Changing the paradigm in frontline CML therapy

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Published: 21 Feb 2011
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Prof Giuseppe Saglio - University of Turin, Italy; Dr Delphine Rea - Saint Louis Hospital, Paris; Jan Geissler - Co-Founder, CML Advocates Network

The groundbreaking introduction of the tyrosine kinase inhibitor (TKI) imatinib as a treatment for chronic myeloid leukaemia (CML) has been followed by the introduction of further second and third generation TKIs. The panel discuss how TKIs act, the effect they have on patients in terms of their benefit and their toxicity profile, the importance of patients strictly complying with treatment regimens and consider the possibility of a cure for CML.

A number of second and third generation TKIs have emerged in recent clinical trials and the panel explain why there has been such a need to develop numerous drugs to combat CML and consider what factors clinicians and patients should take into account when deciding which treatment to adopt.

This programme is supported by an educational grant from Bristol-Myers Squibb.

52nd ASH Annual Meeting and Exposition , 4—7 December 2010, Orlando

BMS Round Table discussion

Changing the paradigm in frontline CML therapy

Speaker key
CH  Chairman
DE  Dr Delphine Rea (Saint Louis Hospital, Paris)
JA  Jan Geissler (Co-founder, CML Advocates Network)
GS  Professor Giuseppe Saglio (University of Turin)


CH Could I ask all of you, we know about Imatinib and the amazing achievements of this agent.  What is happening at the moment?  Who would like to speak first?



GS I’m starting?


CH Yes, please.  Because, we’ve got Imatinib going well, but there are new tyrosine-kinase inhibitors.



GS Yes, Imatinib was, I would say, a revolutionary drug, because certainly it provided the assumption and the proof that indeed by hitting the BCR-ABL in tyrosine-kinase activity, we were able to cure, or at least to functionally cure CML in most patients, and that this was a great success.  It was also the start of the so-called molecularly targeted therapy, also in other types of cancer and so on.


CH But, now of course, there are some new ones?


GS Yes, absolutely, because of this proof of principle, now we know about better inhibitors of BCR-ABL in tyrosine-kinase activity that can provide even better results, so in terms of the parameters that we are generally using, like CCR, complete cytogenetic remission and molecular remission too.


CH Now, that’s the point of view from Italy.  Delphine, in Paris, you’re using Imatinib and other agents in CML, what can you tell us about the way things might be changing right now, from only using Imatinib to going for other agents?


DE Of course, Imatinib is right now the standard of care for newly diagnosed CML patients, and it has provided patients an unprecedented survival benefit, mainly through the induction of complete cytogenetic responses.  However, we know that some patients do not obtain this optimal response.   Some patients do not tolerate the drug, and need other therapies.  

Second generation TKIs have come into this field, and they have shown that they could rescue patients, and because of their higher potency in terms of BCR-ABL inhibition, it was logical to move to the frontline, to see if we could further improve what Imatinib has already given to patients.


CH You’ve been looking at molecular responses, haven’t you?


DE Yes.  The French group has started a few years ago, a study to ask whether Imatinib was able to cure patients.  I mean, most of the patients do well on Imatinib, but they maintain low levels of BCR-ABL which is detectable, but in some patients, the residual disease becomes undetectable, and because a minority of patients get this kind of response, which is called a complete molecular response, that we have shown that when we have stopped Imatinib in such patients, only half of them have a molecular relapse.  So, half of them are able to go on without any further treatment, and that may be a path to cure.


CH Now, doctors all over the world are thrilled with this ability to really impact CML.  Jan, can you tell us what happened to you, as a patient?


JA Well, when I was diagnosed nine years ago, the therapies were very different, so Imatinib was not yet approved, so the alternative was actually bone marrow transplant, with a very different perspective on, let’s say, outcome, cure and survival.  So, I actually joined a phase II clinical trial at the time, with Imatinib and another drug, to be able to access it, and since then, of course the situation for patients has dramatically changed with Imatinib.

But still, I mean, our interest is in cure in the end, because people shouldn’t take that for all of their life.


CH And, your CML Advocate’s Network, do you have a position on the new TKIs?


JA We don’t have a position, but we follow the developments very closely, because we have a lot of patients in our constituency which are resistant or are intolerant to Imatinib, which is only one fifth of the population of newly diagnosed patients, but still they need to switch.  They’re in a very difficult position, mentally of course, psychologically, and they need decision, they need help in deciding whether they, which drug they switch to, and how they handle side effects. 


CH Well, to give them some of that help, Giuseppe, I’d like to ask you about the Decision Study, because you’ve got some data on one of the TKIs.  What we’re all talking about is frontline therapy.  The second generation TKIs have already been available as second line, but we need to know, don’t we, whether it’s possible to move them into frontline?  What have you found out in Decision?


GS In Decision, what was found out is that when used as first line therapy, a good inhibitor of BCR-ABL and a very important inhibitor of BCR-ABL, like Dasatinib, the dosage of 100 mg once a day was able to increase the rate of complete cytogenetic remission, within one year from the start of the therapy, and also to improve what we call the molecular remission, in particular this threshold of major molecular remission, which is really a target in CML therapy, because when the patients are risking very little to have a further progression of their disease.


CH So, in broad terms, in comparison with Imatinib, how much more effective was it?


GS In terms of cytogenetic remission, more than 10%, but I think that the most striking and important data is related to the rate of progression, which is lower, at approximately half of what you would expect of what we see really with Imatinib, and this is a very important point.


CH And, Delphine, what do you make of this sort of finding?


DE Well, we have expectations.  We already see that there is less primary resistance.  We hope for less secondary resistance, and for improved progression for survival, of course, and these are very important points, but there are other things that we do expect.  Data is not mature enough right now, but regarding the molecular response, it’s not only the rate of major molecular response, which is higher on Dasatinib in this trial, but it may also be the rate of complete molecular response, so the hope for the future is that a complete molecular response state would be offered to more patients than with Imatinib, and that we could maybe offer treatment discontinuations to more patients, but this is really what we need to prove in the future.


CH Of course, we don’t want to run away with the idea that you simply desert one therapy and move onto another.  What is the actual picture of how you use the standard Imatinib, and how you consider using alternatives?  Do we really need these TKIs?  Are they going to make a big difference?


GS I think that certainly we need them.  We need them for the Imatinib intolerant patients, because of course these are the only alternatives that we have, and the other point is that the specific subgroup of patients, certainly they are very useful.  I think the high risk so-called patients, which is a sub category of patients that have a very high rate of progression, and…but for what Delphine said before, I would say the higher rate of complete molecular response.  

I think that indeed, all the patients can in the future benefit over higher potency in inhibiting BCR-ABL because we can expect more complete molecular remission and probably more patients will be able to discontinue the treatment, achieving this goal for quite a long period of time.


CH And, Delphine, what do you make of this?  Of the need for new TKIs to be used first line?


DE Well, for sure, as Professor Saglio said, intolerant patients really need the second generational tyrosine-kinase inhibitors, as well as the patients who don’t show a sufficient therapeutic efficacy under Imatinib and these are two major points, and I completely agree with what Professor Saglio says.  Beyond that, there is maybe a perspective for cure.


CH And, the differential use of either Dasatinib or Nilotinib or indeed, potentially in the future Bosutinib, what kind of thoughts go through your mind when you are deciding?


DE Well, both drugs look highly efficient, compared to Imatinib.  Now, they have different toxicity profiles, so that may depend on the patient’s personal history, the choice between the two drugs.  The way the drugs are given also is different.  Dasatinib is given once daily, and Nilotinib has to be taken twice daily, and patients have to fast when taking the drugs, so this also may be taken into account, because these drugs are going to be given for long period of times, so it has to be convenient for the patients. 

It also has to be convenient for long term observance, which is crucial to maintain an optimum response.


GS I would say that observation of the side effects, which are developing during the treatment are certainly one of the best aspects or the best predictors of how patients, individual patients can tolerate one drug or the other, so I think that they must follow in particular the first part of therapy, and to decide if to continue with one drug or the other drug.  It’s difficult to decide in the first instance between one or the other, because if you even for elderly patients that we have seen this year, indeed patients also with specific problems, like cardiac problems and so on, you may see that in terms of efficacy the results are very good, but also in terms of tolerability, they are still acceptable.


CH And, would Dasatinib in the Decision study, what did you find about safety of this agent?


GS This agent is very safe and it’s also very well tolerated.  I think that there is this problem of the plural effusion, which is a secondary effect that can happen in some patients, and we must follow them for this aspect.  This is generally also, and there is a very important presentation by Charlie Schiffer this year, that shows that there is a relationship between this effect and the link for cytosis that Dasatinib is inducing, and this lymphocytosis probably is however, is something positive also for the response of the patients.  

So, I would say that we have a single coin with two different faces.  On one face, we have the efficacy, and on the other face also some side effects.


CH Jan, I’d like to ask you about your findings so far of what patients think about the availability of new tyrosine-kinase inhibitors and whether they would like to go for, first time around, for one of the new TKIs?


JA I think in general, patients are of course very glad that they have different options to choose from, and every, all the three options seem to be very effective against TML.  Of course, there is some worry with the new first line treatments, that patients think, do I lose another option?  So, do I, if by going directly into second generation, do I lose the opportunity to do well on first line?  And, do I probably get more side effects, than on something which has been in human, let’s say, used in humans for almost ten years?  That’s of course questions that patients ask us.


CH I wanted to ask you about compliance, because that’s an issue, isn’t it?  If you do introduce a new drug, you want to be sure that patients find it easy to take.  Do you have any findings on this?  All three of you?


JA There has been data, or there is data that is presented here at ASH, which again shows that there is a compliance issue in all cancer therapies, especially in the CML drugs, and there is a clear correlation between the response and adherence to the therapies, and I think that’s something that the professional community and the patient community needs to work on very closely, to make sure that patients take the drug they are getting prescribed.


CH Delphine?


DE Yes, adherence is a very complex phenomenon, and it affects all patients with diseases, and long term treatment.  It can be affected by patient characteristics, doctor characteristics, and also the health system environment.  Regarding the patient side, we don’t know right now whether the way of taking the drug is, what is the weight of this factor on compliance, but what’s very important, I think, is to provide patients with information on their disease, on how to take the drug, and on how important it is to maintain the response.  They are partners, it’s not just one way. 


CH If you have a drug like Dasatinib though, is that going to make compliance easier, or will it be more difficult?


DE I cannot answer that question, because there is no study which has addressed that issue, but of course, but once daily dosing is much more convenient than twice daily, for sure.


CH And, Giuseppe, firstly a comment about compliance design?


GS Compliance of course, as Delphine said, is a very, very important issue.  I think that with the more potent TK inhibitors, of course, we have a little bit, a margin of tolerance of lack of compliance, higher with respect to Imatanib in which other with therapy is very, very critical.  

Indeed in a study performed by the Hammersmith Hospital this year, even lack of adherence of 10% respective to the expected dosage of the drug was producing a rather dramatic effect in the possibility of achieving later on a major molecular response.  Therefore, that’s why using a more potent TK inhibitors may be also a little bit advantageous in this time.


CH So, you need a good team relationship with your patient?


GS Absolutely, and then this must be kept in a continuous wave for a long time, because what we are doing now is just dominating, if you want, the CML, but we are not…. functionally curing CML, but of course, only apart from a few exceptions, and what we are hoping for the future, we are not eradicating the disease, so we must continue this surveillance and this monitoring for a long time, in a very strict way.


CH Is there a special problem when you’re dealing with elderly patients though, with comorbidities?


GS Of course, because you know that this drug may interact also with other drugs, so we must pay a lot of attention to drug/drug interaction, and the side effects of course can be a little bit higher in patients which are elderly and may be affecting rather comorbidities and so on, but as these drugs are also life saving drugs, I think that indeed a good compromise can be achieved here.  Those are the patients that can benefit in full of the potency of the TK inhibitors.


CH Can I ask you about your experience so far?  I know you’ve both been working with Dasatinib, so Delphine, with patients, how have you found things so far?  With a new TKI in frontline setting?


DE Well, the reactions are diverse.  Some patients are extremely enthusiastic and really are willing to go directly toward a second generation tyrosine-kinase inhibitor in the frontline.  As you said, some other patients are wondering whether they are not burning…


CH Burning their bridges?


DE Bridges, yes, and right now, we don’t have all of the answers to that.  What we can say is that the rate of responses is so high that there is anyway less primary failure in those second generation tyrosine-kinase inhibitors.


CH And, the efficacy so far?


GS The efficacy seems higher with respect to what we have seen with Imatinib, and I would say certainly the tolerability not lower, therefore putting together the two aspects, I would say that these will become probably in the future the standard pairing for treatment. 


CH Well, could I take advantage of your experience with Dasatinib to ask you both and then Jan also, where you think Dasatinib lies in the treatment spectrum now of CML, for the average patient?  I won’t say the typical patient, they’re not typical.


DE Well, right now, we are still in the second line setting anyway, so intolerant patients, and patients with insufficient therapeutic effect.  That’s what we are now in December 2010.


CH So, as it evolves into frontline setting, are there, is there a clear role?  That’s what I would like to know.


DE Well, as you know, the rate of responses is much higher and less patients are progressing under second generation tyrosine-kinase inhibitor in the frontline, so…


CH So, that’s a cautious green light from you?


DE Yes.


CH And, Giuseppe?


GS Yes, I think that however certainly in subgroups of the patients with the so-called high intermediate, so-called risk group, we must treat them with a stronger and more potent TK inhibitor, and I, although the data probably are not yet completely mature, because of the higher rate of complete molecular remission, I would like also to start these also low risk patients with this type of treatment.


CH And Jan, do you think we have the possibility of a cure?  Let me ask you about Dasatinib?  Where that lies from the patient’s point of view?  Is it disease management or is there a possibility with molecular remissions, to get a cure for this disease?


JA Well, at the moment, I think it is a chronic disease and all three drugs turn it into a chronic disease, so I think we are not there, even though the French study has shown that some percentage of patients can stop therapy in complete remission, but we need to realise those that are achieving complete molecular response are only 10%, about 10% of patients, so it doesn’t, it’s not an option now, for the majority of patients to, let’s say, stop therapy.

I think the choice of drug needs to be taken with the doctor, and it has a lot of factors.  It is not only the, let’s say, results from trials at the moment, but there is also a psychological dimension, because some patients are very worried about their CML, and probably they feel more comfortable in taking something which has proven over ten years, against something which has been in a clinical trial setting for less years.  Some are more worried about the side effects and some say, I don’t mind so much about side effects.  I want maximal effect, and so that might also play a role in the discussion between the doctor and the patient, what is the right therapy.


CH I know there was some suggestion that in certain patients, I think it came from France, you could stop Imatinib and see what happens.  Has that, is that still a possibility?


DE Well, you’re talking about the Stop Imatinib trial.  This is true that in this trial, treatment discontinuation has been proposed to patients, who were in a complete molecular response for at least two years, and of course, these patients are quite rare.  So, what we have shown is that half of the patients can, do not have to take the drug again.  In those patients who have a molecular relapse, because in this trial we are very cautious, we didn’t want any progression, so the molecular, patients had molecular assessments monthly during the first year.

What we have shown is that they can take TKI again and respond again, so we have not shown any risk.  Now, this is true that we need to know, if in the long run, patients who are off Imatinib will maintain that CMR state, but we need a longer follow up.  What we hope is that with second generation tyrosine-kinase inhibitors, we will be able to offer this opportunity to more patients.


CH Clearly, chronic myeloid leukaemia has made enormous advances over the last ten years or so.  How do each of you see things going at the moment, in terms of the typical therapies and what order those treatments will be offered, and perhaps I could start with you again, Giuseppe?  What in a few year’s time, two or three year’s time will be the order of therapies that the patient will get, and how effective will those therapies be?


GS I think that certainly, almost certainly second generation TKI will replace Imatinib as first line therapy, and what I think, that there will be an investigational trial, trying to combine TK inhibitors with other drugs, trying to eradicate the disease in most if not possibly in all the patients, and this is mainly because the prevalence of the disease is becoming higher and higher.  The cost of the drugs is not, I would say, negligible, and therefore altogether this is a great need also for all our system.


CH And, Delphine, how do you see the future shaping up?


DE Well, a lot of efforts are being put on what Professor Saglio said, in the past to cure.  Now that we are able to transform the disease into a chronic disease, the next step is to try to cure patients.  Well, of course, it may…tyrosine-kinase inhibitors alone may not be sufficient. 

The other thing is that still there are a few patients who escape this Imatinib and second generation tyrosine-kinase inhibitors, so let’s not forget these patients.  There are also some new drug developments and third generation drugs for these patients.  Although they represent small numbers of patients right now, we must not forget them.


CH Could I ask both of you, though, the big question about whether you should give Imatinib initially, and let that run its course and then use the second generation TKIs for the average patient, or whether you should go fully to second generation TKIs, for frontline therapy?


GS Personally I prefer the opposite.  I would start maybe with an induction therapy with second generation TKI, just to deplete all the possible resistant clones, then it’s questionable if it’s correct or not to go back to Imatinib.  This has not been proven, but this is a possibility. 

I wouldn’t like to start with Imatinib and then to move to second generation.


DE Yes, during the first and the second year of treatment, it is very important to eradicate the cells which have the potency to transform CML into a more aggressive disease, and that happens at the beginning of the treatment.


CH You need to stay ahead of the mutations as well, maybe?


DE Yes, either mutated cells or cells which acquire secondary cytogenetic abnormalities, and who have the potency to give birth to a more aggressive disease.


CH And, Jan, what do your patients make of all of these exciting developments?


JA I mean, we are very enthusiastic, if I remember how it was ten years ago.  We

are coming back from ASH with a very good feeling that there is a lot of progress, both on the, let’s say, TKI front as well as on combination therapies and on vaccination and on interferon.  I think there is, I am so, it is a rare disease, CML is a rare cancer, and I’m always very happy to see how much research is going on, also besides the mainstream, just to eradicate the disease, so if I have a vision for in ten years from now, I think we can eradicate CML, with all the good research that is going on, and I really hope this all continues.


CH And, if I could get a bottom line message from each of you, Delphine, if you wanted to tell doctors and clinicians, and indeed patients, just one thought that they should be taking home, what would that be at the moment?


DE Well, Imatinib has been a major step in the treatment against CML, but things are still moving, and that’s really encouraging for patients and for haematologists who take care of these patients.  The field is moving very quickly, and we are still making more progress, so that’s the message to take.


GS Yes, exactly the same.  I think that we’ve been brought up to have a conservative view on CML therapy, although we’ve obtained a big success so far, but we have to continue to win the final battle.


CH And, Jan, your take home message?


JA I would say, CML is not a ticked box yet, even though some people may think that it is, it is not and it is not for about 20% of patients, and as long as we haven’t had a solution for all of them, I think we need joint efforts on all fronts to eradicate CML in the end.


CH Well, Jan and Delphine, and Giuseppe, thank you very much for joining me here, in Orlando, for the American Society of Haematology meeting, and being part of ecancer television.


GS Thank you very much.


DE Thank you.