17th Congress of EHA, Amsterdam, 14-17 June 2012

The evolving landscape in CML management

Dr Delphine Rea – Saint Louis Hospital, Paris


Dr Rea, we are pleased to get you here to pick your brains again about chronic myeloid leukaemia because this is an entirely exciting area but a frustrating one as well, and you’ve got two agents: dasatinib, nilotinib, to follow imatinib. People are talking about how to get on top of this disease. You are presenting results here from the BMS 034 study that is using dasatinib. Can you tell me what you are doing and first of all which category of patients are the subject of your investigation?

Well this study involves patients who either were intolerant to imatinib and thus could not continue the drug due to adverse events, or who developed sub-optimal responses or resistance to imatinib and who required a treatment change for that reason.

You had a good reason for using another agent then?

An excellent reason.

So what did you do?

So in this study, in fact it is a dose optimisation study of dasatinib because dasatinib had already received approval in this setting when the study started. The initial approval of the drug was at a 70mg twice a day regimen and this study analysed different doses and different regimens in order to optimise the way the drug was given.

So what did you do?

So different doses and doses per day were compared: 100mg per day, 50mg twice a day, 140mg a day and 70mg twice a day. And in fact the main finding is that the 100mg once a day dose is not inferior to the previous dose that was approved which was 70mg twice daily. This led to a new approval of the drug in this patient population at a dose of 100mg per day.

So the 100mg was not inferior?

Not inferior, yes.

But was it superior?

It was a non-inferiority trial so the question was not asked if the dose was better, it was asked if it was not doing badly compared with the previous dose. So in fact the main finding is that the response rate and the survival was comparable to that of the previous regimen whereas the tolerability of the drug was improved because there were less adverse events such as pleural effusion or grade 4 cytopenias.

Right, so let me get this right; you can now give 70mg instead of 100?

No, you can give 100mg once a day instead of 70mg twice a day.

Twice a day, there we are then.

Right, you preserve efficacy but you decrease toxicity.

Right.

So that is very good news for these patients.

Now what sorts of toxicities are we talking about?

Well, the two toxicities that were decreased using a lower dose were mainly pleural effusion and grade 4 cytopenia which of course are a matter of concern because they require drug interruption or dose adjustments and these drug interactions and dose adjustments can impair the response to therapy of course.

Now if 100mg a day was not inferior to 140mg a day, could you go even lower do you think?

This has not been tested in the setting of well controlled studies so I cannot bring a clear answer to that question. Although we know that some patients are doing very well with a lower dose I cannot draw a general conclusion from this isolated experience.

So at the moment what are your recommendations to doctors about using dasatinib when patients are refractory or resistant to imatinib?

Well the current approved dose is the dose of 100mg once a day and it has been so for several years right now. Now what’s new in the presentation is that it provides a six year follow up of the patients who were enrolled in this trial and this is in fact the longest follow up that we currently have in such a category of patients. This is the longest follow up of patients who were treated with a second generation tyrosine kinase inhibitor following imatinib resistance or intolerance.

So you’ve got a firm finding there. Now it has to be asked, what about nilotinib - that’s also under study so clinicians will eventually perhaps choose between the two agents. What do we know about the effects of nilotinib in this similar setting?

Well of course nilotinib is also an important drug in the second line setting and it has been approved. In this setting the dose which is approved is 400mg twice a day, which is different from the dose that we are using now in the front line setting, and the last follow up of the results of this study were presented last year during the last ASH with a four year follow up. Of course this is also a drug which can restore and rescue patients with intolerance or previous imatinib resistance.

So how should clinicians make up their minds, and help patients to make up their minds, about the use of one agent or the other?

What we know is that there are extremely important factors with respect to mutation at base line. When patients develop BCR-ABL mutations that do confer resistance to imatinib, some mutations are more or less sensitive to dasatinib or to nilotinib. In fact there is a spectrum of mutations which confer resistance to nilotinib and some other mutations which confer resistance to dasatinib. So one very important factor to choose between the two drugs is whether a patient has a mutation at base line and what kind of mutation this is.

Does this new knowledge throw any light on how these second generation TKIs might or might not be used earlier on in the disease perhaps in preference to imatinib?

Well, you are aware of the fact that dasatinib and nilotinib of course have been evaluated in the front line setting and these two drugs have been compared to imatinib of course in separate trials, not within only one trial, and what appeared is that the responses were superior; the cytogenetic response rate, the molecular response rate, were superior on second generation tyrosine kinase given front line than that that were obtained with imatinib and these optimal responses were also achieved faster. What we also know is that the use of these drugs in the front line setting decreases the number of patients who progress toward advanced phase or blast crisis, so this is an improvement compared to imatinib alone and now we have the choice between three drugs in the front line setting for CML patients who are newly diagnosed.

But, all things being equal and if costs were not a factor, would you now go for second generation TKIs?

It is clear that we have deeper and faster responses. What is not clear is that despite the fact that these responses are more favourable and that we decrease a little bit the number of patients who progress, there is currently no clear overall survival benefit of using these drugs rather than imatinib but, you know, the overall survival is already extremely high on imatinib so it is going to be very difficult to show a difference and maybe we have to wait and to have a longer follow up in order to fully assess the full benefit of these drugs in front line. But when you have evidence that another drug can give you a higher and better rate of responses then you should go for what’s best.

It seems, though, as if you have got a number of weapons in your armoury now. Does this throw any light on something that came up a short while back about taking a holiday from treatment and very good responders actually stopped taking imatinib, didn’t they?

Right, you are talking about the discontinuation study. Of course the primary goal in CML is first to save the patient and really to prevent the patient to die from CML which means prevent accelerated phase or blast crisis because once this event happens it is very difficult to rescue patients. But now the outcome has become ... you know the life expectancy has almost reached the level of that of the general population so it seems that for most patients this disease has turned into a chronic disease and we have new matter of concerns, new issues, with the lifelong treatment: adherence, chronic and long-term recurrent low grade adverse events. So it is true that now the next step we’d go for a cure, at least would be to go for being able to discontinue the treatment if not a complete cure.

And then of course you need to monitor the progress, the molecular progress, of the disease.

Right.

But you can do that now.

Yes, we have a very powerful tool, I mean the quantitative PCR allowing to quantify the residual disease burden is a tool that we need to use in this setting and standardisation and high quality PCR tests are something very important.

You are sounding increasingly confident but we still, however, have the T315i mutation to worry about don’t we?

Right, this is the gate ketone mutation, this is the one that really prevents the access of the tyrosine kinase inhibitor to the ATP pocket of BCR-ABL so once this mutation is there neither imatinib nor nilotinib or dasatinib can access the pocket and inhibit BCR-ABL. But we are very fortunate because there has been a long programme of drug development and some of them are emerging as very promising and, as an example, ponatinib is a third, let’s call it a third, generation TKI which is really able to overcome this mutation and the preliminary results of the current phase 2 trial which is called PACE, are extremely encouraging for these persons who develop this type of mutation.

So you are really beginning to see chronic myeloid leukaemia as the new diabetes, that you can simply go on treating, so how do you see the future for patients then, dealing with all the different complications they are going to encounter throughout their very long lives?

Right, so one of the points is the next step, one of the next steps; it’s not the only one but we’d go for a cure of course. To come back to the topic that you raised a little bit before, a lot of patients now ask “When am I going to be able to stop the treatment?” and this is really a topic that we are focusing on and a lot of teams all around the world are working and sometimes all together in order to make progress in that field. You may have heard about the European trial which has now started which is called Euro SKI assessing the outcome of patients after discontinuation of either imatinib or dasatinib or nilotinib. This is the first multi-centre academic project on treatment discontinuation, meaning that all different teams with their different experiences are all working together in order to make progress in that field.

So what do you think doctors should be bearing in mind as the one or two really important practical points that are being presented and talked about here in Amsterdam at the EHA meeting?

We have weapons, we now have more weapons for patients who develop specific types of resistance like the T315i and that is excellent news for these few patients but still it is very important to make progress for them. The second topic is that of course in the near future we may aim at being able to offer treatment discontinuation to a larger patient population than we are able to do now but we have to be very careful because this is a very sensitive topic. We should not take any risks for patients and this is still clinical research and the danger is that some discontinuation would be made outside studies, outside well-controlled studies, that may jeopardise patient outcome. So this is still clinical research, this is not a strategy that can be spread widely outside well-controlled studies.

So this is good science that have put it where it is and it needs to stay good science.

Right, exactly.

Delphine, thank you very much for joining us on ecancer television.