Dasatinib vs. imatinib first-line in CML; new study data

Share :
Published: 4 Jul 2012
Views: 4559
Prof Giuseppe Saglio - University of Turin, Italy

Professor Giuseppe Saglio from the University of Turin, Italy, talks to ecancer TV about the results of the three year follow-up of the phase III DASISION trial comparing the second generation TKI, dasatinib, vs. imatinib in patients with newly diagnosed CML.  These data show the continued superiority of dasatinib vs. imatinib in terms of producing a deep, higher and complete molecular response.  Also, the reduced events with dasatinib vs. imatinib.


Professor Saglio comments on the place of the TKIs, how they might now be used in clinical practice and how clinicians may select one over another depending on the goal of treatment, co-morbidities and toxicity profiles.  Also, the importance of mutational changes in treatment choice, and the future role of third generation TKIs.


With functional cure now a real possibility in selected CML patients, Professor Saglio discusses some of the challenges in, and possibilities of, achieving this.  With new therapies, the personalised approach to treatment is now increasingly important in CML.


This programme was made possible with sponsorship from Bristol-Myers Squibb.

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

Dasatinib vs. imatinib first-line in CML; new study data

Professor Giuseppe Saglio – University of Turin, Italy

ecancer television now hears from Giuseppe Saglio. Giuseppe, you’re hot from news about the DASISION Study; you have been presenting here, you’ve got the latest data, this is on a second generation TKI in chronic myeloid leukaemia and, importantly, first line. What are your data?

The data of the DASISION are really important because they are comparing the traditional treatment for CML until, let’s say, a few years ago imatinib versus the efficacy and the tolerability of a stronger TK inhibitor of BCR-ABL like dasatinib at the same dosage that has been used in second line therapy, and indeed now we have a follow up of three years from the start of the involvement of the patients and they are showing us that there is a continuous superiority of dasatinib versus imatinib in terms of performing and producing a higher and deeper molecular response, also a very, very deep degree of molecular response which is the complete molecular response which is, as you know, something which is a prelude to the possibility also sooner or later of discontinuing the therapy.

This is described as an exploratory analysis; what do you mean by that and how seriously can you take it?

It is an investigational study adjusted to see which are really the advantages and disadvantages of using one drug instead of the registered ...

So you now have hard data?


Right. So what is the outcome then?

The outcome is impressing the sense that more patients are achieving good response in terms of cytogenetic response, in terms of molecular response, even very deep levels of residual disease, and this translates in immediate advantage which is the prevention of progression that can still occur in the very few, two or three years from the start of the therapy in some similar patients treated with TKI inhibitors. We have more events in patients treated with imatinib with respect to what we see in patients treated with dasatanib, and these are important events even from the numeric point of view, let’s say, because each event represents a very high risk of death for the patients and therefore is not a trivial events like can be, let’s say, side effects of negligible importance.

Now in the wake of this very interesting study, where does this leave current therapy then?

Of course we have now the possibility to use three different TKIs as first line therapy in Nationale; we have imatinib, we have nilotinib 300 mg twice a day and we have dasatinib 100 mg once a day, and I would say the advantages of the second generation TKIs are they are for the moment able to limit, as I told you, these events of progression that we can still observe in the imatinib treated patients and we can also produce more, what we were calling before, complete molecular responses which means that to reach the level of residual disease undetectable with the usual techniques. And this is what is the prelude to the possibility also of discontinuing the therapy without having a relapse of the disease; what we call operational or functional cure.

This would be nice to have, yes.

We have more patients achieving this degree in a rather short time in respect to what we see with imatinib.

Nevertheless, there are some new answers to this whole story because you have to watch out for the different mutations that might exist in an individual patient and presumably the doctor now has three agents to choose from. How does the doctor choose?

In first line therapy we do not see a high degree of mutations; actually I would say that diagnosis we do not seeing the patients at all in chronic phase. It is important of course in the more advanced phase of the disease, in the few cases that maybe immediately present as advanced phase of the disease, but in chronic phase we don’t see the patients. But we know that some of these patients are developing what we are calling secondary resistance which means that they are developing clones, already present at diagnosis but not so well expanded, that are, however, selected by the therapy that we are using. And the number of patients developing mutation with second generation TKI is lower and the type of mutations that they are harbouring is more limited. I would say it is in particular the 359 mutation which is the mutation which is resistant to all TK inhibitors so far registered, and of course we will have in the future probably also third generation TKIs able also to suppress these other mutations.

Sure, so what is your advice to the doctor now about the use of imatinib and when to use a second generation TKI like nilotinib or, as we are talking about now, dasatinib?

Let me say that it is very difficult at the moment to give a single advice; it is largely dependent also on the goal that you want to achieve in the therapy. Of course if you are aiming to limit the risk of progression, which can be particularly high for patients that at presentation they are what we call high risk patients based on their clinical and haematological parameters, of course we must use a second generation TKI instead of using imatinib because we have less probability of undergoing a progression with second generation TKIs. If we wanted to achieve also complete molecular remission to try to discontinue sooner or later these patients from therapy we must also use a second generation TKI instead of imatinib. And let me say that this can be achieved in patients that are with the low risk group, probably more likely, because these are the patients, the good patients, that can have a very, very good response. And in saying these things you can imagine that I prefer second generation TKI versus imatinib but, however, there can be also a category of patients in which they are experiencing many co-morbidities, maybe elderly patients in which you want also to have a look at their other medical characteristics in which you may prefer imatinib because the side effects of imatinib are better known and we may prefer this because we are not aiming maybe to discontinue the therapy in this group of patients. We can be happy just to put them in a very long survival but without aiming to eradicate the disease.

And you now have a choice, you have several agents.


But you are looking forward, clearly, to achieving functional cure in many patients.


How many?

I would say that with TKI alone we can expect a higher percentage with second generation TKI than with imatinib. With imatinib we do not have a complete picture at the moment because we really do not know the denominators or how many patients ...

With second generation TKIs I mean how many patients could we have ... could it be the majority of patients?

No, I think they will remain approximately around 50% of the patients.

But that’s good.

That’s good, but then there is the remaining 50%.


And of course we should try also to improve the results in this category of patients in which maybe the TKI therapy alone will not be sufficient and we should… in these cases there probably are cases where there is an expansion of the progenitor cells and maybe to limit the expansion we must do other things, not only inhibit the BCR-ABL TK activity but also to add other tools.

You need to ... if you are achieving a functional cure you need to monitor that cure molecularly.


Are there indications that you can do that and can you then tailor the treatment, re-treat and bring patients back?

Absolutely. When patients are entering, and I would suggest that each patient trying discontinuation, to discontinue their therapy, should enter a clinical study just so they can be followed in a very precise and standardised way. Of course you must start from a very, very low level of residual disease and then you must monitor quite carefully, I would say every month at least for the first year, almost the first year, their possible relapses because if a relapse is occurring generally this is occurring the first month after discontinuation.

But can you prevent blast crisis?

In this case prevention of blast crisis, the risk of blast crisis, is very low in this group of patients because they have already achieved such a low level of minimal residual disease which is, I would say, is possible but really unlikely and there are very, very few cases that would progress at this level. So we can prevent it with the depth of the molecular response and particularly during the first period of their treatment; this is the way to prevent blast crisis. But if we wanted to discontinue the therapy we must have a longer follow up and we must carefully monitor the patients for the fluctuation of the residual disease because sometimes these patients have a fluctuation of the residual disease which is no more able to re-expand, even if you are taking out the drug.

And the latest results from the DASISION study are giving you more confidence.


From the EHA meeting here in Amsterdam what would you sum up as the sorts of practical messages that need to be distilled from the very interesting papers that are presented here?

I would say that from the practical point of view we have to decide the treatment on the basis, at the moment, of the characteristics, let’s say, of the patients. If we aim just to decide, this sometimes may be talking with the patients which is the goal that we want to achieve in the therapy for these particular patients. It’s more like that the very young patients should aim to achieve a complete molecular response and deter the possibility of discontinuing therapy; with respect to elderly patients with many co-morbidities already in which the quality of life can of course represent an important aspect so we do not have also to challenge the quality of life just to pursue a goal that is not realistic or whose advantageous achievement would not be a great advantage.

So, very briefly, how would you sum it up for busy doctors?

OK, that you personalise the treatment. I would say this is the best thing to do. You have to be very careful in following, of course, all the rules, all the instructions to monitor the response of the patient; this is a very important aspect. But then you should also consider not only the disease but also the patient who is in front of you, and sometimes also to talk with the patient and to understand if he is ready to take the drug for the rest of his life maybe, if he really wants to get rid of the disease and so on. It is our whole aspect that you have to personalise directly with the patients.

Giuseppe, thank you very much for joining us.

Thank you very much.