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AML Breakthrough Therapies

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Published on June 10, 2020

"In 2017 and 2018, eight new drugs received FDA approvals, the challenge is now when to use them," said Dr. Thomas LeBlanc, Duke Cancer Institute. Watch as he explains what these new breakthrough drugs change for patients and how acute myeloid leukemia (AML) specialists can personalize care determined by a patient's fitness.

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Transcript | AML Breakthrough Therapies

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.

Dr. LeBlanc:

So in 2017 and 2018, we had eight new drugs get FDA approvals, so we have a number of wonderful new tools to use. The challenge now is figuring out when to use them, which patients are the right patients for the particular new therapies. Are we doing all of the testing that we need to do that identifies the specific targets, which are targeted by many of these therapies? And then also how do we combine them together in a sort of a rational way that might lead to improved outcomes without just adding excess toxicity? And although there have been these new approved drugs in AML in the last several years, really we still do a lot of the same things in treating this disease around whether we give either a really high-dose intensive therapy up front, what we call intensive induction chemotherapy or more low intensity therapies, which is where most of the exciting new innovations and approvals have come in the last few years.           

So the main determinant still really is whether a person is "fit or unfit." And a lot of that is really determined on the basis of whether your doctor feels your organ function is adequate enough to tolerate really risky high-dose therapy but then also whether or not you are kind of physically fit, up and about doing things. Maybe exercising some versus sitting on the couch not doing anything and really sort of weakened and fatigued and in a position where a really intensive treatment might actually be more harmful than helpful. So once we know which camp a person is in, are they in the "fit" or the "unfit" group, and by the way, sometimes unfit actually just means of a certain age, because we know that the really intense therapies are much, much riskier in anybody who's in their 70s or certainly age 75 and older.

But age isn't an absolute, and it's not the only important factor. So if a person is in the fit, more kind of intensive therapy group we have a number of different options to choose from now, where if a person has a mutation identified, a FLT3 mutation, we sometimes add a targeted therapy to their intensive induction therapy. So we have midostaurin (Rydapt) that we would add to the old 7+3 intensive induction regimen. We also sometimes add the anti-CD33-targeted drug, gemtuzumab ozogamicin (Mylotarg). That gets added sometimes to intensive induction therapy with the 7+3 regimen in patients who have certain more favorable risk abnormalities in their chromosomes, structural rearrangements in the actual genetic material in the chromosomes in their cells. Obviously, this is very complicated. Things have gotten very sophisticated in how we do the testing and interpret these tests results to determine what therapy might be the right therapy for a person with AML.        

Similarly, another one of the recently approved therapies is basically a lipid capsule around the old 7+3 chemotherapy. So liposomal daunorubicin (Cerubidine) and cytarabine (Cytosar-U) or CPX-351, that's a drug that's indicated specifically for people who have AML arising out of what looks like myelodysplasia-related changes. So if someone had myelodysplastic syndrome and develops AML, they seem to do better with that particular new drug and also, patients who have a therapy-related AML. So if you had a prior cancer, you've got chemotherapy for that, developed AML as a result, that too can be an indication for CPX-351. And so we're combining the new advances in molecular testing with the new drug advances that we have to more personalized treatment in the upfront setting. If we move to the "unfit" category, like I said, this is where more or most of the innovations have taken place.  
So there is another FLT3 inhibitor called gilteritinib (Xospata) that sometimes is used in unfit patients with that mutation, although it's actually approved as a second-line single agent, sort of a therapy. It is in guidelines for off-label use as an up-front therapy. There are also IDH inhibitors. So there are IDH-1 inhibitor, ivosidenib (Tibsovo) and the IDH-2 inhibitor, enasidenib (Idhifa). About 20 percent of AML patients will have an IDH mutation, about 30 or so percent will have a FLT3 mutation. And I mentioned those two drugs already. So if you think about it, we actually now have roughly 50 percent of patients with AML have a targetable mutation and IDH-1, IDH-2 or FLT3, since largely they don't overlap very much. And then in other patients where maybe there isn't a targetable mutation or where we might just think this is a better treatment option and these data are sort of starting to emerge now, and there are no head-to-head trials.      

So we can't definitively say one is better than the other, but there certainly is some exciting evidence about this. That the Bcl-2 inhibitor, the anti-apoptosis drug, venetoclax (Venclexta) has been approved in combination with hypomethylating drugs like azacitidine (Vidaza) or decitabine (Dacogen) or also with low dose cytarabine (Cytosar-U or Tarabine PFS). With any one of those three agents, it looks like it's very, very promising in terms of getting patients into a remission with AML when they can't tolerate an intensive induction therapy, or they may be not "fit" for an intensive induction therapy. And the other drug that I have not mentioned yet to sort of round out the eight approvals is a drug called glasdegib (Daurismo), which is a Hedgehog inhibitor, which also is approved in older unfit patients in combination with low dose cytarabine has been associated with a survival benefit as well.     

So we have all of these new therapies. I tried to go through that relatively quickly without getting too complex into the details but as you can tell, it's very, very nuanced and complicated now. But if we start off with considering fit versus unfit, and then we layer on top of that, which mutations a person might have in their leukemia cells, or which markers are expressed on the cell surface like CD33, for example, then we can have a sort of better sense about which newly available exciting therapies might be available and kind of narrow that down and personalize the treatment together.

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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