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January 25, 2012
Dr. Neil Shah relates the management of CML, for most chronic phase patients, to the management of high blood pressure; while patients should remain diligent and serious about their treatment, they can expect to live long and healthy lives. Dr. Shah explains that this level of disease management has led researchers to begin looking for answers to more sophisticated questions. One such research question hopes to refine the expectations CML physicians and patients should have regarding complete and major molecular responses, and for whom treatment interruption may be a viable option.
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Neil Shah, M.D., Ph.D.
Neil Shah, M.D., Ph.D.
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Dr. Shah, regarding CML, and for patients, what are you
impressed with at this ASH meeting?
Well, at this meeting I think we’re--we’re getting further
experience about the longer term outcomes of the newer drugs, both in the
second-line setting and the frontline setting, specifically dasatinib and nilotinib. And we’re also getting more confirmatory
results that a third generation kinase inhibitor, ponatinib, is looking quite
active in a phase II study. It’s very
preliminary results of a phase II study.
But the way that these studies have gone with both--with all of
imatinib, dasatinib and nilotinib is we tend to learn most everything we need
to know about these drugs in the phase 1 study, and then we expect the phase II
studies to more or less be confirmatory, and it’s reassuring that that’s
happening. And I think there’s a very
good chance that ponatinib will benefit a good proportion of patients. I participated in one of the studies and had
many of my patients benefit durably as well.
I think one of the really encouraging things that was presented
was those patients that are responding in phase I for whom there are--there are
now a couple of years of follow-up, they’re really doing very well two years
out, and this is a group of patients that if anybody was at a high risk of
losing response quickly it would have been this group. So I think that’s certainly all very
encouraging in terms of our ability to deal with resistance-causing
We’ve also learned that patients who stop imatinib with each
successive year of follow-up from the French study that it does appear that
there remains a substantial proportion of patients, between 30 and 40 percent,
who can cease imatinib when in a confirmed complete molecular response and not
suffer any evidence of molecular relapse.
I’m curious to know whether this can be broadened to patients that don’t
necessarily have a complete molecular response but have a deep, a major
molecular response but still detectable PCR level.
In fact there was a study that looked at stability of major
molecular response in patients who had discontinued the second-generation
drugs. It’s still very early, but it
does appear to be consistent with the idea that patients who lose a complete
molecular response may not necessarily lose a major molecular response, and so--the
complete molecular response definition is arbitrary, of course, and we don’t
think that patients who are in complete molecular response are completely free
of BCR-ABL expressing cells, and so you can begin to think that maybe this
maneuver would be possible.
I think people are getting comfortable with the idea that this
could be tried in patients with a major molecular response. Of course, it should only be done in the
context of a clinical trial, and probably patients who have other disease risk
features at the outset which may put them into a better category in terms of
how likely they are to do well on--with treatment interruption.
I’d say one other issue that we’ve--that I’m encouraged by is of
course there are a number of studies that are aimed to take control of this
disease to the next level, and that is to cure patients. And there are a number of studies which are
accruing patients using compounds such as smoothened inhibitors. It’s an inhibitor of the Sonic hedgehog
pathway which has been used--or has been implicated in the survival of CML stem
cells. And it’s certainly hoped that
these combination studies will lead to true disease eradication.
Of course, it’s going to be years before we know, but we are
learning that--we are learning that these--these agents, these smoothened
inhibitors are actually rather well tolerated as monotherapy, and they’re
showing some clinical activity in other leukemia, in other types of
leukemia. So I’m very eager to see how
these studies shake out. So the future
is certainly brighter than it’s ever been for this disease. It’s going to get brighter, I’m quite
I think the pace of improvement over the coming years is going
to be a little bit less. I think we’ve
been spoiled by a decade of really major advances, and this is the first
meeting in a number of years where I have to say that there don’t seem to be
any huge quantum leaps, but I think that’s a reflection of how well controlled
we’ve managed to make this disease, which is, of course, the ultimate
From what you’re describing it sounds like patients can well
manage their disease and then move on with their life.
Yes, this is absolutely the case. When I see a newly diagnosed chronic phase
patient, I mean, I try to reassure them that I believe that in all likelihood
they he can expect to live an otherwise normal life span. Now, there are going to be some exceptions to
that, but I think they really will be exceptions, and with more and more
effective therapies we will be able to not only improve the quantity of life
for most patients but hopefully also the quality of life. So I--I do tell them to try to be optimistic
and live their lives as they otherwise--with the expectation that they would
live to be as old as they otherwise had thought they would be.
It does not mean they can take their disease lightly because we
know left untreated the disease runs its course on average in five to seven
years, and so I tell them they very much have to--have to take it
seriously. But it’s almost become like
the management of high blood pressure where if you can take a pill that’s
ideally well tolerated and controls it, it can prevent complications and you
can live to be, you know, you can live to be 70 or 80 years old. They don’t cure your hypertension right
now. We don’t have confidence that these
medications are curing the disease, but there are a lot of similarities
So there’s a chance maybe in a clinical trial that some
patients could actually stop taking their medicine?
Yes, so again we’re very cautious to use the word cure, but
from a functional perspective it’s possible that we are already curing some
patients. There are rare patients who
stopped for eight years now and have not had their disease recur. Now, that tends to be the minority, but again
I think we’re getting more and more confidence with having--with considering
interrupting in patients on clinical trials with lesser degrees of response
because we’re not convinced that the cells, the few cells that remain in these
patients are going to rapidly reestablish the disease. And so it’s--the picture is brighter than it’s
ever been certainly.
By Andrew Schorr