Selecting Optimal First-Line Therapies for Patients With Acute Myeloid Leukemia

Expert Roundtable Part 2

In this expert roundtable series, Jorge Cortes, MD, Augusta University, Augusta, Georgia leads a panel discussion on the latest updates in acute myeloid leukemia treatment and management with Justin M Watts, MD, University of Miami, Miami, Florida and Rami S Komrokji, MD, Moffitt Cancer Center, Tampa, Florida. 
 
In part 2 of the roundtable, the experts provide insight into optimizing frontline therapies for patients with  acute myeloid leukemia.

Transcript:

Jorge Cortes, MD: Let’s talk about frontline therapy. An interesting question is what is the aim for first line therapy? Of course, we always think about, yeah we're trying to cure the patients, but then [VEN-AZA] (Venetoclax plus azacitidine) has become so prevalent, and as far as I know, I don't think it's curative. So what is your aim for patients with AML? How do you see that and does that play a role in what you're selecting for your patients? Justin, what would you say?

Justin M Watts, MD: With frontline therapy, harking back to our discussion a minute ago, time to treatment. You only get one chance to do your first line of therapy. That sounds silly, but, there's no redo, right? And so once you've treated the disease its forever altered—there's clonal pressures and you can't go back. So I think that, if you can wait, wait. But, younger patients, we still use intensive frontline strategies, induction, 7 to 3 type chemotherapy plus or minus, [gemtuzumab ozogamicin] (GO) or FLT3 inhibitor, [inaudible] in the appropriate situation. I think that's fairly standard practice still.

We do have clinical trials, including at our center, looking at the HMA and younger patients. But those are clinical trials, right? Not standard of care. In the older patients, it gets a little more interesting in the VEN-AZA era and all the VEN-AZA combination trials. In that age group of 60 to 70, there's a lot of options sometimes, and fitness is a spectrum, and that can be very nuanced.

Targeted therapies are going to be incorporated more and more as we learn more about how to combine them and we'll get there, but we're trying to get remission as safely as possible, minimize toxicity as able, but we're trying to get remission, right? We're trying to get an MRD negative remission if we can and then triage whether that patient needs to go to transplant.

Dr Cortes: Very good. Rami, in these patients that are not fit for chemotherapy, do you use any particular—there's been attempts at developing models and classifications and things like that, or you just go by your clinical assessment and decide based on that?

Rami S Komrokji, MD: Yeah, so for patients that are not fit for chemotherapy, I think obviously sometimes we also try to look at why is the patient not fit? Is it disease related? And if we're treating the disease and the patients are gonna be in remission, will they still be candidate, for example, a transplant. So that's a factor I look at. Are we completely excluding the transplant out from a disease point?

I think things are changing and we know, like even from the VIALE-A study and the benefit of patients, it is really based on, like there are patients that will have long-term benefit from those treatments, and some patients have less. For example, if a patient has p53 and he's not fit for intensive chemo and probably not gonna go to transplant, for example, we don't have really solid evidence that adding venetoclax will improve the survival for those patients. So I may omit the venetoclax.

I think when we look at some data, for example, in the IDH mutant, we have some data on the upfront combination of HMA-IDH inhibitors that may be actually a little bit more tolerated at the HMA-VEN and may have be associated with better outcome. So I think we still tailor the therapy even in the patients that are not candidates for intensive chemotherapy or transplant based on that. At least from the HMA-VEN combination, now we know the molecular profile of the long-term benefit and intermediate and the patients that are gonna be almost resistant to treatment.

Dr Cortes: Yeah and you bring up some very, very good points. One important thing is that when we are assessing the fitness, the performance status of patients with AML may be bad from the leukemia, if they're anemic. I think we sometimes need, we need to dissociate that, that, that that poor performance status from the leukemia from a true non fitness for chemotherapy. If you just came up with a acute leukemia, you're not gonna be feeling great, then your performance status may not be zero, that doesn't mean you cannot take chemotherapy if your heart's fine and your kidney's fine and you're a young patient and so on. At least that's my impression that sometimes we over use these non fitness for chemotherapy for symptoms that are related to the leukemia itself.

Let me go to some specific scenarios because I'd love to hear how you guys manage some of these. One of them is a for FLT3 mutated patients. We don't have FLT3 inhibitors. The studies are based on combinations with [7+3], and the approvals are agnostic of age, but if you have a patient that's truly unfit for chemotherapy, how do you manage? The approved combinations are with [7+3]  for both midostaurin and quizartinib. How do you manage that? That patient? Justin, what do you do?

Dr Watts: No. Yeah, yeah. If they're truly unfit for chemotherapy, you can't give 'em chemotherapy, right? If they're not gonna tolerate it, right? First do no harm, right? Even with AML, right? And so VEN-AZA is quite active in FLT3 mutated disease. It's highly active, in fact, right? The [complete remission] (CR) [complete remission with incomplete count] (CRi) rate, it's high as [inaudible] population, right? It's high, right? It's 60, 70%, right? They're very likely to respond, right? There's not as much primary resistance as with RAS mutated in p53, but they relapse or the risk of, not all, but most will relapse, right? I've had some long responders. Those are anecdotal. VEN-AZA is totally acceptable if you don't have a trial with a FLT3 inhibitor combination.

We don't add on FLT3 inhibitors frontline in that population off of a trial, yet. It's not standard of care and do you phase them in? Do you add them on based on MRD, do you wait for complete failure? When do you switch? If they failed, you do a combination with FLT3 inhibitors such as gilteritinib or do you do monotherapy, which may not be that appealing? There's so many questions that are unanswered, but we do have more and more options now when it, when it comes to FLT3 as we'll discuss.

Dr Cortes: Yeah. Rami, how about, IDH? Just like Justin mentioned for FLT3, probably even more for IDH, [VEN-AZA] works pretty good for IDH1 or 2 mutated patients. Particularly for IDH, there's approved indication for both the combination with azacitidine, for example. What do you prefer to do? Here you also have the issue of the need to wait to know that there are an IDH mutation versus you can just start [VEN-AZA] and then realize that they have IDH mutation. What are you doing in these instances? What's your preferred starting treatment?

Dr Komrokji: Right, so as I said, in general, we wait, and particularly I think in the IDH, it may make a difference. To your point, obviously from the VIALE-A study at the beginning, that the responses are great for the IDH mutant. They do well. As we had longer follow up, maybe it's true for the IDH2, not as well for the IDH1, that long term remission. When we look at the data, particularly in more older patients, I think an HMA-IDH inhibitor combination, a little bit better tolerated. One point is the toxicity, and I think the HMA-IDH inhibitors combination is less toxic. The profound myelosuppression neutropenia is less in that case.

I think the IDH1, there is some data that they are probably don't do as well as the IDH2, with the HMA-VEN, and then we have some data that you published and probably know better than me, that probably it may make a difference. Also, sometimes on the sequence of things, it's like, if patients got HMA-VEN, then an IDH inhibitor versus getting the IDH inhibitor and using the VEN in the sequence. From my point, at least in the IDH1, if I have the information, I probably go HMA plus an IDH inhibitor and keep the VEN second generation on second line. Obviously there are ongoing trials already. Some phase 1, phase 2 on the triplet, I've not moved to do triplets in the IDH outside the context of clinical trial.

Dr Cortes: Yeah and you bring a good point there about the, the toxicity. [VEN-AZA], we use it for unfit patients because it has very little non hematologic toxicity, but it is very myelosuppressive and for a truly unfit patient, and especially if you don't have a good access to blood transfusions and management of infections and all that, depending on what your setting is, well that can be pretty, pretty bad and when you have an alternative that that's something to consider.

Justin, let me ask you another scenario. This is for secondary AMLs. So for secondary AMLs, the CPX-351 study, the initial pivotal study, included patients specifically for older patients. Now they were fit for chemotherapy, but they were over 60, 60 to 75. What do you do for an unfit patient secondary leukemia? Where do you draw the line to do CPX versus giving be giving [VEN-AZA] for example, or something else?

Dr Watts: Yeah, I mean, I think in that population, one question is, huge question is, have they received prior HMA or not for their MDS and how much? That has almost as much impact as anything can have, right? Though they're not gonna do as well if they've had 10 cycles of HMA, if they've had 2 maybe, so that's key. But when you look at VIALE-A, right, when you look at those data, none of those patients have prior HMA, right? They all got [VEN-AZA], right?

The patients with secondary AML, so untreated secondary AML, those are the ones who did good, they did outstanding, right? Most of those patients are triple negative. Some will have p53, okay, that's a different disease. We know those do very poorly. Maybe if CMML, , EE and maybe there's RAS, but really like those are the patients with the RUNX1, the ASXL, the splicing, maybe they have an IDH.

Those patients are the ones with long median survival and they tend to do well. Yes, they can transform, you mentioned is [VEN-AZA] curative. I think that's a really provocative question. It might be curative in Hsome patients, right? When you look at the IDH2 data, when you look at the MPM1 data, granted that's de novo, it's hard to argue that some of those patients aren't cured, especially when they're off [VEN-AZA] and not relapsing, right? If they've stopped in certain circumstances.

But when you look at those secondary AMLs that don't have one of those favorable [VEN-AZA] mutations, and you have patients on who appear to be functionally cured, and you're like, how long am I gonna give this, 4 years, 5 years? I think that [VEN-AZA] is a therapy for secondary AML, if you start it after they've had a MDS for 2 years and had a bunch of HMAs is a different story. It's also a therapy for some de novo AMLs, right? It works very well in some of those, right? It doesn't work well in fusion driven leukemias, potentially even for body factor leukemias, right? And nothing works well in P53, fortunately, especially [inaudible], we know that.

That's the landscape as I see it. Many of the older patients with AML are some type of secondary AML, right? Probably half, if not more—so I think that's a really important question.