The evolving landscape in the management of CML
Jan Geissler – Co-founder of CML Advocates Network
Professor Giuseppe Saglio – University of Turin, Italy
Dr Delphine Rea – Saint Louis Hospital, France
JG: This is ecancer.tv and we’re reporting from the European Haematology Association Annual Congress 2012 which is in Amsterdam this year. We’re going to talk about the latest advances in chronic myeloid leukaemia therapy and also to understand what that means to current standard therapy and to the evolution of CML therapy. So with me I have two very well-known experts, which is Delphine Rea from the St Louis Hospital in Paris and Professor Saglio from the University of Turin. I’d like to ask first about the current status quo of CML treatment and the status quo on first and second line treatment in CML.
SG: I think that certainly CML is one of the most surprising diseases because in this year we had the beautiful results from the therapy point of view. This is thanks to the introduction of the tyrosine kinase inhibitors and the first drug of this type to use into therapy has been imatinib. That has been followed by other TK inhibitors, more potent and in some cases also more specific than imatinib, so we have the possibility to use several drugs to obtain now and to give the possibility to the patients to have a rather normal life with an overall survival expectation which is matching almost that of a control population without leukaemia. This is already a result which has been almost entirely achieved. Of course now we are becoming more ambitious, what we want to achieve is also the possibility to discontinue the therapy or of an operational cure, as we say. To do this we have to really achieve a very low level of residual leukemic cells and this is our next goal for the future years to pursue.
JG: There’s a lot of discussion about early response to therapy and going under a certain level within the first three months so can you explain what the latest findings on that are?
SG: This is a very interesting finding, I would say that the most interesting part of this congress this year is dedicated to these quite recent findings in several trials all really showing the same concept that just to achieve a very low response we must achieve a very fast response too. So we know that it’s the dynamics at this point which are predicting for the final outcome. It is of course related to what we want to achieve – we want to achieve really an operational cure, we must achieve a very low level already at three months of therapy. Of course, if we do not achieve this goal of therapy we may expect maybe good results but lesser probabilities of undergoing an operational cure.
JG: And does that mean that completely changes the picture of the choice of first line treatment?
SG: This is a difficult question to answer but I think that certainly it is in part true because we are changing our mentality in terms that we are switching, not only because before we were feeling about the survival of the patients, now we really wanted to achieve almost a definitive cure and as we are not totally certain at the moment this will be possible, and Delphine will expand this concept, we like to call it an operational cure which means just maybe remaining such a little amount of residual disease which is not requiring therapy, just to be controlled. This is what we wanted, we know that this is feasible, it’s already achievable in a limited number of patients, we wanted to expand and to understand which other factors are involved in controlling the disease when it achieves such a low level.
JG: Coming back to that topic, you’ve mentioned cessation of therapy and achieving optimal response, I’d like to ask you, Dr Rea, what were the findings around cessation of therapies and what are the learnings this year and what will happen next on that?
DR: What we learned from the imatinib cessation trial, there was one large trial led by the French group and another trial led by the Australian group, is that in some patients we can indeed stop imatinib in that situation but the requirement before stopping imatinib is very high. First we need very deep responses and then we need that these deep responses are maintained for a very prolonged period of time before attempting to stop the therapy. So these higher requirements are not met by many patients. By using second generation tyrosine kinase front line we may broaden the access to these TKI discontinuation attempts. Why? First because we know that the very early responses to these drugs are more favourable than on imatinib, the responses are faster and deeper. What we know from older studies is that the deepest response during the first year, the highest probability to achieve an extremely low residual disease burden. So then in order to be eligible for therapy discontinuation you need a very deep response and that very deep response may be met only if you had a very early favourable response. So, to come back to the early predictor of outcome, there are two points with this three months endpoint. First, it may allow us to discriminate very early who is going to do well and who will need a very early change in therapy, and I’m talking about progression free survival , overall survival. But there also may be a second advantage of having a very early intervention whenever the early response is not favourable, it’s also for the patients to be able in the future to reach a very deep response and to be eventually a candidate for therapy cessation. So what we learned from the very early trials, imatinib cessation, it is feasible but the requirements are high. The patients who are not successful after therapy cessation, so who need to resume therapy because of a reappearance of a high level of BCR-ABL transcripts, are sensitive again to their initial treatment, that is very important for patients to know that this is safe to try in certain conditions, even though some of them may need to resume therapy we didn’t take any risk.
A second lesson from this trial is that we start to know a little bit about predictors of outcome after therapy cessation. We know that the disease characteristic at diagnosis plays a role, the Sokal score; of course we can’t do anything, we can’t change the Sokal score, this is how the disease presents but there is a second factor that we may act on, this is duration of treatment. The longest treatment before cessation, the highest probability of remaining treatment free and we can play on this second factor. There may be other factors also that play a role but this is the field of results right now, as an example host factor of the immune system, we don’t know very much about that. So right now there is a trial which will allow, and this is a European trial which is called Euro SKI which has just started and it’s a European international multi-centre study, and it will allow to enlarge our experience about therapy discontinuation and also to broaden the access to discontinuation for patients. So this will allow for patients treated either with imatinib or dasatinib or nilotinib who had a favourable response, of course, on treatment, who were treated for at least three years with very deep responses sustained for at least one year, to attempt treatment discontinuation within the setting of this very well controlled trial. So the good news is that we learned from very early trials and we are able now to build a European multi-centre study so the experience with TKI discontinuation, which was at the beginning very concentrated to some centres or some countries, is broadening now, the experience is going to be broadened and the access is going to improve.
JG: This is very interesting, I mean there have been a lot of reports about these studies that you’ve done in France about the cessation trials which also has probably led to the opinion in some that they could individually stop therapies in patients that have been in negative PCR for many years. So I would be interested in your opinion about that.
DR: Yes, we were very enthusiastic about the very first results that we have but we have to be very careful and the danger, of course, is that there may be some treatment cessation outside very well controlled studies or in patients who do not have access to the monitoring tools that we have. In order to be able to discontinue safely in the study there are several requirements: first a very deep and long-lasting molecular response which means that these patients need to have access to an excellent RQ-PCR test. These tests are not widely world-wide available yet so what may be considered as undetectable may not always be really undetectable if the test that has been used is not of high quality. So first we need to make sure that there is an access to a very high quality RQ-PCR test. Second, after treatment cessation there is a risk and the requirements in the cessation studies is that there is a monthly monitoring after treatment cessation, at least during the first year because we know that most molecular relapses occur very early on. So these are requirements. The patients who are doing very well finally are coming more often to the hospital when they enter these studies than they used to do before. So the danger is that there would be indeed some patients who would stop on their own or who belong to centres who unfortunately do not have access to these high quality PCR tools and that may jeopardise patient outcome. And that’s the danger of these very exciting strategies is that they should not be spread without a very well controlled environment.
JG: So your recommendation is that everybody who wants to stop treatment should do that within studies like Euro SKI?
DR: First they should ask, patients and also doctors, they should ask whether do I fulfil all criteria to try to discontinue? This is the first question, this may not be always the case. Do I fulfil these requirements? And if yes, yes, it’s better to do it in a well-controlled study such as Euro SKI than outside in a non-controlled environment. This is important for the knowledge we get from this study but also for the safety of the patients.