An AML Treatment Revolution: Updates From an Expert

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Topics include: Treatment and Treatment | General

Expert Dr. Naval Daver from The University of Texas MD Anderson Cancer Center joined Patient Power to discuss the dramatic progress being made in therapies for acute myeloid leukemia (AML).  He reviews the treatments that were FDA-approved in the last year and helps viewers to understand how this recent surge in approvals is affecting ongoing research. Dr. Daver goes on to share a hopeful outlook for the future of those living with AML. 

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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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.  Well, an acute leukemia is a scary diagnosis, AML, acute myeloid leukemia, had been such a serious diagnosis, and there wasn't much to offer.  But that's been changing, and one physician who has been involved in the research is with us now.  And that's Dr. Naval Daver from MD Anderson.  It's like a revolution, isn't it? 

Dr. Daver:

Absolutely, yeah.  It's really good.  So I mean the easiest way to put it is for 40 years in acute myeloid leukemia we were using standard induction therapy, which was two drugs.  One is called cytarabine (Cytosar-U), one is anthracycline, but there was really—that was the standard and stayed the standard.  And it cured about 50 to 55 percent of younger AML patients, patients below 65, so it wasn't that nobody got cured, but there was no progress, really.  There was a lot of mutational data that we acquired, a lot of clinical trials, and none of them really worked. 

But last year we had approval of four new drugs, so it's—when it rains it pours.  So nothing for 40 years, and then four new drugs immediately approved, all in different settings. 

So one of them was a FLT3 inhibitor.  So one of the common mutations in acute myeloid leukemia is a mutation called F-L-T-3 or FLT3.  It's seen in about one-third of patients with AML, and it's actually a high-risk mutation, meaning that people who have this mutation actually have a more aggressive disease.  They have a shorter duration of responses if they do respond to standard treatment, and they relapse quickly and have short survival. 

So there are a number of FLT3 inhibitors, about six of them in clinical development, but the first one of them completed its Phase III.  It was a drug called midostaurin, also has a trade name of midostaurin (Rydapt), and it showed that when you added midostaurin to the standard three-plus-seven chemo that we have been using for 40 years versus just doing the three-plus-seven, in the FLT3-mutated AML you could improve the survival by about 25 to 30 percent in that group.  So that was the first approval.  So now it's become a standard to check for the FLT3 mutation, in all acute myeloid leukemia patients and if they have it to add the midostaurin to the three-plus-seven. 

The other very nice thing with this study was that it really didn't show any increased toxicity.  So we looked at about 20, 25 different toxicity parameters that we would commonly be worried about when we add a new drug to the already intense chemo, and luckily they weren't worsened.  So that was one of the drugs that got approved and is now kind of standard of care. 

The second one is another mutational target called IDH.  IDH mutation is seen in about 15 to 20 percent of patients with acute myeloid leukemia.  It's not a high-risk mutation like FLT3, so people with IDH mutations have a neutral outcome.  But the excitement came because there was a drug, an IDH inhibitor, called ivosidenib, which as a single-agent pill, in people who had failed standard chemotherapy, which is usually the very bad group where we have very little to offer. But this pill could produce 40 percent response rates, and it was almost with negligible to no toxicity. 

So there was a large study that we did, 200-plus patients in multiple centers in U.S. evaluating this agent in relapsed AML, and with the 40 response rate with good tolerability and improvement in survival, this agent has now been approved.  Now, of course we don't really think five years from now it's going to be used as a single agent.  I think that was a good stepping stone to get into the market, but in going forward we're already doing trials combining with frontline, with the three-plus-seven, combining it with azacitidine, another drug we use combining FLT3 inhibitors, so it opens up a whole new group of combinations that we're doing. 

The third drug that was approved was actually a very unique targeted group that they looked at.  So this was people who have what we call secondary AML.  So secondary AML means AML in a patient who has had a prior myelofibrosis or a prior MDS or a prior CLL or patients who have had prior breast or colon or other kinds of cancer and get chemotherapy for it.  So these are people who are developing AML because of genetic damage caused by prior chemotherapy, radiation therapy. 

And usually these people present with very bad chromosome and molecular mutations, and they usually have a much inferior survival compared to people who have spontaneous AML.  So the drug that was looked at in this phase was a drug called CPX, which is a liposomal combination of the two drugs we talked about, anthracyclines and cytarabine.  And in a Phase III study of 300 patients they randomized patients, the physician didn't know which arm the patients are going on, in about 50 centers across the world to either receive CPX, which was the drug we thought would do better based on the preclinical data, versus standard three-plus-seven, which is what had been done for 40 years. 

And again the CPX showed improvement in response rates, about 15 percent higher complete remission rate.  So they had remission rates of 50 percent as opposed to 35 percent, and more importantly they had an improvement in the overall survival.  So the two-year-plus overall survival was about 40 percent with the CPX as compared to 20 percent.  So 40 percent may not sound high on its own, but it's much better than 20 percent.  And again this will again be used as a stepping stone.  Then we can combine CPX with the FLT3 or the IDH, with antibodies, with other drugs. 

And then the fourth drug that got an approval was a different approach.  We talked about molecular, we talked about a new chemo formulation CPX, and this was an antibody, so an immune therapy.  So just like in solid tumors in both acute lymph blasting in acute myeloid leukemia there's a big surge of immune agents, and I think these are going to make a big impact in the next five to seven years in treatment of all cancers. 

So this was what we call an antibody.  So antibodies target markers on the surface of your leukemia cells that we call antigens, and we can develop these antibodies to carry these toxic payloads.  And we used to use a lot of bacterial toxins, so toxins that in the nature are found.  They're used to be bound to the antibody and then go and target the leukemia cells.  So it sounds like science fiction, but actually it's something that's been done for 10 years, and it works quite effectively. 

So this was a drug called gemtuzumab ozogamicin (Mylotarg), which targets CD33 which is expressed heavily on the AML cells, and it had a toxin, calicheamicin,

that was delivered to those cells.  And the Mylotarg as a single agent had about a 35, 40 percent response rate, but more importantly when it was combined to the three-plus-seven chemo, the one we've used for 40 years, it improved the overall survival by about 25 percent across all AML. 

So unlike a targeted therapy this was really benefitting a frontline induction across AML.  So now it's being used pretty much in all new diagnosed AMLs except for the FLT3 and IDH, which get targeted therapy. 

So these are the four approved, but there are two or three very other exciting ones.  One of them is a drug called venetoclax (Venclexta).  So this is a Bcl-2 inhibitor.  It's approved in CLL, there's exciting data in myeloma, and now there's an AML, a very large, 200-plus study. 

And this study, what was unique is it looked at elderly AML.  So while in the younger AML we always had 55, 60 percent cure rate, in elderly AML for the last five decades there was zero progress.  So the cure rate was 5 to 10 percent in 1960, and in the last year database, 2010, it was 5 to 10 percent.  Now, there was a drug called azacitidine (Vidaza) approved in that indication, and there was a 25 percent response rate. And about a 15 percent, 20 percent of patients could have a durable benefit, but it was still a very small percentage. 

So when we added this drug, venetoclax, to the azacitidine we're seeing the response rates now going up to 73 percent.  So from 25 to 73, not doubling, but tripling, and more important we're seeing the survival, the two-, three-year long-term survival going from 15 percent to 50 percent.  So we are very excited about this.  This is the first time where I can sit with an older AML patient, a 70-, 75-year and them him you actually have an 50 percent chance of being alive two, three years from now, which is really not something we could do for 40 years.  So this is now in a Phase III.  It's enrolling very, very quickly.  We expect it to be out on the market. 

And then there are a number of immune therapies, immune checkpoints which have worked across solid tumors now are showing activity in AML, so we're moving in that arena.  But it's a dramatic progress.  We've had to restructure all our clinical trials.  So we have 70, 80 trials in AML, and now all the single agents have been moved to doublets and triplets, because we have such good drugs that we want to give the best approach to the patient at the first shot. 

Andrew Schorr:

Wow.  So where acute leukemia was sort of—AML for sure, certainly in older people, was a terrible, terrible diagnosis, now there is a great deal of hope.  And there are things you can do, and it's moving in these combinations even faster. 

Dr. Daver:

Yeah. 

Andrew Schorr:

You must be very excited. 

Dr. Daver:

We're very excited.  And again, you know, what I tell my patients is even with, let's say, aza-venetoclax even if it's a 50 percent at two years, in two, three years we're going to be into triplets.  We're going to have combinations of new antibodies, new immune checkpoints.  So again if we can keep patients alive for a couple of years by that time we're going to have even better things that will add another few years.  So I think it's very possible that an even older AML could get five, seven, eight, nine years, which I think would be something nobody five years ago would have dreamt of. 

Andrew Schorr:

Wow.  Okay.  So if you or a loved one is affected by AML, younger or older, you need to get plugged in to this changing array of testing that needs to be done to know what are you dealing with, the approved therapies or combinations, and also what's in research that sounds so promising.  Dr. Naval Daver, thanks for really are giving us the…

Dr. Daver:

Absolutely. 

Andrew Schorr:

…latest rundown. 

Dr. Daver:

Yeah, always a pleasure. 

Andrew Schorr:

Thank you.  Andrew Schorr with Dr. Naval Daver from MD Anderson.  Remember, knowledge can be the best medicine of all. 

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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Page last updated on May 28, 2018