Treatment of myelodysplastic syndrome: Expert Roundtable

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Published: 14 Apr 2011
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Prof Aristoteles Giagounidis, Dr Antonio Almeida, Prof Norbert Vey, Prof Antonello Pinto, Prof Valeria Santini, Prof Antonello Pinto
Prof Aristoteles Giagounidis (St. John’s Hospital, Duisburg, Germany),
Dr Antonio Almeida (Portuguese Institute of Oncology, Lisbon), Prof Norbert Vey (Université de la Méditerrannée, Marseilles, France), Prof Antonello Pinto (National Cancer Institute, Naples, Italy) and Prof Valeria Santini (University of Florence, Italy) discuss the optimal way of treating elderly patients with myelodysplastic syndrome (MDS). Hypomethylating agents such as azacytidine have been shown to be the most effective treatment and should be considered for all high risk patients irrespective of age or comorbidities. In addition, azacytidine should be used as first line therapy as efficacy is reduced when it is used after treatment with other drugs. MDS patient response has traditionally been measured using International Working Group (IWG) criteria which encompass a range of clinically pertinent measurements. However with the development of azacytidine these criteria are out of date and should be updated before they can be used effectively. The panel explain some of the reasons why patients may refuse treatment, speak about how drug administration can influence quality of life and consider what the best way is for doctors to monitor disease progression. 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 myelodysplastic syndrome: Expert roundtable

Participants:
AG: Professor Aristoteles Giagounidis (St John’s Hospital, Duisburg, Germany)
AA: Dr Antonio Almeida (Portuguese Institute of Oncology, Lisbon)
NV: Professor Norbert Vey (Université de la Méditerrannée, Marseilles, France)
AP: Professor Antonello Pinto (National Cancer Institute, Naples, Italy)
VS: Professor Valeria Santini (University of Florence, Italy)

AG: I wanted to ask him, going back to the hypomethylating agents where we heard a lot of things. I would like to ask you – give us a picture, the typical picture of the patient that you would treat with hypomethylating agents who presents to your practice with myelodysplastic syndrome. What does this patient look like?

AA: Certainly following the A001 trial data, I propose almost every patient that has high risk and will accept hypomethylating agents for treatment. So I make a conscious effort not to make any restrictions in terms of age, even comorbidities. The only restriction, really, that I end up having is the patient’s own decision. We’ve been talking a lot these days about ageism and how doctors have an ageism factor but I think a lot of patients have that factor as well. I have a few patients, not the majority, but a few patients, who refuse bone marrows because they feel it’s too aggressive and they’re too old for that; a few patients who refuse hypomethylating treatment because they don’t want to come to the hospital to receive the treatment, in Portugal we cannot deliver it at home so that is difficult. But most of my patients are around 60-65, that’s the majority. I must point out I work in a tertiary referral centre, it’s an oncology institute, so I probably have a selection bias of who is sent to me. But they’re 60-65, transfusion dependent and with high risk MDS as per IPSS, which is what I use.

AG: Norbert, can I ask you, from your point of view, if you have a younger patient, say 58, who presents to you with higher risk MDS and he’s eligible for azacytidine treatment, would you start him right away, keeping in mind that you might transplant the patient, or are there some patients where you would say, “Here I go rather for an intensive therapy following with allogeneic stem cell transplantation,” or do you put azacytidine always, even before allogeneic stem cell transplantation?

NV: I fully agree with you. To me there are very patients who are not eligible for azacytidine, when they are high risk MDS, as a front line treatment. Maybe the exceptions are the patients, the youngest patients, who could get a transplant because we have to remind that in the A001 study the response rate for the patient treated intensively was higher than with using conventional AML criteria whether superior to azacytidine, and that the survival difference was difficult to assess in this group due to the small number of patients. So we still think that an AML type treatment for patients less than 60, let’s say, with no comorbidity, with a donor allogeneic transplant is advisable.

AG: Antonello, if I can just follow up on this. We have criteria, IWG criteria, for the response but here with the hypomethylating agents we run into a problem. How are we going to solve this? I see the patients, I treat the patients with hypomethylating agents with intensive therapy and then after three courses IWG doesn’t help me because there’s no response whatsoever. Then, as you showed yourself, after six, eight or even twelve cycles I might get a response. So is IWG dead?

AP: I think that IWG needs to be changed according to the last result of the trial. The basic concepts which were behind the response criteria, I think, still hold based on the clinical trial data. As every dynamic classification or criteria, this needs to be updated based on the result of trials. We now know, as I showed you before, that not only time to first response keeps a lot of time up on treatment with DNA methylase inhibitors but also that the first response is not necessarily the best response. So more than a clinical problem, we have a problem of cost effectiveness of therapy first. The second issue is, and I think it’s very important, that at least according to my everyday experience, one of the most important risk factors for older MDS patients is not the chronological age, it’s not the likelihood to respond to DNA hypomethylators, but it’s the logistics and the family. In other words, still we have to face the idea that gaining one year of survival in a 77 year old patient is not of the same value as that improving survival of the same one year in a younger patient. This is the first issue, so it’s a cultural problem. The second problem is that you have resistance, also sometimes from the family, because the logistics of the current way of administering DNA hypomethylators is complicated. So the family will tell you, “Oh doctor, I had to keep my granny every day for seven days to the outpatient clinic,” and so on. So once we’ve found a way to move treatment home, then I think that the problem of treating very old people with MDS will be solved, or if we find out oral DNA inhibitors of methylase..

AG:  Thank you. Valeria, can I bring you into this discussion by asking you one thing? There were data shown that prior therapy was a prognostic factor for patients treated with azacytidine, so does that mean that it’s better to treat them early with azacytidine or would you say it’s still reasonable to try different treatments and then when nothing works then come in and do azacytidine with them?

VS: No, I don’t think so. The French data are showing quite clearly that if you come with azacytidine after previous therapy, you don’t do so well as when you use it de novo. Then, as I must say, it’s quite evident that the efficacy of azacytidine is higher than low dose RSC or the supportive care or other options. So I do not think we have to postpone treatment. There is only one case in which I cannot answer you because I really don’t know and there is no evidence about it, is when a patient has a bad marrow but very mild cytopenia, we still don’t have evidence whether we have to start immediately or wait for a while. This is something we should study because I think it’s quite important. Maybe we can even slow progression in this patient by starting earlier and I think I wouldn’t doubt in starting. But listening to the data and the thinking of Antonello, this is a question I have for our three experts – how much do you think we assess and how accurate do you think is the assessment of response in real life? So not really thinking of how it should be but how it is, because we see very often that only haematologically improvement is evaluated and not really the bone marrow response.

AG: Norbert, do you do cytogenetic analysis every six months on your patients?

NV: Yes I do.

AG:  You do that? Would you advise everybody to do it?

NV: Yes, because besides the diagnosis of response we also have to keep in mind that some patients could progress under treatment and so we also have to be able to pick up these patients and so find signs of disease progression. So I think that a complete evaluation is necessary.

AG: Antonio, how do you check on your patients who are on hypomethylating agents? Do you do six monthly bone marrows on them or do you discuss this with them? Especially in the very elderly patients, as Antonello just pointed out, it may be difficult to bring them to the hospital all the time and bone marrows may be really difficult in an 80-85 year old, they don’t like it. What is your way of dealing with that?

AA: Yes, they don’t like it at all, especially they don’t like me when I propose it, the relationship becomes difficult. I must say, I naturally have a bone marrow prior to starting therapy and as a hospital policy we have instituted that we do a bone marrow after six cycles whether or not they have a haematological response, to try and assess some sort of response. Most patients will not want one after that unless they have disease progression or they lose response. Once they lose response I do encourage them to have a bone marrow to see what’s happening and to see whether they still have a lot of blasts and maybe there’s no point in trying growth factors. But if they have few blasts then growth factors might actually help in those situations. But I do very much direct in this real life setting, outside of clinical trials, direct my bone marrows in terms of providing some sort of therapeutic guidance rather than just to assess the marrows. I think it is difficult, we cover a large area and quite a few patients come from far away so an extra visit for a bone marrow is particularly burdensome for them and they don’t want it.

AG: Agreed. Valeria, finally one question – is there any point in stopping hypomethylating agent treatment in a patient who is in remission?

VS: Remission? No, we don’t stop. In our centre we go on until progression. As we discussed very long this morning, I think we will have to set some points for that as well because I have patients treated for years and Lew Silverman who has started the first, has patients treated for twelve or thirteen years. But of course this is something that we should really look upon.

AG: In my personal experience many patients come up to me and say, “Do I need to take it every four weeks, can’t I take it every five or six weeks?” Do you do things like that or are you a very strict person, shouting at your patient and saying, “You come back to me every four weeks!”

VS: No, as you know me I’m not a very fierce person!

AG: That’s true.

VS: No, what we usually do as a policy, when a patient has reached a very stable response and we do assess with bone marrow and haematological situation as well, we tend to delay cycles but this happens after one and a half years or one year and we are really sure that the response is stable.

AG: And delaying is six weeks?

VS: Delaying is six, sometimes after a couple of years or three years, eight weeks but this is rather risky, I must tell you, in my experience.