a specific toxicity profile, carfilzomib does not induce peripheral neuropathy as with bortezomib.
JG: But that has been a big problem for patients to tolerate so do you find it better tolerated but different?
MM: Yes, I think that definitely the tolerability is better, although we have to be careful with some side effects, so renal impairment or cardiac toxicity but in a specific subgroup of patients. I would like also to highlight novel agents such as HDAC inhibitors that have been evaluated also in randomised trials and panobinostat plus bortezomib and dexamethasone showed to be superior to bortezomib plus dexamethasone. But what I would like to highlight of this EHA meeting is that a sub-analysis has been conducted in patients who had been previously exposed to the two, bortezomib and IMiDs. In this specific subgroup of patients, heavily pre-treated patients, the difference, the benefit in median progression free survival has been much more evident with a median progression free survival benefit of approximately 7 months for panobinostat, bortezomib and dexamethasone, confirming the role of HDAC inhibitors in the management of myeloma patients. Finally, I would like to highlight the immunotherapy strategies through monoclonal antibodies. Today we have had the opportunity to hear from Sagar Lonial from the US the results of daratumumab as single agent in heavily pre-treated myeloma patients, exhausted to all conventional agents, bortezomib, thalidomide, lenalidomide, carfilzomib and pomalidomide. These patients responded to daratumumab single agent emerging as a possible backbone for all regimes in the treatment of myeloma patients.
JG: And accessible to younger and older patients.
MM: Yes, so results are very preliminary, only in one hundred patients, but it seems not to have any differences according to the age.
JG: And of course in CLL lots more on the novel agents and follow-up, so what struck you in CLL that you’ve heard from this meeting?
PG: Now the novel agents are a reality in CLL since a couple of years at least. So I would say that this meeting in particular has been a consolidation phase. We saw the long-term results of the use of ibrutinib or idelalisib plus rituximab and indeed they confirm durable responses. They confirm also the toxicity profile that we are now aware of and, in particular, the diarrhoea that is quite frequent, around 40%, in patients treated with idelalisib in the long run. New molecules have been presented also of the same family, I would say, so another PI3 kinase delta inhibitor, TG-1202 that apparently has less toxicity.
JG: Yes, the toxicity does seem less. Less GI toxicity, less hepatotoxicity.
PG: It certainly seems less. It is true that the follow-up is only six months or so but still only 2% apparently so that would be good news. Then we saw also the results of the PI3 kinase gamma delta, so the dual inhibitors also on CLL and other malignancies and the results are also quite in line with what we learnt about idelalisib. And, of course, what we are waiting for are the long-term results of the BCL-2 inhibitors, the ABT-199. The Australian colleagues showed results after 30 months of follow-up of even patients in complete remission who have stopped the drug because of any reason. They showed durable responses, even outside of therapy. They confirmed that over 40% of complete remissions with a very high number, almost 50%, of patients with MRD of the patients responding. So these are promising results and so the future appears to be quite bright.
JG: I think the ABT study showing the MRD negativity look really intriguing because one of the things I was going to come back to talk to all of you about are all of these novel agents greatly increase the potential cost. Certainly in Europe we have to be thinking about the cost to our patients. I guess I was asking about MRD in the mantle cell setting, we certainly look at that a lot in myeloma and now in CLL but therapy that potentially has a beginning and end is probably where we’re looking to go forward in all of these diseases, rather than continuous therapy. Do you agree?
UV: If I can answer you, I think that you are totally right because there are a couple of issues. The first one, as you remember, the issue of the cost that is because all these drugs probably are high cost so it’s difficult to think that we can give to a patient for life. The second point may be that we don’t know exactly yet the long-term toxicity of the drug because all these agents are active on B-cells, B-cell receptor pathway and so on. So we don’t know exactly after some years of exposure how will be the immune functions of our patients. Of course the first goal is to cure the patients, we need to cure, probably, in the relapsed setting but I believe that we need to know more on these drugs and also to try to design smarter studies in order to fix an end to this treatment. Maybe like in CML, you know in CML after some years of complete molecular remission we are thinking now to stop the TK inhibitors and maybe also in lymphoma and CLL, I don’t know in myeloma. But we should think something similar to CML.
JG: Of course in myeloma now we’re seeing, because you have so many agents available, people going through seven, eight, nine lines of therapy. It’s becoming increasingly common to see patients surviving a very long period of time. But of course we also see that patients are sometimes surviving a very long period of time with myeloma with still having increasing morbidity from the skeletal complications of the disease. Are there ways in which we think that some of these new agents are going to impact the long-term quality of life of your patients?
MM: Yes, I think that it is necessary to do quality of life studies in all trials that we are going to conduct because you are right, the survival of our myeloma patients is clearly increasing. In fact, with the daratumumab 60% of patients remain alive after one year and this is surprising because in the past these patients were not alive more than 9 or 10 months. So I think that our efforts have to be towards that direction, not only to survive, to be alive more time, but to try to improve the quality of life of course because the bone disease is one important issue in myeloma patients. So we have to try to control and improve these.
JG: So Paolo, of course in CLL the approved agents that we have are continuous therapy at very high potential cost. Do you also believe that the future has to be to find a way to get these patients into a status where we can potentially stop the drug?
PG: Definitely, yes. Indeed, the next generation of clinical trials will be combinations of the drugs. So we understand that with these new products we cannot achieve a complete remission, or at least the vast majority of patients, so the future is very likely to combine with something else and ABT-199 is probably one of the best candidates. Studies are starting or are designed to combine with either ibrutinib or idelalisib or duvelisib even. So this is the way in order to reach more profound responses, MRD negative responses, and especially to stop after a definite time the treatment.
JG: The idea, of course, would be that even though the cost is three times as much because you combine three agents, it’s at least for a defined period of time and then you can stop.
PB: Yes, of course. You spend a lot but that is for six months, as we used to do with chemotherapy, then probably it’s more affordable than just having no limit in the future.
JG: OK, so what you are hearing from Vienna is continued excitement that in the haematological malignancies there’s a huge number of novel agents which are being used alone and in combination looking to improve the duration of responses, the quality of life, applicable to younger and older patients in a way that chemotherapy wasn’t in the past. So these remain very exciting times in terms of the management of haematological malignancies.
