Treating AML in Older Adults, with Dr. Timothy Pardee

Leigh Clark (00:00):
Hi, everyone. This is Podcast for Patients with the Aplastic Anemia and MDS International Foundation. I'm Leigh Clark, Director of Patient Services and I'll be conducting the interview today. Our podcast series is brought to you, uh, thanks to the generous support of our patients, families, and caregivers like you, and our corporate sponsors. Thank you, everyone, for supporting the podcast series.
(00:32):
Today, we'll be talking about advances in treating AML with older adults with Dr. Timothy Pardee, who is a Professor of Medicine and the Director of the Leukemia Program at Atrium Health Wake Forest Baptist. Thank you so much, Dr. Pardee, for joining us today.
Timothy Pardee, MD, PhD (00:52):
My pleasure. Thank you for having me.
Leigh Clark (00:54):
Uh, what is AML?
Timothy Pardee, MD, PhD (00:57):
So AML, or acute myeloid leukemia, is, uh, an aggressive acute leukemia. It is a kind of cancer of the bone marrow, and what happens is there are white blood cells that are usually, uh, supposed to help us to fight off infection, and, uh, a precursor to those white blood cells, uh, becomes cancerous and continues to grow and, uh, divide even though there is no signal from your body that more of those cells needed. And, ultimately, what happens is the cancer cells, the leukemia cells, end up crowding out the bone marrow where your normal blood cells are made and, uh, it, it leads to bone marrow failure, which leads to things like really low red blood cell counts or severe anemia, as we call it, really low platelet counts, or severe thrombocytopenia, as we call it, and then, these patients are unfortunately quite immunocompromised, which leads to, uh, recurrent infections.
Leigh Clark (01:55):
And what are the current treatments available for treating AML?
Timothy Pardee, MD, PhD (02:00):
So a few years ago, this would have been a really short podcast, um, because, for many decades, we only had sort of an intense chemotherapy regimen that we use to treat, uh, our AML patients, but, thankfully, uh, in the more recent times, we've had a number of new approvals for drugs to treat, um, acute myeloid leukemia. Now this has been particularly helpful for, uh, older patients because one of the big limitations we had in AML treatments earlier with this intense chemotherapy regimen was many patients with AML are older. In fact, the average age at which someone is diagnosed with AML ranges between 68 and 72 and so many of those patients may have other medical problems that don't make them a great candidate for intensive chemotherapy and we used to have very limited options for those patients.
(02:53):
Fortunately, now, we have, uh, more options, including some that are appropriate for patients that may have other medical problems and are not, um, fit or choose not to be interested in a more traditional chemotherapeutic approach. So I think what I'd like to do is kind of divide my answer into what we do for fitter patients and what we do for less fit patients.
(03:14):
So for fit AML patients, (and I'm not using the term older on purpose because there are fit older folks and there are less fit younger folks,) so for fit patients, meaning those who have very few other medical problems, are taking few or no medications for other medical conditions, and are in good shape, able to carry out all their, uh, activities of daily living independently, able to maintain their own households and go to work, if they're still working, those folks, uh, we do still consider an intensive chemotherapy approach, uh, and that includes the very traditional induction chemotherapy, which is a combination of two drugs. One drug is called Cytarabine and the other is called daunorubicin, and those two drugs, uh, are given in a regimen called 7+3, and that's the initial or induction chemotherapy that we give, uh, to these patients, and that requires a four to six week hospital stay, and the goal of that therapy is to put a patient into remission.
(04:17):
More recently, there has been another intensive chemotherapy approach that's FDA-approved, and that's for, uh, fit patients who have what we call a secondary AML, which means that it's an AML that has come from either previous chemotherapy that they've gotten for other cancers that are now cured or from other blood cancers that have been turned into AML, like myelodysplastic syndromes. That chemotherapy is called Vyxeos, and it's a special preparation of the same two chemotherapies that are in 7+3, uh, and it's given a little bit differently, but the hospital stay is, is about the same. It's a long hospital stay, four to six weeks, and the purpose of that initial hospital stay is to put patients into remission.
(05:07):
And so, for our fit patients, we, uh, think about whether they're a de novo AML, meaning it's come from no previous condition and there's no history of chemotherapy or radiation exposure, and those patients, we would, um, think about 7+3. Uh, and then for patients who have a secondary AML, meaning they've had a previous hematologic malignancy or exposure to chemotherapy or radiation, we would consider a drug called Vyxeos, um, and the goal of those therapies is to induce a remission.
(05:40):
So, uh, a quick word on what I mean by remission. Patients, understandably, can sometimes get this confused. A remission is not a cure. A remission means that, when I look in the bone marrow by doing a bone marrow biopsy, I don't see leukemia cells and I do see healthy bone marrow cells, and a remission also requires recovery of their platelet count and their neutrophil count, and neutrophils are a kind of white blood cell. So we need to see some normal white blood cells, we need to see some platelet recovery, and freedom from needing red blood cell transfusions, and then we need to not see any evidence of the leukemia in the bone marrow, and that's a remission.
(06:24):
Unfortunately, a remission is not the same thing as a cure and many patients in remission will ultimately relapse, and so that's why fit patients, after they are in remission, will go on to get consolidation therapy, and that means just additional therapy to try to deepen and lengthen that remission, and that comes in the form of either high-dose Cytarabine, if patients have good risk AML, and that's given, um, with shorter hospital stays, anywhere from three to four cycles, or additional doses of Vyxeos, if the patient was initially treated with Vyxeos, or, for patients who have intermediate or higher risk AML, we will often refer those patients for consideration of a bone marrow transplant in consolidation, once they're in remission.
(07:15):
So that's our pathway for fit patients. For unfit patients, we have a combination of medicines now that we use, and these are two drugs. The first is a drug called azacitidine and the second is a drug called venetoclax, and this was a combination regimen that was approved in 2018 for older patients or those who have other medical problems that make them, um, to not be great candidates for the combination chemotherapies I've talked about before. So azacitidine is an intravenous medication and it's given once a day for seven days. Venetoclax is a pill and it's taken every day. And this regimen is repeated every four weeks.
(08:02):
So patients who, um, start this regimen will have a bone marrow biopsy done usually in the fourth week of the first cycle to see how much leukemia is left and, if there is no visible leukemia left, then patients will sometimes have their next cycle, or cycle number two, delayed by several weeks to allow for count recovery, meaning to allow their anemia to get better, their low platelet counts to improve, and their low white blood cell counts to improve before starting cycle number two.
(08:34):
A couple of important distinctions between the chemotherapy approach for fit patients and this approach, the first is that this approach is essentially indefinite, so the, the plan would be to continue to treat less fit patients with this combination in recurrent cycles, and we do that, uh, until they have resistant disease, meaning the disease comes back and is no longer responding to the combination, or if they have intolerable side effects and say, "You know what, Dr. Pardee, thanks, but I'm not longer interested in receiving this combination."
(09:11):
Now I will say that there is some emerging studies that have looked at the safety of discontinuing this regimen in patients who've had exceptionally profound responses and that does appear to be safe in some circumstances, but I think, for most patients, it should be, at least at this point, considered to be an indefinite regimen that you would do, uh, on a repeated basis.
(09:35):
Additionally, we now have some FDA-approved agents which are specific to specific mutations, or genetic changes, in the leukemia of, uh, of a patient. So there are two genes that are recurrently mutated in about 10% of AML patients and these are genes called IDH1 or IDH2 mutations, and these mutations make that AML susceptible to an oral agent. Actually there are two, one for each of those mutations. So there's ivosidenib, which is a pill, an oral agent, that is, um, targets the IDH1-mutated AML, and there's another pill called enasidenib, which targets the IDH2-mutated AMLs.
(10:27):
And, if you have a very unfit patient who wouldn't tolerate the azacitidine plus venetoclax approach, you can give either of those pills as a single agent, and there is documented response rates, uh, remission rates, uh, for patients receiving those, those medications, as long as they have those mutations. Unfortunately, if you don't have those mutations, those medicines will not be helpful to you. Additionally, there was a recent study, um, about a year ago, that was published that combined the one drug I've already mentioned, azacitidine, with ivosidenib, and this study had really encouraging response rates and survival, so that combination is also a consideration for, uh, less fit patients who have an IDH-1 mutation.
(11:21):
Finally, there is another mutation called FLT3, and that's FLT3. This is a gene that's mutated in about 30% of AML patients or so. If you have this mutation, um, there are drugs that specifically target the mutated protein. So one of those drugs is called midostaurin, that's a pill, and we give that in combination with intense chemotherapy, 7+3, for fit patients. There is a second agent called gilteritinib, which is also a pill, and we give that as a single agent for patients who have FLT3-mutated AML after it has progressed on a frontline treatment like either 7+3 or azacitidine and venetoclax, uh, and that pill is also FDA-approved. So that's a general rundown of the treatments that are currently available for patients with AML.
Leigh Clark (12:20):
Thank you. Uh, what are the challenges in treating AML in older adults?
Timothy Pardee, MD, PhD (12:28):
So one of the biggest challenges, no matter which treatment we use, either the intensive chemotherapy treatment or the azacitidine and venetoclax approach is that patients have very poor bone marrow function, which means that they've very dependent on transfusion support, and it also means that they are very susceptible to infections. So I think one of the most challenging aspects about treating leukemia in older patients is making sure that they're not getting infected, um, and infections are a very serious complication for our leukemia patients and so that can be a real challenge in treating, uh, older AML patients.
(13:17):
I think the second biggest challenge, um, after the sort of bone marrow failure issues, are related to the other medical problems that an, uh, older patient, um, typically has. And so sometimes patients who would otherwise, um, you would recommend, say, a bone marrow transplant for, but, unfortunately, have had, say, a heart attack and their heart doesn't, um, pump normally and they aren't candidates for bone marrow transplant, um, that can be challenging as well and you have to really adapt your management strategy to the patient in front of you and that, that is also a big challenge.
(13:56):
And then, finally, making sure that your patient has, um, the support that they need. So, thankfully, many of our patients have, uh, great family or community support, but, occasionally, you'll have an older patient who is a bit isolated and doesn't have those support systems in place, and so having programs that reach out to those patients, like we do here at Atrium Health Wake Forest Baptist, we have a cancer patient support program that can be really helpful in helping our patients deal with the diagnosis and our great case managers who can help to identify community resources to bring in and, and help to support, uh, those patients. That can also be a challenge.
Leigh Clark (14:36):
Thank you. What is on the horizon for treating AML?
Timothy Pardee, MD, PhD (14:42):
So we've definitely made some improvements, uh, but there's still a long way to go. So, unfortunately, the five-year survival for a newly-diagnosed AML patient, uh, so if you have 100 newly-diagnosed AML patients and you ask the question, in five years, how many of 100 people will still be alive, the answer's about 30. So there's definitely, uh, a lot of room for improvement. And, thankfully, there are some really exciting developments that are coming, uh, that are, that are making their way, hopefully, to clinical practice.
(15:18):
So, um, I'm sure many of your listeners have heard all about how immuno-oncology has revolutionized the treatment of a lot of solid tumors. So there are drugs that are now being used routinely in non-small cell lung cancers and other tumor types that have, um, really improved the outcomes, and they do that by harnessing the immune system to attack the tumor. So we've looked at that a bit in AML and, unfortunately, the traditional, um, immuno-oncology drugs, like Keytruda, or pembrolizumab, uh, don't seem to be really active in AML and so that's been a bit of a disappointment.
(16:00):
However, there are other approaches to activate the immune system that are, um, producing some really interesting, really early data. So one of those drugs is a drug called magrolimab. Um, magrolimab basically takes away the leukemia's invisibility cloak. So your leukemia cells hide from your immune system. They do that by expressing, uh, a protein called CD47, which basically tells other cells of the immune system, "Don't, don't eat me. I'm, I'm a member of the team. I'm with you guys," uh, and what magrolimab does is it really cloaks those, those leukemia cells and, and makes them more visible to certain parts of your immune system, particularly a kind of cell called a macrophage, which would then encourage the macrophage to eat and destroy your leukemia cell in a way that our current therapies really can't. It’s very early days for the studies with this agent, but, so far, they've been very encouraging and I look forward to seeing more data, uh, as it comes out.
(17:05):
The second area that I think has been really encouraging is we're looking at other immuno-oncology targets, uh, so new targets that will help to make our adaptive immunity, our T cells, uh, recognize and attack the leukemia more efficiently are, are being investigated. So these are, these are novel checkpoints, um, proteins like TIM3 that are being, um, looked at for their ability to make AML cells more susceptible to our immune system. And, again, it's very early days, but some studies are starting to come out that are showing some encouragement.
(17:42):
And then we're continuing to move towards, uh, our targeted therapies in AML. So, as I mentioned, there's a drug for mutations in, in IDH1, there's a drug for mutations in IDH2, there's a drug for mutations in FLT3, and there's another drug that's making its way, ac- actually, several drugs, I think there are three companies that each have their own version, um, of something called a Menin inhibitor, and this is a protein that's really important for certain subtypes of AML. So if you have an AML that has a mutation in a gene called NPM1, which is about 30% of AML patients, or if your AML has a genetic rearrangement involving a gene called KMT2A, uh, or MLL is the other name for that gene, a Menin inhibitor has shown really remarkable efficacy in the laboratory.
(18:35):
So in preclinical systems, AML, um, models that have those, uh, genetic changes are incredibly susceptible to the use of these, um, Menin inhibitors, and there are now Phase 1 and Phase 2 studies that are, uh, being conducted with, uh, lead compounds that target Menin that are showing some really promising results, so another area that I'm very excited about, seeing how those studies ultimately turn out and, and, hopefully, eventually, will lead to another approved medication.
Leigh Clark (19:09):
Thank you. If a patient was interested in finding a clinical trial for AML, how would they go about doing that?
Timothy Pardee, MD, PhD (19:17):
Yeah. So I, I think the first thing I would say is to, to please be sure to discuss your interest in a clinical trial with your oncologist. I think that your oncologist should be a really good resource for finding clinical trials for you. And, as someone who believes very strongly in clinical trials, I, I think that that's always my preferred way to have a patient treated whenever possible is on a clinical trial, um, and I say that because, obviously, I'm interested in making treatments better for AML patients, but there's also emerging data in a number of different kinds of cancers that patients who are treated on clinical trials actually do better than patients who are treated with standard, uh, treatments off of a clinical trial.
(20:03):
So I think there are a lot of reasons to seriously consider participating in a clinical trial. So your oncologist should be someone you're involving early in that conversation. I think the other place to look is a website called clinicaltrials.gov. Um, clinicialtrials.gov is maintained by the government, it is not a commercial site, and it has a very user-friendly search engine that you could put in, uh, AML and one of the things that I really enjoy is when a patient comes in to see me who has done their homework and has some clinical trials they found on clinicaltrials.gov and we can discuss, uh, you know, whether or not they'd be an appropriate candidate for those trials. So, I would definitely, uh, advocate for the early involvement of their oncologist, but also, clinicaltrials.gov is a good resource.
Leigh Clark (20:54):
Thank you so much, Dr. Pardee, for sharing your time and your expertise with all of us today. You can find out more about bone marrow failure diseases on our website at aamds.org. You can also find information by following us on Facebook, Instagram, and Twitter, or give us a call at our helpline at 800-747-2820. This concludes our podcast. Thank you, Dr. Pardee.
Timothy Pardee, MD, PhD (21:24):
Thank you for having me.