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

Management of elderly lymphoma patients: Expert Roundtable

Participants:
PLZ: Professor Pier Luigi Zinzani (University of Bologna, Italy)
UV: Professor Umberto Vitolo (University of San Giovanni Battista Hospital, Turin)
BC: Professor Bertrand Coiffier (Hospices Civils de Lyon, France)
MC: Professor Miguel Canales (University Hospital La Paz, Madrid, Spain)
MR: Professor Mathias Rummel (Klinikum der Justus – Liebig-Universität, Giessen, Germany)

PLZ: If there are some questions or comments from the audience first to start with the discussion panel. Yes, please?

Q: I’m Reinhardt Stauder, from Austria. I have a question for Professor Vitolo. It was an excellent presentation and you have shown that, in the study by the Italian group published in Cancer, the parameters of the assessment are predictive factors. So those patients who have bad assessments or have adverse outcome, even if you treat them with R-CHOP. So which are your conclusions, have you started now to integrate those courses into your daily practice? Are you integrating them into your clinical studies?

UV: Thanks for the question. I think that this trial clearly showed that if you classify the patient according to the geriatric scale, you better define the treatment that you can give to this patient. The elderly patient, regardless of the age, even in patients more than 75 or 80, if they are fit enough they can still be treated with Rituximab CHOP standard chemotherapy and they have a very good outcome. So we started to use these parameters in the standard practice, it’s not difficult because it doesn’t take a lot of time just to do some questions with the patient. On the other hand, you can identify unfit or frail patients that it should be a waste of time, not also for us but for the patient, just to start with intensive treatment because the prognosis of this patient with standard intensive treatment is not as good as we would like to do.

BC: Thank you. I think that we have covered diffuse large B-cell lymphoma and we looked at another lymphoma that is frequent in elderly patients, follicular lymphoma. The problem may not be the same for patients with follicular lymphoma so what is your opinion on how to treat patients with follicular lymphoma aged 75?

MC: OK this is a frequent population of patients and it’s important to differentiate those patients who have a symptomatic diagnosis because in these patients the watch and wait strategies are a core strategy. But in symptomatic patients, according to the ideal criteria for example, the resist, the comorbidity, the use of escalation in these patients is sometimes complicated. Actually I treat these patients with CBP in combination with Rituximab but I think these patients can benefit, for example, from Bendamustine in combination with Rituximab, it’s a very adaptive regimen and Dr Rummel has a lot of experience with this scheme. If the patients have a limited stage, I think that radiotherapy is the standard treatment instead.

PLZ:  Mathias?

MR:  So I would consider the elderly patients for a watch and wait period until they have symptoms, despite the presented extract at ASH from the English Lymphoma Group where they treated right away with Rituximab and compared it with watch and wait. This was a very, very meaningful study, however, it is by far too short in the observation period before you can draw some final conclusions. In the other trial presented by the same author at ASH he randomised Chlorambucil against watch and wait and he waited fifteen years before he could present mature results. So at the moment, now, I’m still thinking and I’m convinced that the watch and wait period in asymptomatic patients is absolutely the good one and if patients are in need of treatment with a follicular or indolent lymphoma, I treat them with Bendamustine Rituximab. I don’t see any reason for a more aggressive way, like CHOP with Rituximab and because in our trial Bendamustine-Rituximab was superior even to CHOP with Rituximab, we will not consider something like CBP or Chlorambucil. So all patients in Germany and in my study group are treated with Bendamustine-Rituximab for follicular lymphoma.

PLZ: Umberto?

UV: I certainly agree with Matthias and Dr Canales that first of all we have to decide if the patient needs to be treated or not. Mainly in the elderly I am aware of the data that was presented at ASH but I agree with Matthias that in asymptomatic patients probably still so far it’s better to wait until the disease progresses or there are some symptoms because the data for the Rituximab single agent that were presented have an advantage in time to second treatment but I’m not sure that it can translate into a real advantage for the patient, so at least we have to wait. In symptomatic patients, there are a lot of symptomatic follicular lymphoma patients, I think we usually give a brief amount of chemotherapy, that means three or four courses of chemo with the standard doses of Rituximab, I mean eight doses. We just closed two years ago, and the final analysis we’ll do in the next months, a trial in elderly follicular lymphoma patients in which we gave four courses of Fludarabine intervention and Dextamethasone plus eight doses of Rituximab. The patients were randomised to receive a brief course of Rituximab maintenance or not and the treatment was very well manageable; the CR was 72% that was serious and the progression free survival is good. So of course we can’t use the Bendamustine in first line but now probably Fludarabine and Dexamethasone can maybe be substituted by Bendamustine. But just to stress, I will give just a brief course of chemo, just to reduce the bulk of the disease and then treat the patient with monoclonal antibodies, with Rituximab.

PLZ: Are there some questions from the audience concerning the follicular issue? If not, I have a question for the panel concerning the relapse of elderly follicular patients. What is your daily practice in this particular subset of patients? Miguel?

MC: This is an important question because these are usual, the usual patients unfortunately. In these patients it’s very important, the symptoms at the time of the relapse because the relapse is not always the criteria for the treatment. So in the elderly I have to manage these patients with watch and wait, until  the patients are symptomatic of the relapse. But if the patient needs treatment, I think the novel agents have a role in these patients, obviously Rituximab, Zevalin are an option in these patients. But I think the new drugs – Bendamustine, Lenalidomide can play a role in this setting.

PLZ: Matthias?

MR: So if a patient relapses with a follicular lymphoma, again not everybody needs to be treated immediately. So we wait, again as in front line, until the patient becomes symptomatic and then, if we need treatment, in Germany at least we consider if the patient would be eligible for a treatment with Zevalin, this would be in a small tumour size in a symptomatic patient without a high degree of bone marrow infiltration. When we cannot use Zevalin we also consider again Rituximab containing chemotherapy; you can easily re-treat the patient with Bendamustine because Bendamustine does not have a cumulative organ toxicity to the kidneys, liver or heart so if the response duration was long enough you could, of course, consider the same treatment again. Of course Rituximab maintenance is a very important issue in the relapsed patients once you have achieved the response.

PLZ: Excuse me, the treatment with Bendamustine, it is dependent on the timing from the first treatment with Benda? In terms of response?

MR: Yes, of course. We don’t have the data for that but this is according to our clinical experience. If the patient only responded for six months, it would make no sense to re-treat him; if he has responded for two years then patients very often ask again for the same treatment because they tolerated it very well.

PLZ: Thank you. Umberto?

UV: Well I think the common practice in Italy now is that when the follicular lymphoma patient relapses, probably the most popular drug is Bendamustine plus Rituximab in the last couple of years. There are different options because it depends on the disease – if the disease is extended into the bulk or not or if the bone marrow is involved or not. In my experience radium monotherapy in the elderly is very well tolerated and they produce a higher response rate, a curable response, but I know that radium monotherapy is not very popular in Italy, only myself and Pier Luigi continue to use it, but I think it’s a very nice drug for follicular lymphoma. So in elderly patients that relapse with follicular lymphoma, we may have some room to treat these patients without chemotherapy because there are some interesting data from different associations – Rituximab plus Lenalidomide, Rituximab plus Bortezomib again, that may have effective efficacy in these patients. So if the patient may have some contra-indication to chemotherapy you may treat the patient without chemotherapy. The second point that Matthias mentioned, Rituximab maintenance for relapse, of course everybody of us uses Rituximab maintenance for relapse but we have to think that from now on Rituximab is approved in the maintenance of the first line according to the PRIMA studies. I don’t know, when we treat our patient with Rituximab chemo, Rituximab maintenance in first line, when they relapse we retreat it with Rituximab chemo, if the Rituximab maintenance in relapse will have some efficacy or not because these patients are exposed to more  Rituximab. So the issue of the maintenance and relapse will be re-discussed after the PRIMA study.

MC: This is important and you see the result of the two interrupted question, the inclusion of patients in clinical trials because there are many interesting drugs in clinical trials. But I think the population where clinical trials all must make an effort to include patients in these situations.

PLZ: Again it is so difficult, this particular issue of patients. Bertrand?

BC: The last question: when are you moving to a palliative treatment in patients over 70? Is it a question of line of treatment or response to previous line? What do you do in clinical day to day practice?

MC: The palliative treatment in this?

BC: Yes.

MC: Usually it’s in patients without any option of treatment. In my practice it’s very common to use, for example, a low dose of cyclophosphamide for these patients without any options; a low dose of corticosteroids in the same patients. I try to avoid the symptoms in these patients, if the patient is asymptomatic, no treatment, not at all, but if patients have symptoms I use a low dose of cyclophosphamide or corticosteroids.

PLZ: Matthias?

MR: So you mean in aggressive lymphomas if they have relapse?

PLZ: What were the types of treatment?

BC: The question is more when than what type of treatment.

PLZ:  And we are not oncologists but haematologists.

MR: So when a patient really becomes not responsive to the previous chemotherapy, I would not consider him to re-treat again because then an older patient will have at least the toxicity but probably no efficacy. In such a treatment I also give alkylating agents like trofosfamide which is an orally available compound; I treat many patients with that. Also we treat them sometimes with a smaller dose of Bendamustine single agent, it can be given with 50mg or 70mg/m2, also we saw some responses but again in the palliative situation we consider steroid treatment in some circumstances.

PLZ: Umberto?

UV: I think it depends on histology because for indolent or follicular lymphoma before going to the palliative treatment we have to consider if this patient may be treated with very gentle approaches, as I said before, even in second and third relapse they may be treated without chemo with Rituximab as single agent or association Rituximab plus Velcade or maybe other drugs as they may respond, even at the second or third relapse. In aggressive lymphoma I would usually treat the patient; at the first relapse I would try to treat them but if the patient is an elderly patient, that is progressive after Rituximab CHOP in a brief time, a couple of months after the end of R-CHOP, probably there is no chance for this patient. So I think this is a candidate for palliative treatment or a second relapse in aggressive lymphoma. We usually use PP16 perhaps or in mantle cell maybe RSC, that is a good drug for mantle cell subcutaneously; in low doses alkylating agents, usually not intravenously but perhaps just to leave the patient out of the hospital.

PLZ: OK. Oh, there is a question. Fantastic.

Q: . It’s a question to Dr Matthias Rummel about the substitution of doxorubicin  by liposomal Doxorubicin in elderly patients with aggressive lymphoma. What is your opinion?

MR: The Austrian study group has investigated that in detail and they presented promising results for substituting them with liposome Doxorubicin, which was in that study the Myocet. And the problem is really to identify with good diagnostic procedures who cannot tolerate the Doxorubicin and this question has not been solved so far. Of course in Germany we would have a lot of reimbursement problems if we would use Myocet instead of Doxorubicin but it’s an attractive alternative. However, also if you think about it you can have a longer infusion time of Doxorubicin if the patient has a central venous catheter, you could give it over 12 or 24 hours and then again you have a much lower cardiotoxicity, so there are some possibilities to decrease the cardiotoxic risk.