Understanding Molecular Response with Respect to Cure for CML

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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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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor.  Please have this discussion with your own doctor. That’s how you’ll get care that’s most appropriate for you.

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 mutations. 

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 confident. 

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 goal. 

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 there. 

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor.  Please have this discussion with your own doctor. That’s how you’ll get care that’s most appropriate for you.

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