Hello, and welcome to today’s VJHemOnc podcast. We are a global, open-access video journal bringing you the latest in hematology and hematological oncology. Today’s episode features leading experts Harry Erba, Farhad Ravandi, and Thomas Cluzeau, who discuss strategies to prolong remission in acute myeloid leukemia. They focus on the roles of intensive chemotherapy, allogeneic stem cell transplantation, and maintenance therapies. Key topics include optimizing initial therapy to achieve deeper remissions, the benefits of using measurable residual disease assays to tailor post-remission treatments, and exploring new maintenance options.

Harry Erba:

Hello. I am Harry Erba, professor of medicine at Duke University in Durham, North Carolina. And I’m being joined by two of my colleagues, Dr Farhad Ravandi at the MD Anderson Cancer Center, and Dr Thomas Cluzeau at the Nice University in France. And today we’re going to have a discussion about how to prolong remissions in our patients with acute myeloid leukemia.

As a background, we understand that with intensive chemotherapy, we can get many of our patients into a remission. The challenge has always been how to maintain that remission and potentially even cure the disease without seeing any relapses over time. We have typically used risk stratification in terms of cytogenetics and mutational analysis to help us decide on which patients may be best served by undergoing more intensive post-remission therapy with an allogeneic hematopoietic stem cell transplant, and which patients may actually be able to be cured with chemotherapy alone. But still, even in those patients, we know relapse can occur and maintenance strategies are necessary. And of course, one of the areas that we are all investigating very deeply right now is the role of measurable residual disease assays in determining which patients may benefit from intensification of their therapy or targeted therapies as a way of maintaining remission.

With that, I think I’ll turn it over now and start talking about maybe the one modality we have in acute myeloid leukemia that is most likely to prevent relapse and cure the disease, and that’s the benefits of an allogeneic stem cell transplant. And for that, I’d like to turn to my colleague in France, Thomas Cluzeau. Thomas?

Thomas Cluzeau:

So today to choose which patient to undergo through allo stem cell transplantation, I think we need to define what is the goal before allo stem cell transplantation. So I think first we need to choose the eligible patient, so eligible patient without other disease of course, but also with good health condition before allo stem cell transplantation. So the choose of the type of chemo should be decided depending of this aspect. And as we know today, we could discuss about 3+7, but also CPX-351 with maybe a better safety profile. Of course, we need to decide, as you said about the disease, so which type of disease, which targeted therapy maybe we could had to improve the CR rates before allo stem cell transplantation.

And the last point for me, and maybe should be the challenge for the next year, because now as we know, we have a lot of treatment available in high acute myeloid leukemia or a lot of treatment maybe to add with the usual treatment in acute myeloid leukemia as for example, venetoclax for sure, but other targeted therapy maybe in the future, some menin inhibitors. I guess maybe we need to decide if the goal is maybe to obtain high level of CR of course, but maybe high level of negative MRD with CR before allo stem cell transplantation. So maybe a deep CR before allo stem cell transplantation should be the discussion in the next future.

Harry Erba:

Thomas, I clearly agree with that. And the data definitely suggests that the deeper the remission a patient has prior to allo transplant, the better the outcomes. Now, the challenge for the leukemia doctor taking care of that patient is once you get a patient in remission, how do we safely get that patient into a deeper remission prior to the transplant? Or should we be thinking about taking the patient straight to transplant and then maybe maintenance approaches afterwards? After all, any further treatment may or may not clear that MRD. Farhad, what do you think about that?

Farhad Ravandi:

As you know, Harry, maintenance and MRD are two of the topics that have been very close to my heart over the last 20 years. And I think we all agree that with the currently available strategies, both chemotherapy-based strategies as well as transplantation, we don’t cure vast majority of patients. At best, we are curing about 40% of patients. And I think these are new tools that we can use to try to improve the outcomes. So as you mentioned, achieving a deep remission is the goal. And can we achieve it before or after transplant? And in my opinion, I think either way is appropriate. If you do achieve a CR, MRD negative prior to transplant, you’re likely to improve your transplant outcome.

We have data from Roland Walter, we have data from Chris Hourigan, all indicating that if you have negative MRD, you’re going to do better post-transplant. But also, it doesn’t mean that we should not transplant these patients. I think we do need to transplant them. And then now that we have non-toxic strategies, or relatively non-toxic strategies, such as oral targeted agents, and perhaps in the future to venetoclax-based strategies, we can use maintenance post-transplant to further deepen the remission and prolong survival.

I think maintenance has been something that we have thought about in all hematological malignancies for a long time. And in some hematological malignancies, we had the tools to do maintenance, or for example, in ALL, we had oral, relatively non-toxic regimens that we could use. In AML, we haven’t been doing that mainly because we really didn’t have anything that was non-toxic. We tried interleukin-2 and similar agents, but they’re still not tolerable. Now that we have orally administered effective targeted agents, I think the role of maintenance in AML will expand, and I think it will expand until we have strategies in the frontline setting that we would produce such deep responses that we won’t need maintenance. And this we have seen in APL, we always used to give maintenance in APL, but now with ATRA and arsenic, we don’t need maintenance because we have deep response, we have a good molecular monitoring strategy that has been shown to be highly predictive if you achieve complete molecular remission in APL. And I think this is probably going to be the case in other subsets of AML in the future.

Harry Erba:

Yeah, thank you for that. And I think the challenge that we have right now is picking the best initial therapy to get the patient into that deep remission so that they may be a better candidate for allogeneic transplant or maintenance therapies that may prolong that remission.

Thomas, let’s take this as two different areas. Thomas, I’m going to turn to you to talk about what are the current clinical strategies that are used for maintenance post allotransplant? How do you select that patient? What agents have been utilized? And then I’ll come back to you, Farhad, for a discussion of maintenance in the patient who is not eligible for allogeneic transplant. Thomas, post-transplant maintenance.

Thomas Cluzeau:

So the post-transplant maintenance in my center, it is defined depending of the ELN profile of patients at baseline. So for the intermediate patient, if the patient is in negative MRD after transplant, usually we do not use post-transplant therapy. But for patient of course, for positive minimal residual disease, we use post-transplant therapy. So we could use donor lymphocyte infusion, combined or not with azacitidine. We could use also in clinical trial in combination with maybe venetoclax, so azacitidine plus venetoclax. And it’s what we do usually, except for the FLT3, of course, mutated patient. We use of course a FLT3 inhibitor as sorafenib or gilteritinib.

For the adverse ELN risk, we use post-transplant therapy systematically independent if the patient is negative or positive MRD after transplant because we think that the relapse rate is too high in this specific setting and the outcome is so poor. So it’s why we decided to do a post-transplant strategy for all these patients in clinical trial or in current practice.

Harry Erba:

One of the more recent publications in this area has been the MORPHO trial, which I think was very instructive in that the patients who seem to benefit the most from gilteritinib post-allotransplant were those patients who had measurable residual disease for the FLT3-ITD, either pre, most commonly pre, or a few post-allotransplant. And the use of gilteritinib post-transplant does lead to some toxicities. And so we may be able to better select patients based on MRD who may benefit from a FLT3 inhibitor.

I will be honest with you, I have been using post-allotransplant IDH inhibitors, IDH-1 inhibitor, itacitinib or now olutasidenib, and enasidenib for IDH-2. There is safety data out there. There is no comparative data showing that there’s a benefit of any kind. But what those drugs do for me is check a major box in the choice of a maintenance therapy, and Farhad alluded to this, and that’s safety. And the thing about itacitinib and enasidenib is I’ve been impressed that patients can tolerate those, they tend not to be mild suppressive like gilteritinib. And so in an effort to do whatever we can to prevent relapse in that individual patient without randomized data, I’ve done that. I’m not sure if I’m out there alone or if others would agree with that. Farhad?

Farhad Ravandi:

Yeah, I agree. And I would actually say that relapse still is the main cause of failure in leukemia. The reason we lose most patients with AML is because of disease, so I would advocate any strategy that has even a potential to reduce that risk. And I agree with you, there are not comparative data for many of these things. And of course, apart from toxicity, there is financial toxicity. I mean, these drugs are very expensive. But for example, for FLT3-mutated AML, I know that if a patient relapses post-transplant, that is essentially it. So I would advocate use of FLT3 inhibitors. We used to be a big proponent of sorafenib because as you know, I’ve worked for sorafenib, but I actually think gilteritinib is better tolerated, still not perfect, but I personally actually tell my patients to take it indefinitely if you can pay for it or you can get it.

And of course, the MRD assays are getting better and better and more sensitive. So I will now be a lot more confident even in the absence of large data sets, that if I have a patient with FLT3-ITD who is negative several times by the Invivoscribe deep sensitive NGS assay, then I would actually start considering, “Okay, maybe we can stop the maintenance gilteritinib.” But I think until that point, for me, the biggest enemy remains the relapse and the disease. So I would advocate for anything that even has a potential chance.

Now, of course, I know in the European countries in the UK where I used to be and in France, the cost of this would be probably prohibitive. But I think that’s something that we should all aim towards, and at least we need to develop trials that would actually confirm this so that the authorities will pay for these expensive drugs because I think in the end, they will actually probably be cost-saving.

Harry Erba:

I agree. And we never look at that when we talk about cost since the cost of that relapse and the therapies and problems that patients then experienced. So, Farhad, I’d like to turn the discussion back to you regarding the use of maintenance therapies in patients who are not able to undergo allogeneic stem cell transplant for whatever reason.

Farhad Ravandi:

So again, as you know, maintenance therapy has been tried in AML for the last 30 years in various forms and shapes. But until the AZA-001 study using oral azacitidine data was available, we really had not had any randomized trial that positively demonstrated the benefit of any form of maintenance in AML. There was a European study using low-dose interleukin-2 and histamine dihydrochloride, which did show improvement in relapse-free survival, but not overall survival. And actually, the EMA did approve the drug, but nobody used it as far as I hear from my European colleagues. But the randomized oral azacitidine trial did show that you do improve survival in patients who were above 55 and had received one or more courses of intensive traditional RC and anthracycline-based chemotherapy and were unable to, for whatever reason, to either continue or undergo allogeneic stem cell transplant.

So I do not think that agent oral azacitidine is a curative agent, and if you actually look at the survival curves, they eventually collapse. But it does show that you can improve outcomes by an agent who has even modest activity. So of course, if we have agents who are much better and much more potent, which I hope we will in the future, we are likely to have, as I mentioned, more role for maintenance strategies in AML. And I think with the targeted agents, we are seeing that already with quizartinib in the QuANTUM-First trial. I know the data was not specifically randomized for maintenance, but still there appears to be a benefit for continuation of quizartinib for up to three years. I think this probably is going to be true for other agents like itacitinib and enasidenib, but that remains to be shown, and perhaps menin inhibitors will be the other area that this strategy will be beneficial. So I think maintenance therapy in the absence of transplant is very important, and particularly for all the patients.

Harry Erba:

I definitely agree. I think the way I look at that randomized trial of oral azacitidine, I think it’s very important. These were for older adults who were not able to undergo allogeneic transplant. And my understanding is even when they relapsed, they were unlikely to go allo treatment, undergo allotransplant. So I guess you could still question if you had a group of patients who you’re not going to transplant first remission but may be able to undergo transplant in second remission, maybe there wouldn’t be a benefit there. But we don’t really know because that group of patients wasn’t studied.

But that’s the challenge I often have. For example, in my NPM1-mutated patients, that’s where we saw the benefit of oral azacitidine in the subset analysis. But it begs the question, is it worth giving patients a treatment that does cause some myelosuppression, some GI toxicity, to delay a relapse that might occur anyways, you’re just delaying it, but then could get them back into remission with AZA-VEN or a menin inhibitor and then take them to transplant? I think these are unanswered questions. Okay. I see you nodding, so I-

Farhad Ravandi:

Well, yeah, I agree with you. And I mean, please remember that this study was designed when, I remember the first time we sat together, it was designed in about 10, 15 years ago where we had really no new drugs in, I mean, this was before midostaurin, and there was really no major development in the horizon except for perhaps some FLT3 inhibitors. So yes, with the availability of better agents, I mean, I think oral azacitidine is not extensively used in the US at the moment for maintenance. But I think the importance of the study was that it showed that even a modest agent can delay relapse. Now, if you have better agents, it may further delay or even completely eliminate the chance of relapse, and that’s something that needs to be answered.

Harry Erba:

So this has been a great discussion. Let me close it out by focusing on something a little bit different. We’ve been focusing on the post-intensive chemotherapy, post-transplant maintenance strategies, which are clearly very important to prevent relapse in this disease, which, and I agree with Farhad, this is the biggest challenge we face now is the relapse, but let’s not lose sight of your initial therapy. The initial therapy may be very important in also delaying relapse or curing this disease.

Let’s go back to the CPX-351 versus 7+3 study. There was a survival benefit with the CPX-351, but I think the most impressive data from that study was that in patients who achieved a complete remission with 7+3 or CPX-351, when they went on to an allotransplant after that, the survival was quite dramatically better in the CPX group than in the 7+3. Now, we don’t really understand why. Some people have speculated that maybe CPX-351 made patients better candidates for the transplant. I’m not sure that’s the case. I really think that maybe this was a deeper remission by targeting the leukemic cells in the marrow, but we don’t know from that study.

But the QuANTUM-First study actually I think has an important message for us that goes way beyond just FLT3 biology. And that is in that study, this was a prospective trial where we used the Invivoscribe assay, or something like the Invivoscribe assay, for the FL3-ITD MRD assessment. And what we saw in that study is regardless of whether patient got 7+3 with quizartinib or 7+3 with placebo, if they achieved a CR that was MRD-negative, they had a better survival regardless of their therapy. But what was really impressive to me was that in patients who did not undergo allogeneic transplant in first remission for the entire group, there was a benefit of quizartinib in survival, which to me says that this drug has some activity that we did not see with midostaurin alone. It’s a more powerful second-generation drug.

On top of that, what we saw was that patients who achieved this MRD-negative remission at every step along the way after induction, after consolidation, before maintenance, they had a better survival. The benefit of the quizartinib turned out to be in the numbers. More patients achieve that with the addition of quizartinib. So I think the QuANTUM-First study showed us that if you have a targeted agent that really has independent activity and you add it to what is already working and you get deeper remissions, those patients will do better in the long run. We actually see a benefit of quizartinib post-transplant, but I think we need to look at that data a little bit more closely.

Farhad Ravandi:

Yeah, I agree. I mean, I think this is all evidence that a sensitive MRD assay is very important, and I have been hoping that the FDA will start accepting MRD as a good marker of outcome in AML as they have just recently done, I believe, for myeloma. And I think one of the unfortunate things about the CPX trial that you mentioned was that they did not do any MRD assessment because that would’ve answered a lot of the questions that you just asked and you just mentioned. And I think this is why it’s important, all future studies, and I’m so glad that the QuANTUM-First study had the assay written to it. And also, the oral azacitidine maintenance study, we actually, I can say that the company should be proud that they did assess flow MRD every three months for the entire duration of the study. And the information that was gained from that was invaluable. And so I think, again, more and more, this shows how important MRD is and how these assays that are being developed are going to be very useful in the future in terms of patient management.

Harry Erba:

Agreed. Thomas, any final words on the subject?

Thomas Cluzeau:

Yeah, so maybe I could add something about CPX-351. So I totally agree with you that the hypothesis is that the curve we observe after allo stem cell transplantation could be related to the deeper CR before allo stem cell transplantation. So as you know, unfortunately, there is no MRD data in the phase three clinical trial, but in the real life experience in France and Italy, we recently reported the MRD data we performed in our patient, and it was not a comparative study, but we observe deep CR after CPX-351 around 60%. So in secondary AML and therapy-related AML, it’s a good result. And when we observe negative CR before allo stem cell transplantation and positive CR before allo stem cell transplantation, after CPX-351, we identify a significant difference for this patient. So I guess it could confirm maybe that with CPX-351, if we could obtain negative MRD before allo stem cell transplantation, we could obtain the good overall survival we observed in the phase three clinical trial.

And finally, in Europe, we perform two clinical trial evaluating CPX-351 versus 3+7, one in Germany and one in France. And the aim is to evaluate CPX-351 in AML except therapy-related and secondary AML like in the approval of the drug. And the goal is to define the MRD after one induction and to see. So in France, this is the primary endpoint of the clinical trial. And in Germany, this is a secondary endpoint, but the aim is to show that with the CPX-351, we obtain more deeper CR after CPX-351 like 3+7. So maybe in the future we will have this answer.

Harry Erba:

Thank you, Thomas. Let me close out this discussion by just building on what Farhad and Thomas have just said regarding the benefit of CPX-351 in preparing a patient for allogeneic transplant. I completely agree with all of those comments. I applaud you in Europe for giving us this real world data. Thank you for mentioning that regarding CPX-351. But what neither of you mentioned was the other therapy that we fortunately now have available for our patients have completely changed everything based on the pioneering work from basically MD Anderson, Courtney DiNardo, Marina Konopleva on the benefit of venetoclax in addition to hypomethylating agents completely has changed my practice. But one of the topics that has been in greatest discussion recently are the outcomes of patients who get CPX-351 versus venetoclax and hypomethylating agent in this area.

And they’re all retrospective studies, but what I’d like to focus on is remember these are different agents given for different purposes or different regimens. When I have a patient that I think is going to benefit from an allogeneic transplant and be eligible, I go with CPX-351 first. And the reason I do that is that the data supporting the survival benefit post-allo is in patients who got an induction with CPX-351 and maybe one or two-cycles consolidation. And we think it’s because of a deeper remission. With AZA venetoclax, of course, we get good remissions, but the rate or the kinetics of achieving that MRD-negative state is pretty linear over the first 11 cycles or so, and you don’t know how many cycles you need to do to get them into that deep remission. So it’s not really a fair comparison between the two. So I still think that there is a role for considering CPX-351 in these patients, especially when you’re going on to want to go onto a transplant very soon after that.

But fortunately for our patients, we do have regimens, which I guess we could call them maintenance regimens now with venetoclax and hypomethylating agents that is prolonging survival in older patients or hypomethylating agents with IDH-1 and maybe even IDH-2 inhibitors. We’ll see. And as Farhad mentioned, I completely agree, we’re all excited with the development of menin inhibitors. Hopefully the next great advance in AML yet to be seen, but the preliminary data is very exciting, and the combination data of menin inhibitors with standard chemotherapy intensive and venetoclax HMA-based regimens will be coming out soon based on clinical trials.

I want to thank… Yes, Farhad, did you want to-

Farhad Ravandi:

I agree with you, but also want to say that of course, we now have multiple options, and I think that many of the questions you ask need to be answered in trials. But unfortunately, because of the number of options and the number of combinations, it may become more and more difficult to decide what are the best trials to design. And I think that really needs really well-designed trials with amazing correlative studies. And we don’t have the tools, so we need to do that if we want to further improve the field. Because right now, I think it’s every person doing what they feel is the best and without a great roadmap.

Harry Erba:

Farhad, I want to thank you for that. You lobbed a ball to me, and I am shamelessly, shamelessly going to promote the MyeloMATCH initiative because, and so maybe that’s what you meant to do, but that’s what MyeloMATCH is. MyeloMATCH is deconstructing every step along the way of the patient’s journey, inductions, consolidations, transplant, and maintenance. And we’re designing randomized phase two studies with multiple arms, not compared to each other, compared to what we consider standard and using early endpoints at every stage, MRD-negative remissions by flow. And we are also going to be incorporating CLIA-certified labs doing MRD assays, and the IDE for that is going to the FDA now. So we’re hoping that the MyeloMATCH is just one of many efforts that will be going on around the world to help us understand the role of MRD and how we can best utilize these regimens in terms of efficacy and safety.

Well, with that, I think I’ll close it out. And I want to thank my colleagues, Thomas Cluzeau and Farhad Ravandi for joining me. I always learn something by talking to my colleagues, and today’s been no exception. Thank you.

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