An Expert’s Review of CML ASH 2015 News | Transcript | Chronic Myeloid Leukemia (CML) | Patient Power

An Expert’s Review of CML ASH 2015 News

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

Andrew Schorr:  

Hello and welcome to Patient Power.  I'm Andrew Schorr.  Of course, a lot of news comes throughout the year but particularly in the American Society of Hematology meeting every year in December about CML and with us now is a noted expert in the field, Dr. Michael Mauro.  Dr. Mauro, welcome back to Patient Power.

Dr. Mauro:           

Thank you, Andrew. 

Andrew Schorr:                  

Dr. Mauro, with ASH in mind, and of course any updates even from members, as you think about what has transpired, what do you think is important for patients to know as to where we are now in treatment, research and even managing side effects? 

Dr. Mauro:           

We continue to get updates every year in the field of CML, and particularly at ASH.  The research continues.  We have answered a lot of questions well over the past decade or more, with regard to a paradigm shift in therapy with now a repertoire of kinase inhibitors that are highly effective, with a lot of data on duration of remission and stable remissions.

But there are some folks—well—but there are some definite focus points that we have, or some areas that we are focused on moving forward.  I think the first point from the ASH meeting was what can we do to do even better than we are now, meaning how can we optimize our current available therapies?  Can we optimize imatinib (Gleevec)?  There was a nice abstract on optimizing imatinib based on plasma trough levels, something that isn’t routinely done now but has been done in the research setting. 

That was impressive that we could see improvements in molecular response by adjusting the dose of imatinib in patients who probably had different metabolism or slightly different exposure based on these drug level testings.  This was, again, something to think about. 

Maybe we can start to bring that test back and do it in the real world.  We saw research on combining therapies, still.  We had a nice abstract looking at combinations of current available TKIs like dasatinib (Sprycel) with interferon, pegylated interferon to be specific.  And that, as well, is able to boost response rates above what you’d see with the TKI alone and brought response rates up to one of the highest levels with regards to emissions at 12 months; major molecular emissions and deep molecular emissions, MR 4.5 or what’s previously called complete molecular emissions were boosted for patients who were able to add interferon to dasatinib.  So we’re asking and answering questions about how to optimize the current therapies. 

We’re being critical and using our best technology to help identify mutations and resistance.  There was a nice work presented on next-generation sequencing and how well does it capture low levels of mutations or maybe relevant mutations that would be not seen with standard sequencing that could help us adjust therapy, change therapy or predict resistance.

We’ve delved a fair bit into the immune system and how the later parts of TKI therapy, the good news is that patients in deep remission, we start to think about treatment discontinuation or treatment-free remission.  I think we have a much better handle on what the immune system does and how it responds to a patient when they’re diagnosed, how things look when they’re on therapy, how things look when they’re in remission to really help us understand what we can harness or what might be beneficial, or perhaps a marker for folks most likely to be successful over the long term or successful with treatment-free remission.

There wasn’t a lot of new information on treatment-free remission, but there certainly was something new and interesting.  And that’s that sometimes withdrawal of TKI isn’t as simple as you’d think, and someone might have side effects without their TKI.  And there was a nice cumulative presentation looking at some of the larger trials, the STIM trial and the EURO-SKI trial combined their data to show and describe what is the withdrawal syndrome, we’ve now called it, look like for patients with CML who come off their therapy?

That’s still something we do only in the experimental setting, that is treatment-free remission or discontinuing TKIs.  We clearly now want to know more about some of the things that are happening when patients stop their drug, and I'd encourage everyone to pay attention to that data and also to report any side effects and problems that might occur, so we can learn the most about that.

If we ask the question about what can we do when perhaps things go wrong in multiple ways, meaning someone hasn’t had luck with multiple TKIs and do we have anything new, any new therapies, probably the most promising report out of ASH in my view was I'm fortunate to say something I was involved in, which is a trial of a drug called Abel 001, which is now a fourth-generation kinase inhibitor, much in the vein of the drugs we have available—oral, very well tolerated as far as we know from fairly robust Phase I data.

Again, a drug orally delivered, taken once or twice a day.  So a different kind of kinase inhibitor that inhibits the Bcr-Abl enzyme that drives leukemia but by a slightly different mechanism, slightly different region and the kinase is altered or corrected—something called the mirror stellation site.  And the drug was designed to just do that, to be able to overcome kinase resistance around the target where the current available drugs are binding.  And the Phase I data is very encouraging.  We see activity in patients at various doses.  We’ve been through a full range of doses and haven’t necessarily seen a limiting toxicity. 

We’re in fact, at this point in the trial, expanding cohorts of patients treated at what I would say were moderate doses where the benefit-to-risk ratio is optimized.  And I think that’s a really encouraging project and something that I hope will lead to yet another kinase available, particularly for patients with resistance or inability to have stable remission with the current available drugs.  And also ultimately that drug may be something we can use in combination. 

We’ve never seen a combination of able kinase inhibitors before.  But because the drug’s binding at a slightly different part of the able kinase, now I think we can conceptualize and really see combination therapy for CML with two drugs that are both targeting the driver of the disease.

Andrew Schorr:                  

Dr. Mauro, when you put all this together with the broad range of CML patients now, when somebody comes to see you, based on everything you’ve discussed, trials and group therapies, do you feel that you have something to offer them long term, so they can live pretty well? 

Dr. Mauro:           

I certainly do.  I think the prospects for someone newly diagnosed with CML are remarkably different than they were just a few years ago, and clearly worlds different than they were a decade or decade-and-a-half ago.  So I try to focus with my patients on understanding the disease.  There’s so much information out there, both available to us and to patients together and helping people navigate is very important. 

So the art of CML is really successfully navigating treatment choice in the beginning, careful monitoring to make sure things are going well because odds are they are.  But, of course, that’s not for everyone and there are gaps, and there are folks who don’t do as well and need to be captured.  We need to identify things before we get into trouble.  We need to identify suboptimal response, early resistance, know when to change therapy, and importantly to be listening to patients about their side effects to understand when it’s right to change therapy for side effects or a mixture of maybe not an ideal response and also some degree of intolerance. 

We don’t want to run through the drugs too quickly.  There are some toxicities that aren’t tolerated and are dangerous.  But we’ve also stumbled across some toxicities, which are more worrisome, particularly in the cardiovascular space.  And also I like to help my patients navigate how do we sort out what drugs have those risks, how do we screen and hopefully detect them early, how could we intervene in very basic ways, really, in the beginning?

Meaning let’s take a good look at cardiovascular health and make sure its questions are being asked, patients are aware of what their risk factors are; we can reduce them.  And we study hard and hopefully unravel what the basis for some of these side effects are.  So, Andrew, we definitely have a lot to offer a patient nowadays, and we can really show them a roadmap of how we can make good choices, monitor carefully and hopefully get to an end game, which we would envision being potentially a treatment-free remission. 

Again, I emphasized that earlier that that’s still something that’s in the realm of research, but I'm hopeful that that’s where this is all going, that CML comes a disease that’s highly treatable and something that doesn’t require treatment lifelong.

Andrew Schorr:                  

And, of course, many people, sometimes because of side effects, want to stop treatment.  But it sounds like still that is a research question. 

Dr. Mauro:           

I would encourage everyone to still only consider that to be done in a clinical trial.  There are some circumstances where it may be necessary; pregnancy, other illnesses, other treatments. 

So there are circumstances that come up where treatment cessation may be indicated.  But to do it simply to see if it’s okay, and that the remission can be retained, I think that’s still a research question.  We’re still learning about predictors and the depth of remission and how we can really maximize the odds of success for that question.  And the good part is that while many people do have side effects, I don't think for most people that we’re dealing with a heavy burden or a dangerous side effect profile.  Sorry, the inadvertent phone ring.  I can answer that question again. 

Female Speaker:                 

I'm sorry.  Apologies.

Dr. Mauro:           

You asked about stopping therapy and research, right?  So with regards to the question of stopping therapy and whether it should be done in the research setting, I think I would still encourage folks to think of it that way. 

There are circumstances where a cessation of therapy may be indicated, and it can happen in a trial if someone achieves pregnancy, someone has another illness or needs other treatment, or other circumstances.  So those can happen.  But we’re still learning about treatment-free remission and what some of the predictors might be, how do we monitor correctly, how do we monitor over the long term? And we still are answering the long-term questions on how stable that treatment-free remission might be. 

So I think we’re close, but I think I might say we’re still not ready for prime time across the board and to be doing that outside of trial broadly.  But I want everyone to stay encouraged that we’re working hard on that. 

Andrew Schorr:                  

Dr. Mauro, given everything you’ve said, what’s going on in research, what you’re learning, nuances, even next-generation sequencing to understand better a patient’s situation, it seems like an active dialogue between the patient and the physician on how they’re doing and hopefully a long-term relationship, that really active dialogue in patients became known for how they’re doing and post-analysis of their situation; that’s really important. 

Dr. Mauro:           

Absolutely.  The dialogue between the patient and their CML specialist is paramount.  Some of the questions we ask are generated by the things we observe in the clinic.  And this field has developed essentially on the roll, as we’ve gone ahead, obviously, where there’s careful thought and decades of research in order to develop targeted therapy for CML.  But the questions have evolved over time based on—and in real time.  So some of the things I think we need to work on, or that I think are important, are the toxicities. 

Because we have such good response rates and we simply are seeing things we don’t understand why.  They’re not in the majority of patients, but we should be able to unravel the mechanisms of action and maybe come up with better strategies to triage patients and who can receive what drug, and what’s safe.  And if people need a certain drug with a certain risk, how can we lower that risk as low as possible.

And, again, I'm referring to the toxicities in the cardiovascular and cardiopulmonary space.  So I have some research interest there and I think others do, as well.  So I think as a field, we’ll hopefully move forward.  You know, we are trying to use our molecular diagnostic tools even better with regards to sequencing.  We have to be careful there in not to overestimate or overcall what we might see.  But I think we’re seeing that we probably can predict sooner if someone's beginning to show evidence of a resistant clone and intervene earlier.  And that’s probably going to be beneficial. 

And then with regard to the therapies, I think this new, fourth-generation inhibitor really represents I think a step up, or a next level that we’ve reached that we can move outside of the family of ATP-binding Bcr-Abl kinase inhibitors and now look at other drugs that have similar safety profiles, similar ease of delivery but yet might really be a way to get to this question of cure or to treat the small but real number of patients who don’t get good remissions with their current available therapies.

Andrew Schorr:                  

Dr. Mauro, as I always ask you to wrap up, what do you want to say to patients and families who are, whether they’re newly diagnosed, newly affected by this or living with CML for a long time, to give them hope for a good, long, full life? 

Dr. Mauro:           

You know, the first thing I always intend to say but sometimes don’t when I meet someone who has just been diagnosed with CML is to stop and just say simply that this is a very treatable condition, and the prospects are good.  As scary as it sounds that it’s leukemia and we’re talking about chemotherapy, we’ve really come a long way.  And no one wishes for any of this to come upon them but if—amongst the diseases we treat—this one we really have made great advances.  So I try to help people stay encouraged.

And the next most important thing to say is that knowledge is power, much like Patient Power is part of your name.

I think as much as folks can learn about where they’re at, what things they should be looking for, what the expectations are and how this is gonna go, the better the treatment’s probably likely to be, the better the relationship’s gonna be and the more comfortable the patient’s gonna be with their treatment and their outcome.

Andrew Schorr:                  

And for someone who’s been living with CML for a long time, it sounds like you have more than ever before, tweaking doses, changing drugs, new understanding.  So for them, too, who may have been living with CML a long time, it’s encouraging. 

Dr. Mauro:           

Absolutely.  That’s the good news, is the number of people living with CML is increasing exponentially.  It’ll reach almost 200,000 by the year 2050, so the CML community is growing and in just the way we want, that people are living with their CML or hopefully living past their CML.  But that’s where the focus also needs to stay.  This is a marathon, it’s not a sprint.

So the long-term treatment management and vigilance, even for those who have been on therapy for many years and even those who have potentially entered into trials of discontinuation, we need to follow everyone very carefully. 

Andrew Schorr:                  

I want to thank you so much for updating us, and thank you for your work in the field.  Dr. Michael Mauro from Memorial Sloan Kettering, we appreciate you being with us on Patient Power once again. 

Dr. Mauro:           

Thanks for everything you do, as well, and I appreciate you having me.

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

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