New emerging treatments and challenges in MCL, MM and CLL: Expert panel discussion
Prof Simon Rule – Derriford Hospital, Plymouth, UK
Dr Maria-Victoria Mateos – University Hospital of Salamanca, Salamanca, Spain
Prof Paolo Ghia – Università Vita-Salute San Raffaele, Milan, Italy
Prof Antonio Palumbo - University of Turin, Turin, Italy
SR: Hello and welcome to ecancer.tv. We’re here today in Berlin at the Haematological Malignancies Debate and I’m joined by three esteemed colleagues to discuss some of the new issues that have been coming up today. So I’m Simon Rule, I’m a haematologist from Plymoth in the UK and just introduce my fellow colleagues here.
MM: I am Marivi Mateos and I work as a haematologist at the University Hospital of Salamanca in Spain.
PG: I am Paolo Ghia working as a scientific co-ordinator of the lymphoma unit at the San Raffaele Scientific Institute in Milano, Italy.
AP: And I’m Antonio Palumbo and I’m working in Torino, Italy.
SR: Great. So, Antonio, if I could start with you, we’ve been discussing some of the newer management aspects of myeloma and some of the changes in the guidelines. Perhaps you’d like to outline what you see as being the new issues at the moment?
AP: Yes, an international guideline just came out a few days ago in Lancet Oncology. This is probably going to change our way we are deciding when we need to start treatment. Basically until now the rule was that we should start treatment when we do see organ damage, that is defined by the CRAB criteria, and today on top of this criteria that are not changing, so bone damage, anaemia, hypocalcaemia or renal damage, we are adding other basically three criteria. One is the use of more sophisticated imaging such as low dose CT scan or MRI and the presence of at least two focal lesions on MRI will represent a new criteria that will define the bone organ damage that will tell us to start treatment. The other two basically parameters will be a massive plasma cell infiltration, more than 60%, that is again telling us that we are very close to a bone marrow or a bone damage, and the other one would be a free light chain ratio more than 100. So what everybody should start to remember that we need MRI to define bone damage, we need with the bone marrow more than 60 and with free light chain ratio more than 100; without any bone damage these are still criteria to start therapy.
SR: So, just for my information really, MRI scan of the whole spine, is that what you would advocate? And skeletal surveys do they continue?
AP: No, basically there what we are going to change is the skeletal survey is going to be… the low dose CT scan is going to take the place of the x-ray and the MRI should be whole body when feasible because definitely that will be the standard. If you don’t have it it’s close to the spine.
SR: OK, that’s very interesting. Great. Paolo, we’ve been talking about CLL today as well and of course there are lots of new drugs that work in CLL. What are the sort of practical issues around newer agents that people need to be aware of?
PG: Yes. It’s a very exciting period for CLL. You have to think that in the last year we had four new drugs that had been approved for use in CLL; those are two inhibitors, ibrutinib and idelalisib, and two antibodies, obinutuzumab, GA101, and ofatumumab which was already approved but in relapsed refractory patients, now it is approved in first line in combination with chlorambucil. So, as you may already understand from these four drugs, we are moving towards a chemotherapy free treatment of CLL and so we have very exciting results, a high number of responses and prolonged responses, but it is true that also the pattern of toxicity is changing and is nothing comparable to what we have been using so far with chemotherapy agents. Therefore we have really to change the way we are going to manage our patients because we will face new and diverse side effects that we never saw before. So typically with the inhibitors many patients complain about diarrhoea, that can be early onset diarrhoea immediately after starting treatment or late onset, so even after one year of treatment. We are facing inflammatory diseases, not infectious diseases but inflammatory diseases like colitis or pneumonitis which also are somehow putting a challenge in our daily care. With the new antibodies, these are more potent apparently as compared to the previous ones. They are also more potent likely in inducing an allergic reaction so we have also to be ready to face more frequently these new allergic events. Going back to the inhibitors, though, for example, as I said diarrhoea is a common pattern with these inhibitors and also with other new drugs that are coming up in the future, each of the drugs has particular and specific side effects like, for example, with ibrutinib patients complain very often of bleeding events which are in the majority of cases of minor relevance but can also lead to major events like an intracranial haemorrhage that one has really to keep in mind. On the other side instead, idelalisib has been more frequently connected, associated, with ALT AST liver enzyme elevation and that also has to be taken seriously into consideration. All these side effects stop, usually patients recover after stopping the drug and usually they become tolerant after re-introducing the drug even at a lower dose. So we need really to start learning again to be doctors rather than haematologists so we can face and appropriately manage all these new, let’s call it, side effects.
SR: I think we’re doctors as well as haematologists usually.
PG: Sometimes we forget.
SR: But the general approach with the toxicity that we’re seeing, particularly with the PI3 kinase inhibitors, is stop the drug and then reintroduce at a lower dose rather than stop and not go back again?
PG: Yes. That’s what we are also learning, we are all in a learning curve so of course being used to chemotherapy agents we tend to stop drugs and not use it any more when we see especially G3 G4 side effects. With these new drugs instead we learn that even if you have a G3, G4 side effect like diarrhoea can be very dramatic or like pneumonitis for sure you have to stop the drug, manage the adverse event, resolve it and then you definitely can re-challenge the patient, very cautiously and very likely with a lower dose and be ready to stop it again. It’s not like with a chemotherapy agent so you can really stop and go… I don’t want to say too often but really you can try to titre the drug in order to have the patient tolerant to it.
SR: Fascinating time, isn’t it? So Marivi, with myeloma of course there’s the challenge of how you manage patients long-term, whether you’re giving continuous treatment or you’re pulsing treatment. Would you like to comment on that and perhaps the role of alkylators these days?
MM: Concerning the role of continuous therapy or fixed therapy for the management of myeloma patients is a hot topic of debate at the present time in both transplant and non-transplant candidate patients. In young patients after autologous stem cell transplant there are promising results coming from randomised trials conducted with novel agents, so lenalidomide single agent or bortezomib, as continuous therapy after autologous stem cell transplant. The benefit in terms of progression free survival is clear and progression free survival has been duplicated as compared with the placebo arm. The problem is the benefit in overall survival, it’s not so clear as the benefit in terms of progression free survival and in addition now in Europe maintenance therapy is not yet approved to be used outside clinical trials. So probably in the near future we will have to define what is really the patient population who might obtain a significant benefit from continuous therapy because there are some questions unanswered: maintenance for all patients? For how long, until disease progression or just for two years, three years? How are we going to monitor the efficacy of this continuous therapy in patients already in a complete remission? What is the long-term safety profile? What is the compliance? So we need much more trials to really answer what is the role of continuous therapy after autologous stem cell transplant.
Concerning your second question, the role of alkylators in the management of myeloma patients, again this is a hot topic of debate due to the introduction of novel agents because now it is possible to treat myeloma patients with alkylator free regimes. In transplant candidate myeloma patients I think that Antonio Palumbo published recently a paper in New England showing that transplant is better than consolidation with melphalan prednisone plus lenalidomide in young, newly diagnosed myeloma patients. So now transplant after induction with novel agent based combination is a complementary strategy rather than an alternative strategy and we have to continue offering transplant to our young patients. In elderly patients, again due to the introduction of novel combinations such as lenalidomide plus low dose dexamethasone, it’s also possible to treat elderly patients without alkylators. But I think that alkylators have an important role in the treatment also of elderly myeloma patients because MP was considered the backbone to which novel agents were added and now we know that bortezomib plus melphalan plus prednisone resulted in a significantly longer progression free survival and overall survival. So we have to continue using alkylators in the treatment of our myeloma patients.
SR: Sure. Just one question analogous to what you’ve just been discussing, so the great hope for the novel agents was that it would be able to replace the role of the transplant. That’s not the case. Do you think that’s going to happen in the future? Is it that we don’t have the combinations right yet or do you think transplant is always going to have a role?
MM: Yes, in fact in addition to the trial conducted by Antonio Palumbo and recently published, there are other randomised trials that they are currently ongoing to try to evaluate the role of transplant at the beginning, in the up-front setting, or at the moment of relapse. So probably we have to wait to obtain results coming from other trials to well evaluate the role. But now, at the present time, I think that physicians can offer the transplant to the myeloma patients.
AP: I completely agree that at present and probably even for the near future transplant will remain standard in myeloma. What about mantle cell lymphoma? Do we have something new and what is exciting right now?
SR: Mantle cell, I’ve been interested in mantle cell lymphoma for a long time and, a bit like myeloma, a decade or so ago there were no drugs. Now we have all these potential drugs, they’re very exciting. I think the standard treatment for young and elderly patients is relatively straightforward. It’s like in myeloma, your decision is do you autograft or not and high dose Ara-C followed by an autograft is standard of care for young patients. For older patients it’s CHOP or bendamustine with rituximab with maintenance, that’s fairly standard. These patients all relapse though and the first remission is usually your best remission and the challenge has been how you get decent second remissions. So there are a number of drugs that are increasingly being used; Velcade is the first one that’s probably going to come into combinations, maybe even front line, some good data that Velcade in addition to CHOP is better than CHOP or R-CHOP. But then of course we’ve got ibrutinib and ibrutinib is really a game changer in mantle cell lymphoma. 70% of patients respond irrespective of their clinical scenario under which you’re treating them. The really exciting bit is the trials that are just starting now. We’ve got a trial that’s going to start in the UK next year looking at ibrutinib rituximab versus chemotherapy rituximab, so asking the question can you use that drug instead of chemotherapy front line. So similar questions that you’ve been asking in myeloma, using novel drugs instead of conventional treatment. We’re also going to at the European Mantle Cell Lymphoma Group level ask whether adding ibrutinib to high dose Ara-C obviates the need for a transplant. Again, very similar questions to the ones you’ve been asking but now we have a tool that potentially allows us to do that it’s really very exciting.
AP: So the same question to you: will be the transplant still there in the next five to ten years or is probably more…
SR: It’s exactly the same questions you were asking five years ago and I guess maybe what’s a little bit disappointing from the myeloma setting is that it hasn’t taken the place of transplant. So that was a surprise, I guess, for many people. We’ll see. The other really exciting prospect in the lymphoma is the possibility of combining these novel agents, you’re going to see that in CLL as well, not just with antibodies but novel, novel and see whether that transforms care. The trouble is with a rare disease, and I’m talking about a far more rare disease than you are, it’s difficult to do trials with all the drugs and all the potential combinations there are. But it’s a very exciting time.
AP: Certainly. I think even in the near future we are going to change even more because more and more agents are coming so definitely it will be a very exciting next ten years.
SR: Indeed. And with that I think we’ll thank our participants and thank you as well.
AP: Thank you very much.
PG: Thank you.
MM: Thank you.
