From Lab to Life

Hello and welcome to our program titled Mastering the Complexity of AML Treatment, a Multidimensional Approach to Diagnosis, Therapy and Side Effect Management.

My name is Dr. Amir Fathi, the director of the leukemia program at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School. I'm joined today by my esteemed colleagues, Dr. Courtney DiNardo, professor of medicine in the department of leukemia at MD Anderson Cancer Center, and Dr. Brian Jonas, professor of medicine at the University of California Davis. Our disclosures are displayed on the screen.

This educational activity is supported by independent educational grants from AFI and STELUS. The learning objectives for this program are to utilize trial evidence and guideline -based recommendations concerning targeted therapies to manage AML case scenarios typically encountered in community settings and to develop effective strategies to monitor for and manage treatment -related toxicities in patients with AML. I'm going to talk specifically about factors that we looked at prior to

recommending a patient for transplant. Transplant has really become the main consolidative option for younger patients and more fit patients as a modality of consolidation because it has the potential to cure as opposed to many of the other options that we may have that are less likely to do so. Particularly in patients who have intermediate risk disease, those who have persistence of MRD, and those who have adverse risk disease,

If they have a donor, if they are sufficiently fit and appropriate in terms of organ function, we do recommend transplant. Factors that impact transplanted success as well as choice of conditioning therapy depend on multiple factors, including the donor and the recipient age, comorbidities of the patient, HLA mismatch between the donor and the patient, history of hereditary AML. As mentioned earlier, if a patient has a hereditary mutation syndrome,

want to be thoughtful about family members who may want to choose as donors or not choose. And that's the source of the donor cells, whether it's a match related donor, unrelated donor, or a half match donor, for example. And then the thought process around persistence of MRD following induction and consolidation, as well as age.

because it would make a difference in terms of choice of non -myeloablative versus myeloablative conditioning prior to transplant. And then the choice of post -transplant maintenance as was mentioned before for GILTA -RITNAM is also an important consideration, MRD. The adverse effects of transplant are multitude and variable, and they could be related to conditioning such as sinusoidal obstructive syndrome, mucositis,

GI toxicities, they can be related to graft failure, graft versus host disease, cytopenias that develop shortly after transplant, infectious sequela of all sorts, pneumonitis that can be severe and overwhelming, as well as idiopathic pneumonia syndrome. And then the long -term effects, and that's why we have so many survivorship clinics now emerging in various cancer centers across the country, chronic GVHD,

chronic and recurrent bacterial infections, reactivations of various viruses, including as Oster, infertility, lymphoproliferative states, and chronic pneumonitis. So transplant and the discussion around transplant requires a lot of consideration of the patient, their disease, as well as donor sources. And I think some of that goes to balancing the treatment benefits and toxicities of AML, not just transplant.

that I just mentioned, also the treatment that precedes it. And we have, I think, made a substantial amount of progress in recent years, even before the rush of approvals that we saw 10 years ago. Over the course of the last 10 years, I should say, there was an incremental improvement over time in survival, which was really due to supportive care, managing patients, expert transfusional approaches.

so that patients now getting treatment for AML are much better managed in terms of nausea control, mecositis control, transfusional support, social supports that allow them to get through intensive and long -term therapies. So I think we have a lot to provide patients who undergo treatment for AML, including ophthalmotherapies, relapsed refractory therapies, and transplant -based therapies. But nevertheless,

As we've talked about over and over again, the tolerability and safety issues are very important and paramount, can be overwhelming and need to be considered in every case because there is a risk benefit consideration in almost every discussion. And that brings us to the shared decision making aspect of all this. We talk about the diagnosis with the patient, we talk about the molecular markers that allow us to make decisions regarding.

what we're going to incorporate into the upfront setting versus the relapse refractory setting and sometimes in the maintenance setting and look at the data that supports that and then talk about what we would expect to get from therapy and the potential toxicity and safety issues that emerge. And with that, we try, at least I try my best to engage in a back and forth with the patient to come up with a shared decision regarding what best fits their goals and their needs. And my job is really to provide the information

provide my recommendation, but also hear what the patient has in mind regarding what they understand and know about effectiveness and safety, concerns about side effects, their fears and anxieties regarding relapse and potential death and complications that may emerge from their disease. And then talk about quality of life, of course. And they also have financial considerations here, which I think is a good idea. I mean, this is becoming more and more an issue as many of these drugs that are emerging are highly, highly expensive.

and require oftentimes a significant amount of paperwork and effort by our support staff at the hospital so that patients can afford it and take it. The best practices in terms of shared decision -making in our management of AMO patients require close consideration. So talking together as a team, providing options for patients and coming together in terms of decisions. And there is this method called the PACE's method.

that I maybe don't use as much as I should, but I think it's a useful method of presenting information, making sure the patient understands what you're saying, checking their understanding, asking questions, allow them to ask questions, express appropriate concern and support, and then go through the preferences that the patient has. And I think if you follow that guidance, then I think many of us do probably, but this sort of a check mark type approach to discussions with the patient and a shared decision -making approach, I think you're more likely to have

a fulfilling discussion and a satisfactory outcome. We have previously explored some strategies for making treatment recommendations for our AML patients. I'd like to discuss this further with my colleagues and see how these strategies can work in real world clinical situations. Here's a case. Elaine is 62 years old. She was recently diagnosed with AML. She has 82 % blasts in her bone marrow.

presence of a FLIT3 ITD mutation. We think based on her performance status, that she is eligible for intensive induction therapy. With that in mind, Brian, what would be your approach for upfront therapy for a patient like Elaine? Good question. When you think about what's available in terms of drugs that are approved for FLIT3 ITD mutated patients,

you think about quasartinib and mitosinrin, I would favor 703 and quasartinib in this patient based on the quantum first trial. The reasoning is the age, which was included in that study up to 75, I think this was mentioned before, ratified did stop at 59. And there seems to be some tolerability benefits to the quasartinib, which we can discuss further.

So at our institution, we've done using more Guzartenev over time since the approval and would favor that combination in this patient.

But every time you use a FLIT3 inhibitor, as you know, we have to sort of think about the potential for adverse events that may emerge. Have you seen a lot of QT prolongation in your experience with Quizartnib or any other challenges that you've seen with this agent?

I mean, we monitor it, you know, of course there's a lot of good guidance in the package insert that I recommend that people review and follow. in our institutional experience hasn't been a major problem, but it's something that is theoretically out there and needs to be monitored closely and the dose adjusted if the QTC interval increases.

And there's also the other issues are concomitant medications, which also might require just modifications of quizartinib, which could also run into trouble with QT if they're not followed. And this is a question that oftentimes we now deal with because patients go home and rightly so read up on the drugs that we recommend to them and they find something that is of concern to them. So Courtney, when you are recommending, let's say,

Ivosidinib or anacidinib or guilt or it was artinib in this case, I guess. And the patient expresses some hesitation or anxiety. What is your general approach in that sense?

You know, people can be nervous about things for all sorts of different kind of underlying reasons. And so, you know, my first step is just to try figure out, you know, what is the underlying concern and what is it stemming from? And helping just people, you know, understand, you know, one of the things I say a lot to people, you know, as they're reading an informed consent document that has...

know, dozens of different risks is, you know, this is, these are all potential, but it is very unlikely, you know, that all of these things are going to happen to you. And so there's going to be potentially one or two different side effects. And so whatever it is that you're experiencing, right, that's new or different, let me know, and we can help you work through it. I often say, because it's true, you know, if you read the label of Tylenol, it's terrifying, right? And, you know, and these are chemotherapy drugs. So they...

have more risks than taking a Tylenol pill. But oftentimes people can tolerate things well. so it's really just, it's education. is time spent with patients and family members making sure that their concerns kind of are heard and validated. And then we help them understand as best as possible. Now that we have had some changes to the prognostic scores and the diagnostic approaches to AML,

FLIT3 mutations are not necessarily going to be adverse risk. So in a scenario where, let's say, Elaine, she seems like a lovely lady, I suspect she will get a remission following therapy and tolerate treatment quite well. What is the next step after induction? What is now the general approach to a FLIT3 mutated FIT patient who has achieved remission following upfront therapy?

I'll start with Brian and then maybe Courtney can chime in. At our center, we still recommend a transplant and the goal would be to try and get them flit three negative prior to transplant, but if not, then transplant and maintenance.

Well, I'm here, think you kind of stole my thunder a little bit, but yes, I agree. No, and I think that's how we're practicing at UC Davis as well. Most patients are gonna be taken to transplant. Our transplant group still believes that FLIP3 ITD, even if you achieve a good response, still mutation that merits strong consideration of transplant and first remission. And so that's still a standard around our patients.

Of course, transplants, don't know how it is at your institutions, but we're not usually ready to go right after induction. So patients are going to get cycles of consolidation with the foot three inhibitor. If it's ratify or quantum first, follow whatever strategy you started with and stay on those consolidation cycles until such time that transplant is ready. And hopefully patients will achieve MRD negativity, which has been shown to improve the outcomes.

know, after transplant, some, you many patients are going to be considered for maintenance as you alluded to, especially those that are going to derive the most benefit from it, which seems to be the MRD positive. But I'll see what Courtney has to say in case there additional things. Yeah, I think, I mean, I think, I think that's exactly right. It is a testament to FLIT3 inhibitors and improved therapy outcomes, right? That FLIT3 ITD has moved.

for many patients from an adverse risk disease to an intermediate risk disease. But that's because of the effective therapy that we have with a therapy plan that includes intensive chemotherapy with the FLIT3 inhibitor followed by a transplant. So we still feel pretty strongly that transplant should remain part of that treatment pathway for a FLIT3 ITD mutated patient. There is some increasing evidence that for patients who are NPM1 mutated,

and FLIT3 ITD mutated and become MRD negative by kind of all MRD negative means, but in particular the NPM1 and the FLIT3 PCR that we could potentially have cured those patients without the need for a transplant. So that is something that maybe time will tell, but still I agree with what has been said at our institution, FLIT3 ITD mutated patients, that curative pathway includes transplant.

Great, thank you both Courtney and Brian for this thoughtful discussion. So in summary, transplant is the only curative treatment for the majority of cases of AML, not all, but the majority. And transplant is not available to all patients due to various reasons, including their functional status, their age, the availability of donors, and the availability of transplant. With an increase in novel therapies and targeted therapies, patients face

potentially more complex decision making and must balance the vulnerability, efficacy, prognosis and quality of life concerns in coming up with a decision that hopefully is a shared making approach with their physicians. That's all the time we have for today. I would also like to thank our sponsors for their support of this program. We would like to ask the learners to please fill out this evaluation and post -test to receive CME credit. This provides us with valuable feedback that will be used

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