Treatment of elderly or unfit CLL patients: Expert Roundtable

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Published: 14 Apr 2011
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Prof Michael Hallek, Dr Francesc Bosch, Prof Peter Hillmen, Prof Clemens-Martin Wendtner, Prof Robin Foà
Prof Michael Hallek (University of Cologne, Germany), Dr Francesc Bosch (Hospital Vall d'Hebron, Barcelona, Spain), Prof Peter Hillmen (St James's University Hospital, Leeds, UK), Prof Clemens-Martin Wendtner (University of Cologne, Germany) and
Prof Robin Foà (Sapienza University of Rome, Italy) discuss the implications of recent advances in the treatment of elderly or unfit patients with chronic lymphocytic leukaemia (CLL). Rituximab has been shown to improve outcome but it is not yet fully understood how this should be combined with other drugs to achieve optimal results. Rituximab could potentially be used with lenalidomide, a drug which is proving to be highly active and well tolerated in the elderly. The panel outline the approach for deciding upon the optimal dose of chlorambucil, talk about ways to modify drug combinations to make them more suitable for the elderly, speculate about the role of TKIs and antibodies in the future treatment of CLL patients with comorbidities and discuss the reasons behind the lack of older patients in clinical trials. The discussion took place at the Blood Cancer in the Elderly European Expert Forum, Rome, 19-20th March 2011.

Blood Cancer in the Elderly: European Expert Forum, Rome, 19—20 March 2011

Treatment of elderly or unfit CLL patients: Expert roundtable

Participants:
MH: Professor Michael Hallek (University of Cologne, Germany)
FB: Dr Francesc Bosch (Hospital Vall d'Hebron, Barcelona, Spain)
PH: Professor Peter Hillmen (St James's University Hospital, Leeds, UK)
CMW: Professor Clemens-Martin Wendtner (University of Cologne, Germany)
RF: Professor Robin Foà (Sapienza University of Rome, Italy)

MH: We have a couple of minutes for questions and discussion and I wish to take on the discussion from what we heard in your question and answer session. However, most of the questions that we have seen were unanimously answered. There’s a strong feeling that Rituximab is basically improving the outcome in the first question, so there shouldn’t be much of a debate. I think the principle question is how can we combine this now best, and I think Peter and Clemens have addressed this. Maybe I’ll ask Francesc about his opinion, what would be your favourite comparative or combination partner for Rituximab in elderly or unfit patients?

FB: That’s a difficult question because all the trials are on-going now to define the best treatments for those patients. We have to take into account that we are still lacking a tool to define a specific comorbidity for CLL patients so CLL is different from other diseases, patients are really immunosuppressed, renal function is particularly important for Fludarabine, so we are still lacking a specific tool for this kind of disease. So when we have this tool, we will be in better shape to define the best treatment for those patients. On the other hand, we have interesting drugs – Lenalidomide is an important drug for patients and MD Anderson is running a couple of clinical trials in elderly patients proving that it’s an active drug, well tolerated, that it’s not only active in CLL in the elderly but it’s even increasing immunoglobulin levels in more than half of the patients, so it’s an interesting drug for those patients. So we have to define a better combination for those patients.

MH: I have one challenging question to Peter Hillmen because he was saying we should use Chlorambucil properly in elderly or unfit patients. Well, for the sake of a good discussion I would say I strongly disagree because in our trial we used the smallest, the lowest dose of Chlorambucil and yet it was not inferior to Fludarabine. So in unfit elderly patients, achieving a CR or having an efficacious treatment doesn’t really matter, the only thing you wish to achieve is symptom control. What would you answer to that? Because you said several times that we need to give it right, you need to do it at a high dose and I say no, it doesn’t really matter, what would you answer?

PH: It’s interesting you don’t think we should use Chlorambucil properly.

MH: Yes, that’s a good answer. What would that be?

PH: I think the evidence we have in all the CLL trials, and most of them are predominantly with younger patients but we have some emerging evidence in older patients, is that better responses lead to better remissions. Particularly in the elderly and certainly in the data from collating the younger patients, your best chance of getting a durable remission is in the first approach of treating a patient. By treating patients and getting low responses you induce a P53 dysfunction, and potentially resistance to subsequent therapies.The data we see from our CLL4, 30% of the patients were over 70 and the issue was salvage therapy, that you can’t salvage the elderly patients as well as you can salvage the younger patients. So if you use inferior treatment in terms of response rate, then you’ve got a bigger problem, a quicker  problem, trying to salvage patients. So if you’re using lower doses or lower duration of therapy you’ll have a bigger problem earlier in trying to salvage.

MH: And I have to say, I do agree and because what we have seen from our data is, Clemens has shown this, most of these patients even with comorbidity die of CLL and not of related diseases, so I agree with you. Now a question to Clemens Wendtner on the last part – there was a unanimous vote, at least in Europe, for Chlorambucil being the favourite and maybe influenced by the presentations already, and there are still 10% others. After the last ASH meeting one could say there are plenty of new drugs coming, some of them with very, very mild toxicity or even non existent toxicity – kinase inhibitors. How would you speculate on treating CLL patients with comorbidity in ten or five years from now? What’s your favourite for the future? Still Chlorambucil or do you think there are new things to come?

CMW: I think all of us would wish that we could skip the cytotoxic component of our treatments and, in line with this, we’re now in the phase I investigations with these new drugs, with these tyrosine kinase inhibitors; we think ten years ago we didn’t even think about tyrosine kinase inhibitors in CLL, this was just in CML. Now CAL-101 and also these related  tyrosine kinase inhibitors, very interesting drugs, and my vision, in answer to your question, would be to combine these cancer inhibitors with an antibody, for example. Then the question comes into play, what is the right sequence? We know from these new drugs that patients get a hyperleukocytosis when we treat them so even the old-fashioned response criteria do not assess correctly the responses so they are underestimated with CAL-101, for example, because you get the hyperleukocytosis at the beginning. So the future vision might be first use these TKIs followed by an antibody, most probably a CB20 antibody.

MH: Kinase inhibitors. Any comment from other persons, like Robin?

RF: Can I try to tie together everything because I made some notes while we saw the comments through the keypad and the comments that came up here. If we tie everything together and start from the first question, the large majority agreed that Rituximab should be added to first line treatment. However, as I mentioned, in the statement the word elderly wasn’t included. So then I would assume that people thinking, as we would all agree, that for the young people that is the combination. But the issue, therefore, is the elderly and if we go back to the CLL8 trial, Clemens you showed that the elderly fit can be included. But if you quantify that, it’s 10% of the patients that in fact, from your study, went into the trial. So that means that based on a physician’s judgement, the large majority of the over-70s were not deemed fit enough to enter the protocol because of toxicity with the FC, as we know. So I think that is the second important point – 90% of patients were not considered eligible. Then if we go to the final question we read that in Europe and also colleagues from, let’s say, closely neighbouring countries, Chlorambucil still comes up as the largest utilised drug for the elderly. Putting that together with the fact that we learnt that 75% of patients over the age of 70 don’t go into the trial, it is clear that in the context of the congress here the issue of the elderly with CLL, which are the large majority, let’s say that that is really the clinical unmet need. So I think this we would probably all agree, that that is where we have to strengthen our clinical research. That would also tie with what they are commenting now, do we need for all these patients to have chemotherapy? If we started to include maybe some prognostic markers even in the elderly, we could one day maybe identify sub-groups who could benefit either with new drugs or maybe only with antibodies, I don’t know, I’m just putting this as a potential question.

MH: I would like to, actually also for getting a good discussion, again challenge one of your statements and maybe go to one of the results we had or I can actually mention it – 75% of you have never included a more than 70 year old patient into a clinical trial, so the majority,  and the other problem, or the same problem from this one here. You can also rephrase it by saying usually we are not accustomed, we are not used, to include patients of more than 70 years into clinical trials. Because the thing I want to challenge, the 70 year old patient has a 40% or 50% chance, if not more, and Dr Balducci’s data early on showed this, to be physically fit while we only have 10% of these patients in our trial for selection criteria bias of physicians and all these things. It is not true that a 70 year old patient usually is not fit enough, there are numbers showing that the actual fraction in this 70 year old group is about 40-50%. We simply do not include these patients in clinical trials because we are not used to it and I think we have to change the habits and improve. So my question would then be, maybe Peter you want to comment and you wanted to say something anyway, how can we improve the recruitment and the performance of clinical trials in the elderly in Europe? What’s your recommendation or idea about that? I think you wish to comment afterwards.

PH: I have to say that we have not had trials with the elderly group until very recently and so it helps having trials that we can actually recruit patients into. And then having acceptable treatments that in our previous trials you could only select the fit patients because one of the arms was very intense and you couldn’t risk them being randomised to those trials. I would take slight issue  with Robin’s assessment of FCR and we don’t have a problem with younger patients. FCR is the best treatment at the moment but three-quarters of the patients get through six cycles, a quarter don’t. We’re starting to see early relapses and we have real problems dealing with those; we’re starting to see malignant transformation with  more intense therapies. And so the new therapies that Clemens points out, which I think are very exciting developments in CLL, have the advantage that they’re targeted so they have less of the off-target effects that we’re talking about, both for the younger and the older patients. My experience of the elderly trials that we’ve done is that patients don’t necessarily want to have three days intravenous infusion over a month when the alternative is an oral therapy. So the oral therapies are a distinct advantage, particularly in the older age group patients.

Q: Thank you. I just wanted to comment on something that Dr Hallek said before and I think is very important in the perspective of geriatric oncology. You mentioned that unless you treat the CLL right since the beginning with what you consider appropriate doses of Chlorambucil, you may be dealing later with a disease which is much more difficult to treat. That, I think, is something that we have forgotten in the discussion of geriatric oncology, in other words cancer, all types of cancer, are dynamic entities that change as a result of our therapy or maybe also on their own. An example that I was going to bring but, because of time, I could not bring is the example of prostate cancer. We used to think that in men of 75 or 80 should not be treated for prostate cancer because they are not going to die of prostate cancer. That is true if those men are going to die at age 85 or 86 of some other disease but if those men live to be 90 or older, many of them developed a Gleason 9 prostate cancer which is rapidly killing; we have just got the report on the last JCO about that. I think that that may be the case in haematological malignancies with CLL or with low grade lymphomas. So I’m not ready to say that we should treat all of these patients aggressively because people can live longer, I just want to say a word of warning that if people’s life expectancy keeps increasing, as it seems to be, we may be dealing with very aggressive diseases when we thought that we were dealing with very benign diseases. Thanks for the opportunity.

MH: Thank you. Now we have a couple more minutes and if somebody wants to address an important point please go to the microphone and ask your question. Identify yourself. Yes please?

Q: Marco Gobi, Genoa. When you speak or compare Chlorambucil and FCR, you consider always the CLL8 schedule of FCR but in an elderly patient you can also use low dose Fludarabine, an oral Fludarabine dose together with Cyclophosphamide. So you can obtain better results than with Clorambucil using a lower dose of Fludarabine and Cyclo.

MH: I would agree and I’ll also let Francesc comment on this aspect later. The only point I wish to address is there is no real formal data on that but in principle you’re right, there is a regimen published by Ken Foon in the JCO and some others trying the same. However, the average of age, again the problem that we are discussing, the average age in this trial with an FCR-light regimen with a lower dose of FC, as you suggest, is 60 years. In other words, I’m just saying the clinical research that we are doing in CLL is sometimes totally useless for the real patient population because they have comorbidity and they are older than 60 years again. But I think your idea is well taken and that’s what we think as well, to modify the existing standards to make them better tolerable for elderly or less fit patients. Francesc?

FB: Yes, I have nothing to say, nothing to add because we don’t have real true data on this trial. It was a phase II trial with 100% responses so we have to check this combination in real elderly patients. We know that if you add more therapy, for instance in the CLL8, when you analyse the MLD at four cycles and you compare MLD at six cycles, if you have more treatment you are getting better responses but we don’t know exactly the response rate in elderly patients.

MH: If you have no more questions, what I would like to suggest is to give us the chance. We have five more minutes to go, approximately, to give the discussants the chance of having a final statement, including to comment on everything they want except on non-CLL topics. So maybe Clemens you want to start, then Francesc until we go just the way back.

CMW: Just before the final statement, to the person asking the question before. It’s true that the mean number of cycles in the FCR trial in the elderly, this was significantly less so these figures show, but this was the reason why I pointed also out the Australian trial. This is an on-going effort to define maybe a dosing regime for, I would call it, the not so fit but they are not unfit, they are not so fit patients; somewhere in-between an unfit and a fit one. Otherwise I would say, for myself, the main take-home message is that you should always assess in some way, whether it’s geriatric assessment scoring or something else, you should assess comorbidity. Do not judge on passport age, we have heard this morning. Then if you think it’s an unfit patient, you should try to define a clinical trial, is another message from the session, that you should really seek for clinical trials. There are trials around, not only by the German and UK groups, then you might also help the best your elderly patient.

FB: Yes, my final statement is that we have to learn and that we have to extend our active treatments to elderly patients’ biological minimum age. We heard a lot during the session on that topic so I think to extend geriatric assessment  to elderly patients and use comorbidity scales and recruit patients into clinical trials. I think it’s important to answer the questions we are raising in this session.

PH: To address the question of oral FC, we’ve used oral FC in CLL4, which was without the Rituximab and in our subsequent front line trials for the fit patients we’ve used oral FC and we’ve dose reduced patients. Because creatinine clearance is a key part of the elderly assessment of CLL and a lot of the patients can’t have FCR for that reason we’ve dose reduced. We’ve allowed patients to have FCR down to 30ml/minute creatinine clearance but dose reduced between 30 and 60 to 50% for the Fludarabine. That seems to be a safe and effective way to treat those patients. The other issue is that we’re now starting to assess patients’ biological criteria. 17p deletions are clearly not chemotherapy sensitive and I think over the next few years we’ll be doing more and more splitting of patients into more and more specific therapies. We mustn’t forget the elderly in that assessment of biological markers to direct therapy.

RF: If I may just take, again, privilege to tie up a couple of things and then Michael will conclude. I think what we’ve been enjoying  since the Congress here is on the elderly, the fact that there is a change in drug development in CLL as in myeloma. We heard that this morning, in fact most protocols have been designed as a matter of fact for younger patients and occasionally maybe for fit elderly, but very few have been designed for the real elderly which are the majority for certain conditions. Only now we’ve gone into this issue and we’re discussing and we’ve started to design. So this has been a problem and I think this has to change. In this respect it’s obvious that the definition of performance status should be included, it’s not only defining age as it came up in all ways this morning, but we have to be much more precise to manage to include more of the elderly in protocols. So that, I think, is an important point. And then in the elderly, the issue of compliance came out this morning and this is very important because the elderly might be lonely – who is going to take them to the clinic, these very practical issues which are going to increase because the aging population is increasing. So the issue of oral drugs is important, clearly. I would like to add that Rituximab has been developed in a sub-cutaneous formulation so that is another possibility because if we could get oral drugs in sub-cue that could, in the long run, make life easier certainly for patients but for us too. Rituximab has to be given  in the clinic and we obviously have problems with beds. So that, I think, in a way ties up. My final point, and then I’ll give back to Michael, which came to my mind, I had it in mind earlier and then it came back to my mind when Clemens mentioned tyrosine kinase inhibitors, I’ll tell it to Gordon who is right in front of me, we don’t have ALL in the programme. Now I’m saying this because I don’t know if Jani Pietzole is in the room, but just to remind everybody that in the era of molecular biology and subdivision of patients, the Philadelphia positive ALL was the worst condition that we could ever diagnose, I would say not only in haematology but in cancer and maybe in medicine. Now with tyrosine kinase inhibitors we can put patients with Philadelphia positive ALL in remission even in their 70s, 80s and even 90 year olds. Jani Pietzole in Verona, and we discussed it many times, had a patient who was 89 with ALL.Luckily he was tested for the Philadelphia chromosome because in the regional network this is done. Then since he was luckily positive he was put on Imatinib and went into remission. He turned 90 driving a car and conducting a very good life. We have films of him, pictures, we don’t have time here. He was put on second generation inhibitor, went into second remissionwhen he turned 91, then he died 2½ years later. Now this is one case but it’s not the only one and I would like to add that all patients go into remission with tyrosine kinase inhibitors, irrespective of age. I would like to add one final point, which is that over 50% of the over 60s with ALL have the Philadelphia chromosome. So this is extremely important that we test them and we treat them even without chemo. So there’s something for the next meeting, Gordon, I think you might consider that. So I say that and I give it back for the final conclusion to Michael.

MH: I wanted to thank you all, but I have to make a few very, very concise remarks. I think we have to solve this entire field and at this meeting, hopefully, there will be some recipes for that. If you talk about kinase inhibitors in 90 year and older patients, the expense and the cost issue will be a topic and that needs to be discussed. Another point that I really am concerned about is the standardisation of the assessment. If we do clinical trials and if we do the assessment, we need to have a consensus, some kind of an agreement, how to assess them with a minimal set of data because a real comprehensive geriatric assessment is something that really requires physician time or caregivers’  time and we never will be able to assess them as systematically as in a geriatric unit. So there need to be some guidelines for that otherwise we will have all kinds of totally different assessments and we will never be able to compare different trials and results  even in CLL, in one disease, and I’m not talking about different diseases. So these were the concerns I have for the future. With this, I thank the speakers, the discussants and the organisers for giving me the opportunity to chair this meeting. Thank you very much.