Progress in the treatment of CML

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Published: 18 Feb 2011
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Dr Jerald Radich - Fred Hutchinson Cancer Research Center, Seattle, USA
Dr Jerald Radich speaks about the treatment options that are available for chronic myeloid leukaemia (CML). Tyrosine kinase inhibitors such as imatinib dasatinib and erlotinib have allowed to clinicians to effectively treat CML without the need for transplantation. However there is still a portion of the patient population who cannot be effectively treated with these drugs. Dr Radich talks about some of the research that has been presented at ASH 2010, outlines how he believes CML treatment will progress in the next ten years and speaks about the role of patient advocacy groups. Dr Radich concludes by discussing the International CML foundation and the work this organisation does to combat CML in emerging countries.

2010 American Society of Hematology Annual Meeting 3rd - 7th December


Interview with Dr Jerald Radich - Fred Hutchinson Cancer Research Center, Seattle, USA


Progress in the treatment of CML


IV         Interviewer

JR        Jerald Radich



IV         Hello, this is ecancer TV. We’re reporting live from the American Society of Hematology meeting in Orlando, Florida. I’d like to welcome Professor Jerald Radich, from the Fred Hutchinson Cancer Centre in Seattle, and I’d like to talk to you about CML: chronic myeloid leukaemia. At the meeting you’ve presented about CML: Where are we now and where are we Going? So it’d be very interesting your viewpoint where are we today with CML?


JR        Well, right now we’re at a remarkable point of time; really in CML we’re almost blessed with an embarrassment of riches. We have imatinib, which is the standard of therapy, which has really completely changed the natural history of this disease; whereas before the only curative or intent what could be done with transplantation, now with imatinib we get similar results in survival, so it’s a remarkable change of events.


And now we have actually two other drugs that have just been approved recently in the United States: dasatinib and nilotinib, the so-called second generation types of Tyrosene Kinase Inhibitors, which actually seem to be even more efficacious. So now we have at least three drugs that can be used that really completely change the natural history of CML, and really make it a disease where before, without transplantation, you could expect people to eventually progress and die of the disease, now progression rates are extremely low, and so we’ve really changed the whole landscape of CML therapy.


IV         But what are the key challenges now? I mean we’ve had a lot of progress on new drugs, but of course it’s not a tick box with CML, so what are the challenges today?


JR        Well, if you look at patients who are treated with the standard imatinib therapy, about 10% of those patients just will not respond to therapy at all, and another 10% or so will relapse on therapy, and for those people who relapse on therapy you can try to salvage them with a second-generation tyrosene kinase, and about half of those people will respond but will go on to eventually relapse again. And the other half won’t respond at all and they’ll need some type of transplant. So the issue is once people have progressed, we think that progression may be forever, and maybe what you have a multiple clones or resistant disease coming on, and as you give more second-generation drugs, you’re just doing a Darwinian selection, and eventually those clones will relapse. So there are a couple of key issues.


One is, can we prevent resistance from occurring, or can we identify patients who are going to be prone to resistance and add a second drug, or put them on experimental ones? And then once people progress, can we salvage them in better ways, and basically prevent those people from going on and getting, you know, lethal blast crisis. So I think those are the main challenges, is if you imagine a patient walking in the door, first, can you identify their risk of eventual progression, and can you tailor the therapy appropriately to prevent that risk? Can you identify people once they’re getting therapy who may not be doing as well as you want by molecular monitoring and the like, and then intervene early to prevent a relapse? And for those people who escape all that and relapse, can you salvage them in some way to prevent them from ultimately going on to resistant death and death?


IV         What do you think are the most important news that is presented this year at ASH?


JR        Clearly the update of the frontline of nilotinib and dasatinib data, which shows that, as you’d expect, that the changes in efficacy are still there compared to when they were presented a year ago. But there’s been no new toxicity data. That was one of the key issues for patients who were newly diagnosed is, do you try a drug that’s a little bit more efficacious when you really don’t have any long-term toxicity data? Now after another year of therapy, there doesn’t seem to be any new toxicity with these new second-line agents, so I think people are going to be much more comfortable adapting those upfront, and I think that’s very good news.


The other issues that are coming on, is that there’s promising data, mostly in vitro data, with a number of drugs that are targeted to hit stem cells that may help people go and actually eliminate disease fully. Because now it looks like we can get people into so-called complete molecular remission, and there’s been studies presented here and now recently published, that if you get people in complete molecular remission, you may actually be able to take those people off drug. So whereas before we thought that you have to stay on tyrosine kinases forever, it actually looks like if you get in this complete molecular remission, about 40% of those patients may be able to get off drug, and that’s really exciting news. If that’s true, then there’s going to be an impetus to actually look at patients upfront, and say well, we can give you nilotinib or dasatinib, but maybe if we add that with another agent that targets stem cells, we’ll have more of a chance of actually pushing you to extinction [sic]… your disease to extinction, and then being able to get you off drug. And so I think that’s a really different strategy. Because in the past, we’ve thought that, well, maybe if you really want to cure people, eliminate all their CML, maybe transplant was the only thing that would really do that, and given that, if you were going to be on one of these tyrosine kinases, you’d really have to stay on drug forever; otherwise, when you took them off drug, those clones would escape and you’d be in trouble. Well, if this is really true, then there’s going to be some people, probably people who we catch early on and treat aggressively enough, who actually may be cured really with this targeted therapy and without transplant. So I think that’s very exciting news, especially for younger patients who are looking at trying to be, you know, alive, you know, at 30, 40, 70 years from the time of their diagnosis.


IV         That’s very interesting. I mean if we look at the last ten years, CML therapy has changed dramatically. Do you expect a dramatic change again for the next ten years and visiting all the developments you’ve just outlined? What is your vision for CML 2020?


JR        I think by 2020, you will be able to take people when they walk in the door, and really be able to re-stratify them by molecular methods and the like, and pick a cocktail of drugs that has the best chance of getting to a point where they can get off therapy, so that therapy will be limited. And then that cocktail of drugs will really depend on what your expectation is. That may be very different from a 70 year-old who doesn’t want to - can’t - live another 70 years, than someone who is younger who may take a more aggressive cocktail of medications. So I think they’ll be able to really tailor therapy on both what their disease genetics are, and what are the expectations, what the best way to treat them, you know, how aggressively we need to do, to actually get them to an end point of really, you know, curing their disease, or at least making their life as pleasant as possible with their disease.


Of course all this depends on patients taking their medicines, and one of the things we found in looking at imatinib is that a surprising amount of people actually aren’t compliant with their medications, and even though we can do all of these fancy genetic assays and the like, if people don’t take their medications, none of that matters. And so one of the things I think we struggle with is we talk about having increasingly complex oral agents, is getting people to actually take them, to somehow educating them about the necessity of taking them, and in keeping that going. Because realistically some of that doesn’t happen because of issues of understanding of education, some of that’s called monetary issues, that patients are paying for this out of cash, which a lot of places that we see in the United States have to. There are de-incentives to be really compliant with your medication. So these are all hurdles that we have to do: they’re educational, they’re societal, they’re governmental, on how we finance these drugs and the like.


IV         Do you see a role of patients groups in achieving that, in improving compliance in patient information?


JR        Absolutely. I mean I think that that realistically… you know, traditionally MDs, you know we’ve been bad at doing that, and I think that patient advocacy groups can really be important conduits of transmedia information in letting people know, you know, how important it is to stay on drug. Because the studies have been done. It doesn’t take much difference in compliance, like, you know, maybe just down taking 90% of your drug instead of all of them, or 70%; it’d actually make a big difference in efficacy. So it would seem modest for a patient to miss a dose or two during the week, and it probably has a big difference in efficacy, and I think that’s something where as many ways as we can get patients to understand that, as many inputs, the better.


IV         I would like to point to a completely different topic. You’ve recently joined the board of directors of the International CML Foundation, which objective is to support physicians in emerging countries where there are specific challenges for patients and for doctors.


JR        Yes.


IV         So can you tell a little bit about that activity, and why you engage for emerging countries?


JR        Well, I’m doing this because, you know, really when you look at it, we’ve done spectacularly well in CML, and certainly my research emphasis in the lab is on that, and will continue to be on that. But when you look at the impact you can make in patients in developing countries, there’s going to be a ceiling on that. We’re doing awfully well, and we can do better, but when you look at what impact you can make as individuals or as groups, I think where it really is in developing countries, where getting these drugs to them, getting the technology that we routinely use is just… is absolutely minimal. I think if you say what contribution can I make, what contribution can my institution make, to overall health in the world, I think this is a huge area where anything you can do is going to make a vast improvement.


We got involved in this probably about three to five years ago with the Max Foundation in Seattle, because they had people in El Salvador that they had contacted, who were trying to get, you know, free Gleevec though Do Novartis, and one of the rules of that programme was that they actually had to have the diagnosis of CML. And no one in El Salvador could do cytogenetics or any molecular tests at all, and so the Max people asked me if I would be willing to do that. And so what… one thing led to another, and now we basically take care of all the diagnostic from all the CML patients in El Salvador, and it was through that I wanted to get more and more involvement, because I just think it’s a good thing to do.


IV         It’s fantastic. I think you have also participated in a pilot programme of the International CML Foundation now with a perceptorship programme.


JR        We aren’t doing that directly, but we’ll be happy to do it. And we’ve done a fair amount of international education outside the CML Foundation, basically bringing people in from India, and some other countries, Africa, to teach them basically how to run a molecular lab, so that they could actually have the tools and send the protocols back to them, so they can actually set up those shops in their own countries. That’s something we’re pretty active and devoted to.


IV         I’d like to thank you very much, Professor Radich, for your insights.


JR        A pleasure.


IV         And this is ecancer TV from the American Society of Haematology. Thank you very much.