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February 24, 2012
Dr. Michael Deininger, chief of hematology at the Huntsman Cancer Institute at the University of Utah, explores ongoing research to fine-tune treatment for CML. Dr. Deininger discusses second-generation TKIs in frontline therapy, considerations for switching or ceasing medication, and the need to refine molecular testing into a sophisticated, reliable prognostic method.
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Michael Deininger, M.D., Ph.D.
Michael Deininger, M.D., Ph.D.
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Dr. Deininger, what are the key themes in CML at this
meeting, in your opinion?
One of the key themes of the meeting is whether we are ready to
change the treatment paradigm for newly diagnosed patients with chronic phase
disease, in other words whether there’s agreement on whether starting everyone
on a second-line tyrosine kinase inhibitor such as nilotinib or dasatinib or
whether there is still a role for imatinib in the frontline. So I think some of the data coming out of
this meeting sheds some additional light on that. That is an interesting theme.
Another I think focus of the meeting is to see whether there
are patients where we can stop treatment altogether, so patients in whom the
response will be maintained in the absence of any active treatment. And that’s of obviously--that’s obviously of
major interest for the community and for an increasing number of patients who
live long, have excellent responses but have to continue taking the drugs.
And a third I--I think interesting development is the third-line
inhibitors for resistant disease. So in
other words we are interested in improving results in the very good responders
to a degree that allows us to stop treatment altogether, and on the other
extreme of the spectrum there are people with very aggressive disease where we
try to push the envelope towards, you know, inducing remissions in these
patients who failed other inhibitors.
And I think there are some interesting drugs developing along these
So what about for patients who are doing well on imatinib, on
Gleevec? They are always wondering, if
there’s second-line drugs that are more powerful, should they switch.
I think a general answer would be that I don’t think there is a
reason to do so unless you have significant side effects or the response you
have achieved is not quite as good as you would like it to be. And there are criteria developed by the
European Leukemia Net and really the CML community that allow you to make these
decisions to together with you. But
there is certainly not a carte blanche to switch now from imatinib to a second-line
agent. If you’re tolerating imatinib
very well then you always have a risk of side effects if you switch to another
inhibitor, and in the big trials that have been conducted there may be a rate
of 15 or 20 percent of side effects that are of clinical significance.
And what about new patients starting on these more powerful
As far as the front-line treatment goes, that is an evolving
field. I think the data that we have
seen presented here really do suggest that the second-line inhibitors,
nilotinib in particular but also dasatinib, have higher activity in newly
diagnosed patients in the sense that they do reduce, specifically nilotinib,
reduce the relapse rate.
What we haven’t seen yet is an impact on overall survival, so I
think it needs to be balanced with each other.
We certainly see a reduction of relapse rate, and the expectation is
that this will translate into an overall survival benefit at some point, but it
will require more observation time.
It should also be noted that there are differences in terms of
response according to the individual patient’s risks. So low-risk patients tend to do very well on
Gleevec, or imatinib. High-risk patients
tend to do less well on imatinib and may be prime candidates for drugs like
nilotinib or dasatinib.
Do you have the tests to tell which patient is at higher risk
and which not?
Well, the tests that we’re using currently will establish
clinical prognostication systems, that is the Sokal score--also the so-called
European score. There is a very recently
developed imatinib score. Now one has to
be realistic as to what these scores can deliver. They are imprecise measurements of disease
risk, but they give us some indication of whether a disease behaves
aggressively or not. They’re not
perfect. I think what we are doing in
the lab is to try and go beyond that and develop molecular tools to very much
more stringently risk stratify patients.
Because if you--it turns out if you look down your microscope the cells
of a patient who is about to develop blast crisis may look exactly the same as
the cells from a patient who is looking at stable chronic phase for many, many
years to come, so we need to go beyond this level.
And obviously one approach to that is to use genome-wide
scanning techniques to get at the genomic makeup of bad disease versus good
risk disease. And we’ve done some work along
these lines. Other labs [have] also
worked along these lines. So I think we
are getting closer to defining high-risk disease on a molecular basis, but we
need to do more work, and it needs to be done within a prospective study. So one appeal of course to everyone in the
CML community is to not, you know, start--stop thinking about clinical trials
in CML because it’s a disease that is easily treated in the general
practice. If we want to make progress
and really put this disease on the heap of history we’ve got to continue these
studies, and enrollment in clinical trials is the very basis for that.
You mentioned the idea of maybe being able to stop treatment,
and that would be music to the ears of people who otherwise have to take a
medication long term. Where are we with
Maybe the first thing to say to this question is it shouldn’t
be done without a clinical trial. So you
should, if you want to do that you have to enroll in a clinical protocol so
that it gets all the framework of close monitoring around that and you minimize
your risk from that. Having said that,
there are data from Australia, also from Europe that suggest that maybe 40
percent or so of patients treated with imatinib into undetectable disease do
maintain responses in the absence of continued treatment.
So does that correlate or is that equivalent to a cure? Well, the answer is we don’t really
know. There is no way of knowing whether
in these patients there are still sleeping residual leukemia cells, or whether
they--the clone has died out, has just been subject to death by attrition over
time. In reality, we’ll never be able to
know that because it’s just a limitation of sensitivity, and maybe any
successful cancer treatment is just like that.
We will never know whether we’ve got all the cancer cells.
But for practical purposes these patients have been maintaining
their responses now for--for long periods of time, so I think that there is
something that clearly needs to be exploited.
And we need to understand who are these patients who will be able to
maintain their responses and can we--can we--is there wiggle room for us. Can we improve from therapeutic side? So maybe the exciting thing about the new
inhibitors is that they do increase the number of patients who achieve
undetectable disease, which is arguably the basis to even think about stopping
Now that we have so many more treatments, more coming, how does
that help in the management of side effects for the individual patient?
I think the big advantage of having more than one drug
available is that you can be selective.
If one agent doesn’t work for you may well do extremely well on another
agent, and fortunately the side effects are not--you know, they’re not cross
specious, if you wish. So if you do--say
you have a lot of skin issues with one agent that doesn’t necessarily mean that
you will get skin issues again on another agent.
The only exception to this rule to some extent is if your blood
counts drop very low. That is a more
repetitive theme, so if you have that maybe you just don’t have enough normal
marrow to make up for the dying leukemia cells, and that of course is going to
occur with any agent. But just like with
a number of other things where you have therapeutic choices it’s a good thing
for the patient to have because, you know, you just figure out what works best
Certainly sounds very encouraging.
It is. But I’m--I’m
still not looking for another job. I
think there is still a lot of work to be done, especially on--on the disease
eradication side, being able to stop all drugs.
And so we need to understand better what are these cells that survive
despite tyrosine kinase inhibitor therapy, sometimes even despite--you know, there
are so--there so few of them that we can’t even detect them but if we stop the
drug they may very well come back with active disease.
So these leukemia stem cells we need to learn better how to
characterize them, how to define their survival signals that allow them to
hibernate in the presence of a TKI, and I think this is a major challenge to
the field. It’s not easy to study that,
but I think we’ll see incremental progress over the next few years. And maybe at some point we’ll turn CML into a
disease that, you know, you had it at some point in your life and now it’s a
thing of the past.
By Andrew Schorr