iwAL 2024 | Discussion: should less intensive therapy be used in all older newly diagnosed pts with AML, even if fit for intensive chemo?

Jessica Altman:

Hi everyone. My name’s Jessica Altman. I’m speaking to you from iwAL here in Phoenix, Arizona, with my dear friends and colleagues, Dr. Tapan Kadia and Eunice Wang. I’ll allow them to introduce themselves.

Tapan Kadia:

Hi everyone. I’m Tapan Kadia from MD Anderson Cancer Center in Houston. I’m one of the leukemia doctors there.

Eunice Wang:

And I’m Eunice Wang from the Leukemia Service at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Jessica Altman:

So we’ve had some very exciting sessions at this meeting thus far. And I think probably the most exciting session to date is the one that we just came from, where the two of you presented an argument really focused on offering HMA-Ven or lower-intensity therapy for all older adults, irrespective of fitness. And you had some opposing views of that that’s not the most appropriate therapy for all older adults. So could you start with the high level thoughts that you have, Eunice, regarding the treatment for an older adult?

Eunice Wang:

So I think a lot of it has to do with obviously, the heterogeneity in AML patients. Obviously, there’s significant heterogeneity in the biology, as well as performance status and age of patients. As you know, the median age of presentation is 67 to 70. But when you’re talking about a gentleman or a woman in their 60s, they could be extremely fit or they could be one that has lots of comorbidities and looks older than their stated age. And so the debate was really, for that 60 something year old individual that looks fit for intensive chemotherapy, what would be the best induction regimen? Would it be an intense cytarabine-anthracycline based regimen, or would it be a lower intensity regimen? Which could be ven-aza, it could also be things like cladribine, LDAC et cetera.

And so what I was really focusing on a little bit, was some of the emerging data, albeit in very small subsets of patients, of the very, very high success rates in specific biological subgroups of AML, those with IDH1, IDH2, FLT3, and now NPM1-mutant and KMT2A re-arranged. And the advent of multiple targeted therapies, specifically FLT3 inhibitors, IDH1/IDH2 inhibitors, and the emerging class of menin inhibitors. The success of these targeted agents added to a ven/HMA backbone has been remarkable within very small studies. The overall response rate is 80, 90%. And the ability to transition these patients with very, very little mortality in the 0% 60 day mortality for a lot of those regimens. So really the question in my mind, is for patients that have these particular subgroups, even if they’re fit, wouldn’t it make sense to offer these therapies? And I think there were some opposing arguments. And my colleague can talk about some of the just standard chemo, regardless of targeted therapies.

Jessica Altman:

So those are phenomenal points. I think there’s a lot we will hopefully have time to dig into. Maybe before we do that, Tap, could you go through a little bit about what you think about in terms of both patient characteristics and disease characteristics, when you’re having a conversation with your patients and thinking about the available therapies?

Tapan Kadia:

Yeah, absolutely. Thanks, Jessica. I think, like I said, Eunice and I, we had a great debate with our colleagues. When you’re talking about patients 60 years of age and older and getting an induction chemotherapy for AML, we fortunately now have many different options. We have intensive chemotherapy, which we’ve always had. 7 + 3 are along those lines. But now we have new therapies like HMA-Venetoclax, we have HMA + IDH1 inhibitors for IDH1-mutated patients. And so there was a heterogeneity of treatments and we need to match those to the heterogeneity of the patient. So you ask a great question, how do I evaluate a person who comes to see me, who’s 60 and older saying, “Doc, I have new AML. How do I treat?” So the things I look at are what I think of as patient-based characteristics, and then disease-based characteristics.

So the patient itself, their age, obviously, but age is often just a number. There are many fit people who are older than 60 and unfit people who are younger than 60. So it’s age, it’s their fitness, it’s their ability to perform their normal ADLs, as well as beyond their ADLs. It’s their organ function, what their kidneys, liver are doing. It’s their performance status, are they able to perform normal activities? Not only now, but what were they doing three months ago, six months ago before their diagnosis? So that all plays a role into how I choose the intensity of the chemotherapy. Then we go into the disease characteristics. There are some disease subsets in AML that unfortunately, to this day are still very resistant to chemotherapy. You can drop a nuclear bomb on them and they’d still be alive. And these things are P53 biolytic mutations, complex karyotype, chromosome 3 recomb/rearranged, where you can give them intensive chemo or low-intensity chemo and see no difference in outcomes, but you will see excess toxicity with the intensive chemotherapy.

And so we ask ourselves, is it really important to give those folks intensive chemo? And so I think that disease characteristics including the genomics, their karyotype, their mutations, whether they have certain mutations that are targetable with things like FLT3 inhibitors, or IDH1/2 inhibitors, where we can use those different therapies. And then finally, one subset, which we sometimes forget about, but in the heat of the moment, you often don’t forget, is the patient’s wishes or their goals of therapy or their family’s goals of therapy.

What is their support system? Are they trying to get to allogeneic stem cell transplant? Are they trying to cure their disease with whatever means necessary? Are they open to accepting a little bit more toxicity if there’s a chance for cure? Or on the other hand, are they more of a goal where they’re saying, “Look, I understand I have a difficult disease. I want to get into remission and maybe have some extra years of life that can be added.” All those things play a role into how I select a patient. And we do it together. I mean, this is not a one-way thing. Obviously, I have the experience and expertise, but what the patient wants is a key thing that I take into account.

Jessica Altman:

Outstanding. Thank you for that summary. And I agree completely. And it becomes an increasing complex conversation when we meet with our patients and their families. So I want to dig a little bit more. We know that, while we have an increasing understanding of the predictors of response to HMA-Ven, we have more comfort with understanding the standard predictive tools when it’s in relationship to intensive chemotherapy. I think a bigger, important question becomes the patient who’s in their sixties who has disease that is predicted to be chemo-sensitive, and when I say chemo-sensitive, I mean sensitive to intensive induction chemotherapy, i.e 7 + 3 or something built along that. Which of those patients are you offering an intensive chemotherapy strategy versus an HMA-Ven, and what conversation occurs? You can think about NPM1-mutated disease or something similar to that.

Tapan Kadia:

Yeah, great question. So I think that’s the key, right? We were on the debate side of low intensity therapy, and so we were promoting that, but the other side clearly made some good points. There are subsets of patients, even if they’re 60 and older, if they’re fit, who have very sensitive disease as you said, and those are patients who have favorable karyotype, core binding factor A21, inversion 16, or those who are NPM1-mutated, FLT3/ITD-negative who are very favorable diploid karyotype. They have sensitive disease to intensive chemotherapy. So the core binding factor, even if they’re over 60, I actually sit with them and offer them an intensive chemotherapy regimen, even though my stance is still low intensity, because there is a chance that, with this intensive chemotherapy, usually cytarabine-based with gemtuzumab ozogamicin, that we can potentially cure that patient with a time-limited therapy that may last anywhere from three to six months of therapy, and then they’re done. Something that we can monitor.

Similar with NPM1. Now the caveat with NPM1 is that although we achieve excellent responses now with intensive chemotherapy, and we always have, there’s new data from Donor and colleagues in Blood in 2024, looking at patients who are treated with HMA-Ven. And indeed, if you look at those Ven-based treated patients who are NPM1-mutated FLT3/ITD-negative, they actually do very well with high rates of response and high long-term survival rates with just HMA-Ven. So that is becoming a little blurred, but I think those are the things that I look for.

Jessica Altman:

I think that’s great. I wanted to get Eunice’s take on the potential of time-limited therapy. So I agree with you that the outcomes for adults with NPM1-mutated disease, who receive an HMA-Ven approach, and especially an isolated NPM1 mutation without other molecular abnormalities, fare very well with that. But how do you grapple with your patient and deal with the thoughts of a time-limited therapy versus continuation of therapy? And is there the opportunity to stop treatment on an HMA-Ven approach?

Eunice Wang:

Well, I think that we’re just starting to learn which biological subsets are most responsive or less responsive to Ven-HMA therapy. And while there’s some intriguing data emerging, that as we have more and more experience that there are subsets of patients for whom we might be able to safely stop the venetoclax HMA. Now, this has been published both in the case series, as well as in clinical trials which have been presented. The STOP-VEN trial presented at the ASH 2023 were patients who had achieved a morphological complete remission with, ideally, MRD negativity and had received about 12 months of an HMA-based therapy, were able to stop or were on a trial where they stopped therapy. Now many of them stopped because they didn’t want to, where they had side effects or toxicity or inconvenience.

And amazingly enough, what we found, and again, this has been verified in a case series or observational experience, is that patients that had very sensitive disease to Ven-HMA, i.e those with NPM1-mutant in the absence of FLT3 ITD, those with IDH2-mutant disease, were able to safely stop the therapy and stay off therapy for an excess of three to four years. And again, in a case series when they looked at patients that stopped versus the patients that didn’t stop, when those patients, some of which relapsed, when they relapsed, they didn’t relapse any sooner than patients that had stayed on continuous therapy. Now, this is a lot of implications, quality of life, clinic visits, transfusion dependence.

There’s even financial implications for not having to take an HMA or an oral BCL2 inhibitor that costs upwards of $10,000 a month. So I think that this is something that we are actively thinking about doing. And then also removes an argument as our colleagues made for why we need to give intensive therapy. They said intensive therapy is time-limited, is potentially curative, therapy would end. And if we are able to, for example, give 12 months and then stop, I think that would be a great advance, knowing that many of our older patients are not interested in continuous therapy.

The advent of oral HMA therapies has allowed us to design trials using completely oral regimens for our patients. So we’ve gone from intensive chemotherapy, central line transfusion dependence, IV antibiotics in the hospital for four to six weeks, to patients taking three drugs in the outpatient setting. And I think that this, as one of our colleagues said, is bewildering the number of choices that we have. But I think that it needs to go down to, as Dr. Kadia was saying, individualizing patient treatment, for basically the patient’s wishes as well as for the underlying biology.

Jessica Altman:

Those are excellent points. I wanted to bring up one thing that I think is worth mentioning, again, that you mentioned in the larger session. And that is, how do you treat your adults with newly diagnosed acute myeloid leukemia who are receiving HMA/Ven? Are you treating them in the hospital? Are you treating them as an outpatient? I think this is especially important as we think about moving to all oral therapy with the first cycle of treatment.

Eunice Wang:

So our feeling is that regardless of whether they’re getting into what we call standard 7+3 or cytarabine- anthracycline-based therapy or Ven-HMA-based therapy, when patients present with acute leukemia, they are very, very sick. They have hyperleukocytosis, they may have DIC, coagulopathy, many of them have undiagnosed pneumonias or bacteremia. So our practice and our center, and also for geographical and logistical reasons, is to hospitalize all of those patients, not necessarily because of the delivery of the medications, but just because of all of the acute leukemia-associated complications, which can be difficult, challenging, if not impossible to manage in the outpatient setting.

Having 24/7 eyes on the patient allows us to quickly diagnose and mitigate those and attenuate those things before they become life-threatening. So we do what we do as an induction, regardless of the regimen in hospital. And we are then administering one to even two rounds of either HMA and/or what we call induction cytarabine- anthracycline-based therapy, achieving disease control before transitioning the patient to the outpatient setting, potentially to their local oncologist. And I think that that also allows us, for those patients that are eligible for allogeneic stem cell transplantation to start the process to bring them to a transplantation, ideally within 10 to 12 weeks.

Jessica Altman:

Yeah. Similar practice at MD Anderson?

Tapan Kadia:

Yes. So we hospitalize all of our patients for induction, whether it be even the oral HMA and venetoclax actually, we hospitalize them. Because as Eunice pointed out, many great points, they have bone marrow failure. I mean, they’re requiring blood product transfusions, they have infectious complications. So we certainly do that.

Jessica Altman:

Great. I’d like us to dream a little bit more with the last set of thoughts and questions that I have. I think the two of you made a very compelling case for the use of HMA-Ven based therapies for the majority of older adults who are being treated for acute myeloid leukemia. And there were some comments from colleagues in the audience. For instance, if someone ends up having favorable risk disease, can be consolidated with curative intent with an intermediate-dose cytarabine or high-dose cytarabine-containing regimen. So I’d like to dream and push a little bit more, about when will it be appropriate to offer HMA-Ven based therapy for all adults with a newly diagnosed acute myeloid leukemia?

Tapan Kadia:

So let me start. I think the argument we made is that there are low intensity regimens that we can use for all adults greater than 60. But I think as you point out, as we go forward into the future, similar to what’s happening in acute lymphoblastic leukemia, we can start offering these lower intensity therapies to younger and younger patients. There is, in addition to HMA-Ven, we have developed a cladribine low-dose cytarabine-based regimen that has no anthracycline, has low-dose cytarabine instead of anywhere near the intermediate dose of cytarabine, and venetoclax. And what we realized is that these new agents venetoclax, FLT3 inhibitors, IDH inhibitors, they’ve allowed us to increase the efficacy close to what or maybe equal to what we get with intensive chemotherapy, while maintaining a low adverse event profile. And I think that’s the key.

So I think that you say when, we’re starting to do it now. I mean, we’ve reduced the age of enrollment for our cladribine/low-dose cytarabine/ven program to 50 years of age. Now again, we’re not going include all 50 years, but we’re starting with patients who, for example, are not eligible for intensive chemotherapy. They may have received anthracyclines for another cancer. We’re enrolling those patients and seeing equally high response rates, getting them to allogeneic stem cell transplant, which I think is another potential goal, whether you give high or low intensity chemotherapy, to move to transplant. I think we’re there. I don’t know about you, Eunice?

Eunice Wang:

Yeah, I mean, I think I envision a world in the future where we’re not starting with the treatment algorithm being age or fitness, but the trigger of algorithm that would start with disease biology, as well as potentially patient preference, and that incorporates a decision to go forward with the transplant or not. And so looking at that, we are now doing clinical trials where regardless of age or fitness, if the patient has normal organ function, they would potentially go on to a trial with a triplet regimen then HMA-targeted therapy, for example, gilteritinib, then it’s venetoclax and azacitidine in the upfront VICEROY trial. And then we would go from there. Obviously, patients could go on to get intensified consolidation if they needed to, and that could include either intensive or intermediate or high dose cytarabine, or it could include a transplant.

And I think that we need to be driven by exactly what’s happening with our colleagues who treat ALL. As we develop more tools in our toolbox, we drop the chemotherapy as something that we only add on during intensification or consolidation as needed. But that we start out with lower dose intensities and then escalate or de-escalate. And that is because, when you have a number of different modalities, you have the option to do that. I think our colleagues that treat CLL are also having regimens, where they’re able to stop. Our colleagues that treat CML, have treatment-free remission. Why aren’t we getting to the point where we are driven by the disease biology to use whatever agents we have with the option that at some point we would stop treatment?

Jessica Altman:

Outstanding. I agree completely. I think you’ve summarized things very well. And really, it comes back to, as we think about acute myeloid leukemia moving forward, really a focus on disease biology, patient preference. And regardless of initial induction regimen of choice, defining those patients who can be cured with and without stem cell transplant.

Eunice Wang:

Yeah.

Tapan Kadia:

Absolutely.

Jessica Altman:

So thank you both. I as always really enjoyed learning from you and spending time talking to you.

Tapan Kadia:

Thank you, Jessica.

Jessica Altman:

Thank you.

Eunice Wang:

Thank you.