Drs. Hagop Kantarjian and Elias Jabbour Discuss Important AML, ALL Updates From ASH 2022

Hello everyone, and welcome to the first episode of your new podcast, The HemeOnc Pulse, the podcast that is dedicated to all things hematology. Everything in the world of hematology, from clinical trials to new advances to controversies and debates and to discussions about healthcare policy, drug pricing, and everything that impacts patient care in the world of hematology. The Hemang Pulse is your new favorite podcast coming to you from Blunt Cancers today. I appreciate you tuning in and supporting This first episode and many future episodes that will be coming to you. It's very special to start the HemOnc Pulse during the annual American Society of Hematology meeting in the beautiful city of New Orleans, Louisiana. We could not have picked a better venue or a better time to start this podcast. You need to keep the lines of communication with me and tell me About topics, ideas. What do you want to hear on this podcast? Every single email, every single text, every single tweet will be answered timely and will be taken seriously. You can direct message me on Twitter @ShadiNabhan and follow me there for more updates on the HeMonk Pulse. You could also send me an email to shadinabhanoo. at outlook.com and let me know any ideas that you may have pertaining to the podcast. The first few episodes of the HemOnc Pulse are going to tackle new updates that have been presented during the American Society of Hematology meetings. I'm going to bring thought leaders in the fields of leukemia, myeloma, lymphoma, myeloproliferative neoplasms, and myelodysplasia and try to dissect what are the clinically relevant data and abstracts that have been presented during the American Society of Hematology meeting. I really appreciate you tuning in. Your support is going to mean the world to me, to the producers, to the organizers, and to the sponsors. Welcome. Welcome to the Hemang Pulse, the podcast that's going to bring you all the news that you need in the world of hematology. Thank you for tuning in. Okay, well, what's better than to start the first episode ever of the Hemonk Pulse with 2 phenomenal, unbelievable, amazing guests coming to me live from Houston, from MD Anderson Cancer Center? I'm very, very grateful to be joined by Doctors Ali Jabbour and Hagop Kantarjian, who will introduce themselves in a little bit. And the goal is really to talk about what intrigued them from the abstracts that are being presented at the American Society of Hematology. We won't have a lot of time to make full introductions because these 2 guys probably can spend an hour telling us about their accomplishments. But Hagop won't remember, the first time I probably met you, Hagop, was almost 20 years ago at one of the George Washington Board Review courses. And you probably still do them. And I could tell you nobody was able to simplify— at the time you were giving a talk on, I don't know if it's ALL or CML, but it wasn't AML because AML, I think, was Marty Tallman was giving that episode. It was so— you simplified such a complex topic and I felt very, very good about it. And since then I've been following your work and I'm very honored to have you on this podcast. I'm one of your biggest fans and biggest admirers. So why don't you tell listeners a little bit about you and what you do and day in and day out, and a couple of things they may not know unless they listen to this podcast.

So first, I'm an admirer of you as you are of mine. I've come to MD Anderson in 1982, and I've stayed since there. And I have only one mission, to treat leukemia and perhaps to die treating leukemia. And hopefully that most of the leukemias will be Either curable or cured by the time I die.

Eli, a little bit about you and tell us a little bit what's, you know, and how do you end up here?

Well, my name is Eli Shabour. I arrived to MD Anderson. Dr. Kantarjian recruited me back as a fellow in 2003, quote unquote, for a few years of fellowship. I did my fellowship. I still— I stayed there since then. And, you know, working with him has been the best thing I could have ever dreamed about. Essentially, I have to live at 600 miles per hour speed, but it has nothing been— it has been great.

So we decided to cover AML and ALL, and in all disclosure, we can agree that it's impossible to cover everything. I mean, you know, there's Goodness, thousands of abstracts out there. So I promised my listeners we'll focus a little bit on the ones that we think they're very clinically relevant, maybe close to either changing how they treat patients, things like that. So let's start with an abstract in acute myeloid leukemia. Hagop, you want to take that for AML and maybe share something that intrigued you or?

Sure. I'm going to give you a broad idea about what intrigued me in AML. And I'm going to divide them into 3 categories. The first category is the risk prediction. And there's a lot at ASH about risk prediction. And it mostly focuses on the cytogenetic and molecular features and the new ELN 2022 recommendations. The bottom line from all of this is that One can combine the cytogenetics and few of the molecular profiles to divide the patients into different risk groups. What the ELN and those predictive models do not achieve is 2 things. One is in the older patients, even though they may or may not categorize them into different risk groups, those patients do much worse. And so those risk models do not account for the features related to the patients or the organ dysfunctions. So they are very useful, and people should get acquainted with them. And the most important findings are things we have known. For example, complex karyotype is worse. And some of the molecular abnormalities are very important. TP53 is adverse. NPM1 in general is favorable. And there are fewer others that may be relevant, like in our experience, the PTPN11, which is adverse, and the MECOM, which would be the inversion 3. So one could divide the patients into those risk factors. And what we need to do is account now for the targeted therapies that could change the outcome. among these subsets, particularly the FLT3 and IDH inhibitors, which seem to move a lot of the patients who used to be adverse into the favorable. The second large broad view in acute myeloid leukemia from the ASH is in both the younger and older patients, we are starting to move to the addition of targeted therapies to chemotherapy. So if we take the younger patients, You will see a lot of regimens with either 3 plus 7 or the newer regimens like the FLAG-IDA or the CLLIA or the cladribine, high-dose aracytine, mitoxantrone, where people are adding either the old gemtuzumab, azogomycin and showing better results, or they are adding venetoclax and they are also showing better results. So the gemtuzumab, the venetoclax, the FLT3 inhibitors and the IDH inhibitors are going to stay with us and be incorporated into the standards of care in the younger and older patients. Similarly, in the older patients or the older unfit, there were a lot of studies looking at the combinations of hypomethylating agents and venetoclax and showing that the results are better than the hypomethylating agents alone. I want to highlight 2 studies from our institution. One is with what we call the CLLIA regimen and venetoclax, which we updated with a much larger number of patients. And we're showing marrow CR rate in excess of 90%. And now a 2-year survival rate of about 70 to 80%. And then a new regimen in the older unfit AML. So we are stuck with the hypomethylating agent venetoclax, At MD Anderson, we moved to what we call the triple nucleoside regimen, which is cladribine, lodosaracil, venetoclax, alternating with azacitidine, venetoclax. Again, now we have a much larger number of patients than what was just published. We're still getting marrow CR rates in excess of 85% and 2-year survival rates of 65%, which is significantly higher than what was reported in the randomized trial of azacitidine with or without venetoclax. The third portion that you will see at ASH in acute myeloid leukemia are the novel strategies. And the one that attracts my attention are the menin inhibitors, which are maturing very nicely, showing that several menin inhibitors, at least 2 of them, are giving very good results in patients with refractory relapsed acute myeloid leukemia with either MLL translocations, translocation 11q23, or with NPN1 mutations. So I think the menin inhibitors are targeted therapies which are here to stay with us, either in combination with intensive chemotherapy or with low-intensity therapy. Then you see some additional therapies, for example, with targeted antibodies that target CD123, like the IMGN632. Some studies with immune therapies like CD123 or CD33 BiTEs, but these have very modest effects, so they did not attract as much attention. So 3 general features, risk models and predictions, which are important. But do not advance the therapy unless we combine the old regimens with the newer targeted therapies. Then you see the large body on therapy of acute myeloid leukemia, either younger combining intensive chemotherapy with venetoclax plus 3 inhibitors, IDH inhibitors, or in the older unfit starting to use triple regimens. with hypomethylating agents, venetoclax, and another targeted therapy. Among the novel strategies, I highlight the menin inhibitors because I think they are going to be very important. But again, a slew of other novel strategies which appear to be perceived as important, but I have seen only a modest effect so far from all of these.

Thank you, Hagop. And I am going to ask you some questions about these in a little bit just to get some dialogue about them. But before we do that on acute myeloid leukemia, I'm going to move to Elie a little bit to see what intrigued him at ASH. And then we'll go back. I have a couple of questions pertaining to these categories of AML and ALL, but I love the way you divided them because at least for my simple mind, I'll be more organized in the couple of questions I have for you. Elie, in ALL, what captured your interest?

Great. Thank you, Shadi. I want to summarize the effort I reviewed from ASH this year. And again, I will not be able to cover everything, as you said at the beginning. But number one, I'd like to highlight that in the older ALL patients, there is big data reported from the German group and the French where older patients, they have a worse outcome, where survival is still behind what we've seen in adult patient and a younger patient because of less NCR and more aggressive biology. And to improve on this outcome, investigators are using immunotherapy into the frontline. At MD Anderson, we did develop the mini-CVD inoblena in a frontline patient with ALL, and we reported survival at 5 years of 50%. At this ASH meeting, we do see update and presentation from a German European integrating inotuzumab into the frontline. and belinatamab into the frontline with promising results and improvement of survival. Again, these are single— multicenter single-arm trials, but at least highlighting the point that if we want to improve the outcome for older patients, we need to integrate immunotherapy into the frontline. This is for the older. For younger patients as well, we are adding belinatamab and atezolomib into the frontline setting. There's data that will be presented at the ASH meeting from MD Anderson as as well, where we had hyper-CVAD, obinutumab into the frontline survival of 85%. Now we added irinotecan as well, and now we have 100% survival. Of course, the follow-up is still short, but what the message I would like to make here is the old days of intensive chemotherapy for 3 and 4 years are past, and the future is to integrate immunotherapy and to monitor our patients very carefully using NGS technique to assess the depth of the response and tailor therapy accordingly. So at ASH meeting, there'll be several presentations toward this be presented. Second bullet I'd like to highlight is the Philadelphia positive ALL, the role of transplant. Do we need or we do not need it? And there are several presentations at the ASH meeting showing that if you get into MRD negativity by PCR or by NGS or whatever you want, a transplant is not needed. So the question of transplant is settling here where it won't help much in somebody's Still, at the ASH meeting, there's several abstracts where they highlight some poor biology, among them Ikaros deletion or Ikaros deletion plus, where the outcome is still poor for these patients. And toward this goal, we have a presentation with obinutamab and ponatinib, which is totally chemotherapy-free regimen. No chemotherapy at all. In 43 patients who received obinutamab and ponatinib and achieved a CMR of 85%, 88% by NGS, and the survival at 2 years and a half, 95%, with only one patient receiving transplant. Of course, there was no in-depth assessment for Ecarstisium Plus, but when you have everybody responding and the survival of 95%, the deduction is such a regimen can overcome the poor biology. In the PH+ANL as well, there are some abstracts about what we call CML-like picture because we aim to assess this— we aim to induce a complete molecular remission. And we do so by measuring the BCR-ABL by RT-PCR. And we know today there's certain patients where mainly P210 transcript, they do not go into CMR by RT-PCR BCR-ABL. But the lymphoblasts are gone. Therefore, we need to assess response by using an NGS technique assessing the immunoglobulin receptor. And this patient, they go into complete molecular remission and transplant would not be needed. So they have a CML-like picture where the transcript is identified in the myeloid cells. So we need to keep them on TKI, and these patients do not need a transplant. Now, moving forward in the PH1A, the question is, if we want to get rid of transplant, can we shorten therapy? For how long we give TKIs? And here we're implementing NGS prospectively to assess the dynamic of the response, the depth of the response, And the duration of response. Maybe patients who achieve an NGS negativity sustained for a few years be able— be candidate for treatment discontinuation down the road. That is really matter of clinical trials. The 3rd bullet I like to highlight is MRD assessment. Assessing MRD by flow cytometry has its limitation. We and others have shown that this technique, 40% of patients who are MRD negative by flow are still MRD-positive by NGS and they can relapse. At ASH, there will be a presentation assessing the importance of MRD assessment by NGS that can give you a depth of assessment to 10 to the minus 6, 10 to the minus 7. And these patients who reach this level of response are eventually outliers who will not relapse. Therefore, we need to integrate biology but assess MRD by novel techniques. Speaking of MRD, at ASH will be 2 presentations assessing anetuzumab for patients who are MRD positive. Ionotuzumab is a CD22 antibody conjugated to claritromycin. 2 presentations, one from MD Anderson and one from Italian expert. They show this drug is effective in eradicating minimal disease, as obinutuzumab has been shown. From a series from MD Anderson, we have around 28 patients. The MRD— the conversion to MRD negativity is around 70%, and the 2-year survival is 75%. In an Italian study, they have 39 patients. They report a lower response rate of 40%, but they give on average one course of inotuzumab. And for patients who are PH-positive ALL, do not get TKI till later on. That means the treatments are not identical and may be suboptimal. But here again, highlighting the role of inotuzumab. The last category I'd like to highlight to you, Shadi, today is the RAC factor ALL. We have the Blenat, the inotuzumab, and we'll still see CAR T cells are being offered. And we have an update of the ZUMA-3 trial will be presented at the ASH meeting. We have a survival of 20 months or 18 months, high price to pay. But we know today these drugs are not competitive. We need to use them in a more optimal fashion, in a combination sequentially, because by doing so, we can induce higher response rates early on, and then CAR-T can be given as a consolidation thereafter. where it has been shown to be safer with more optimal outcome. And maybe in the future, CAR-T will replace allotransplant. These are the abstracts I reviewed, and this is my summary of them.

I think there are 2 most important messages in ALL from the ASH meeting that I did. The first one is, for 50 years, we have stuck with the tradition of using intensive chemotherapy in ALL for 3 years. Since 1970, this is what we've done— intensive chemotherapy with 15 agents given over 3 years. And that model has been very successful in childhood ALL with a cure rate of 80%. And it gives a 5-year survival in adult ALL of about 50%. And that's why people are very reticent to challenge this tradition because they are worried that if you change it very quickly, some patients may be adversely affected. And I think this is completely incorrect because we do have now novel antibodies which are targeted, which as single agents are superior to the intensive chemotherapy in refractory relapse setting. So now there are a lot of single-arm trials from single institutions like MD Anderson, and from cooperative trials that are showing significantly higher results when investigators are using some form of chemotherapy. It doesn't have to be the old intensive chemotherapy, to which they add lenatumumab and inotuzumab. So I think we have to absorb this kind of information and decide, are we going to stay with randomized trials, which could slow the pace of research and discoveries? Or are we going to revert to a Bayesian approach, where we do single-arm trials and modify them according to the experience and the results? And the second very important point is the following. Today, In community practice, we use the novel therapies as per the FDA approval. So belantamab and inotuzumab as single agents in refractory relapsed ALL, and the CAR T-cells in refractory relapsed active ALL. So we're paying a lot of money for these very novel strategies with a very modest benefit. So I think we should also break from the tradition of following the recommended approval and move to studies that could give us better results for the money that we're paying, a better treatment value. And I think the better treatment value is going to be by combining those novel antibodies, belantamab, inotuzumab, with the standard chemotherapy in the frontline and salvage setting. And perhaps start investigating the CAR T cells, not for active relapsed disease, which gives you a potential cure rate of 20% in the adults, 40% in the children, but use them in the setting of minimal residual disease, or in subsequent remission as we do for allogeneic transplant, which will hopefully give us much better cure rates than with the single-agent activities.

This is really very interesting, and I appreciate you giving me the highlights, and to the listeners as well. But obviously there are some questions that I have, and really mainly the questions are going to be centered on the practicality of certain things. So I want to get your opinion about 2 things because there's a common theme Hagop mentioned the category of risk stratification and trying to look at the TP53, the NPM1, whether you do this with a variety of techniques. Similar to you, Elie was talking about the MRD assessment, which in my simple mind, it's almost risk stratification. If you're MRD positive at the end of therapy, you're higher risk than if you're MRD negative. And in fact, what Elie said, you can even avoid transplant for some of these situations that are MRD So my questions to both of you, and I'll start with Elie, do you see this is happening in the real world when you talk to your colleagues outside of Anderson, whether it's community practice, less resourceful university settings? Do you see the risk stratifications, the MRD assessments? Are they done up to what you expect them to be done in the trials that you are quoting?

Shelly, I think leukemia in the United States of America should be treated in a center of excellence and not in the community. ALL is a rare disease, and then we've seen patients receiving treatment in a community in a very suboptimal way. I think at least patients diagnosed with leukemia should be referred to centers of excellence. There's data published and reported, for example, in AML, if you treat in NCI-designated centers, the outcome is much better. I give an example in AML. at MD Anderson, our mortality during induction is less than 3%. So when you go to the community and other centers where supportive care may not be optimal, decision makers are not so great, that death in CR early on is 10 to 15%, and that can compromise the outcome. So I think these patients should be referred to centers of excellence and be receiving care over there.

But it just doesn't happen.

The reality is it doesn't happen. So, but let's take Shadi's question and let's address first the MRD. So should the NGS MRD in ALL be a new standard of care?

I think absolutely it should be because it gives you 2 layers, 2 logs of depth of the response. And these tests can be done in bone marrow today, in the future can be done on peripheral blood. So I think we should assess MRD from the beginning, have a sample sent at at the baseline to establish clonality and at assessment of a CR in every 2 months thereafter.

So that's question then to Hagop. If basically to answer the MRD, but then is there a threshold that you guys have agreed on that this is the threshold where you call somebody MRD negative? That's one question. And is there an agreement on the technology, which technology to use?

So Shadi, let's distinguish measuring MRD in ALL from measuring MRD in AML. In ALL, the next generation measurement of MRD for the immunoglobulin heavy chain improves the detection of residual disease from 1 in 10,000 to 1 in a million. And there's no doubt that the relapse rate is significantly lower in a patient that reaches an NGS MRD negative, so zero cells. in a million cells that are detected. The only issue is we don't have the large numbers to start making the statements. There are pilot studies from our institution and elsewhere that show that in ALL, a patient who is NGS MRD negative has a much lower relapse rate. Actually, in small numbers, it's as close as 0%, and 2 to 3-year survival of 90%. All we need is to increase the numbers to show that NGS MRD negativity is superior to flow cytometry MRD negativity. And then how do we use this? We can use it to change therapy in patients who may remain positive. And also in patients who are NGS MRD negative for a certain period of time, say 6 months or a year, we could stop therapy. So instead of going blindly with 3 years of intensive chemotherapy, we can then say, if somebody is receiving one form of therapy, let's say hyper-CVAD in ObliNa, and they have become NGS MRD negative at 3 months, and they remained negative for the year, can we stop the treatment? And will that imply a relapse rate of 0%? So the NGS MRD in ALL, I think it's gonna be very, very important. It should penetrate the community practice very quickly. And the sooner we get the large numbers of patients, the faster we can convince both the investigators in ALL and the community practice to change our practices to target NGS MRD status. In AML, it's a different issue.

Before we go to AML, just before we go to AML, Elie, for ALL, If you have ALL PH positive, you are obviously using a TKI along whatever treatment you're using for PH positive disease. Are these patients more likely or less likely to get MRD negativity? I mean, do you see that? You know what I mean?

Chadi, great you asked me about this question because I want to bring up something to you. You asked me if what we're doing can be taken to the community and the MRD, we discussed it. I think if we're improve the outcome in the PI3K-positive ALL, you need to improve the MRD negativity. And to that point, we have 2 great drugs, belantamab and ponatinib. Together, when given together, we're suppressing resistance that can be driven by the acquisition of a mutation called T59, and we're deepening the molecular response by going from 50% with hydroxybutyrazatinib or imatinib to 90%. Essentially, everybody responds. But then the question, how we can take this regimen and make it standard of care? Right now we have around 100 patients at MD Anderson treated, and elsewhere people using Blenatadz or others. But the problem is when you give hyper-CVAD or chemotherapy plus DKI and you go for transplant, we talk about a long-term treatment. Compliance is an issue, delivering a treatment, complications, being in the hospital. And for that, you're not getting optimal response and nor optimal outcome. If you give belinaponatib therapy for 5 to 6 months and all being given as an outpatient, you, for your healthcare system, you're doing much better. And for the people with lower income or with not as privileged, they can get treatment for 6 months and keep working without much side effects. So I think this treatment will change the life of people across the world.

Hagop, back to you about MRD in AML. I think you're trying to talk about this. Tell us a little bit your views on MRD in AML.

So let me first address MRD in Philadelphia-positive ALL because it brings another layer. So traditionally we're used to measuring the PCR, right, which looks at 100,000 cells, but the NGS MRD looks at a million cells. So now we're doing both the PCR and NGS MRD in Philadelphia-positive ALL. And again, how will this help us? Today in Philadelphia-positive ALL, we're doing ponatinib, lenatumumab, and then ponatinib goes indefinitely. If we can get to a point in time where we find that patients are not only PCR negative, but NGS MRD negative at the measurement of a million cells, and they remain so for, let's say, 3+ years, we could start implementing what was implemented in chronic myeloid leukemia with the durable deep molecular response and treatment interruption. So actually, one of the aims of our studies in Philadelphia-positive ALL is to measure the NGS MRD. And if it's negative for 3 to 5 years or more, we're going to discuss with the patient stopping therapy and see if we can cure Philadelphia-positive ALL the same way as is done today in chronic myeloid leukemia. Let's go now to acute myeloid leukemia. And in acute myeloid leukemia, we don't have the level of sophisticated residual disease measurement. We can measure APL, PML, RAR-alpha, and the core binding factor acute myeloid leukemias by PCR. And when we do this, it is a very effective modality to predict for lack of relapse. So PCR negative status in APL and in CBF-AML predicts for lack of relapses. So that's very important. Among the other patients, people have been able to develop PCR technologies for NPM1. So that's a technology that could be applied to the NPM1 positive patients to try to look at residual disease, and then perhaps decide on transplant or no transplant in the other patients. If you take the rest of the patients with AML using flow cytometry for MRD measurements, the positive flow cytometry MRD predicts for a high rate of relapse. But a negative flow cytometry MRD does not protect from a substantial rate of relapse. So in my book, even though people say, well, we're going to look at the pretreatment characteristics, and then the flow cytometry MRD status, and refer to transplant only the patients who are MRD positive, I still find that on the— in the average patient, doing a transplant is giving us still better results than not doing the transplant. And the fact that the patient has become flow cytometry MRD negative, particularly if they have high-risk features at the past, those patients cannot be spared the option of a transplant. On average, a transplant will be better than no transplant.

Dr. Kantarjian, can I ask a question, Shadi? So for the FLT3-ITD-positive AML, if we have very potent FLT3 inhibitors and a way to assess the depth of the response like we have in ALL, you think The FLT3-ITD AML would be like PH positive, right?

Correct. So that's a different issue that Ali is suggesting. Because we know that the FLT3 inhibitors are quite potent, particularly the third-generation ones, gilteritinib, and perhaps quizartinib. It is possible that in the future, once we incorporate the FLT3 inhibitors with the intensive chemotherapy, and perhaps with some form of venetoclax, that the patients who become FLT3 MRD negative by some form of superior measurement, PCR, some measure that looks at 100,000 or 1 million cells, those patients who are FLT3 mutated, either FLT3 ITD or TKD, once they receive the FLT3 inhibitors, we could look at residual disease and decide not to take those patients to transplant if they have become MRD negative in this setting.

We're going to do some lightning rounds because I know that you've been very generous with your time, but it's so much fun. But we're going to do lightning rounds. What that means is we're going to do quick questions and answers, right? So Elie, my first question is to you, and actually it's in AML. Is there any scenario where you would not use venetoclax in older patients with AML?

Maybe in IDH1, I will use HMA-IDH1 inhibitor. But that being said, I favor HMA triplet, not doublet. Means I will do HMA-ven-IDH1 inhibitor or HMA-ven plus other targeted therapy.

Another subset are the TP53 and MECOM AML. They are the worst of the worst, and the addition of venetoclax would not help them much.

Hagop, is there any situation whatsoever in AML that you would use 3 and 7 alone?

I have never used 3 plus 7 throughout my career since 1982. So I'm not going to change that now.

What do you mean you have never used 3 and 7?

When I started, we were into the high-dose RAC regimens. So we went with The IDE high-dose RAC, and subsequently we went to the FLAG-IDE, the CLLIA with the additional—

Okay, fine. I'll get you another one. Is there any situation in young fit patient with AML that you would not recommend consolidation allogeneic transplant?

Acute promyelocytic leukemia, core binding factor acute myeloid leukemia. Otherwise, even the leukemia group at MD Anderson is divided. I try today to refer all patients to transplant. And then I will look in the large proportion of patients to see which patients may or may not benefit. Within our group, there are younger people who are deciding on transplant based on the risk at the start and the MRD status. So many leukemia doctors say if I have a patient with a normal karyotype, NPM1 positive, FLT3 negative, and MRD negative, I'm not going to take them to transplant. So there are a bit of differences in opinion, but on average, the allogeneic transplant will be better.

Elie, quick question, although the answer may not be a lightning round because I do think it could be complex. There are many folks out there that would argue that you still need randomized controlled trials in certain scenarios. I'll give you a scenario and have you react to it. MRD-positive disease, definitely prognostic. Patients with MRD positivity definitely do worse than MRD negativity. But many academicians would say we don't have data to act on MRD positivity without a randomized study. In other words, they would— if you have an MRD-positive disease patient, they would prefer to randomize to immediate therapy or treatment at the time of morphologic relapse or something that suggests relapse beyond MRD.

Yeah.

What do you say to these folks?

Fadi, uh, excuse me, Shadi, there's nothing minimal about MRD. MRD means relapse, and we know historically the outcome is really poor, of a median survival in ALL 12 months with or without transplantation. So we added the belantamab to patients who are MRD positive, and the survival in a large trial from Europe showed a median of 3-year survival at MD Anderson, the 5-year survival 60%. How want to be randomizing patient to no chemo to transplant or standard care chemotherapy versus what's effective. I think we are, as Dr. Kantarjian mentioned, we're exploring in a Bayesian design fashion. We're not at the place to do randomized trial right now for such a thing.

Shaji, was your question about AML or ALL?

This was on ALL, but I will ask you about AML, same question.

So I think randomized trials are the standard of care. This is how all of us have been indoctrinated. And educated. Randomized trials are the only way to make progress. But if you look at multiple aspects of life, for example, the way we live, we're not living in a randomized fashion. When we send our, our kids to school, we do not randomize one child to School A and another to School B. When you are trying to pick your spouse, you don't go 50 times with Candidate A and 50 times with the candidate B, and then—

I think that, well, Elie and I may disagree on that. We probably want to be randomized.

Actually, what you do is you gain experience. And as you have encounters, you apply your knowledge to the next situation. So in leukemias, I think randomized trials have still a role. And they have a very important role in the 2 extremes. If you have a land of research desert where you have only one drug to test, and the results are so bad, or in the opposite situation where the cure rate is so high, like in childhood ALL, people are reluctant not to go with randomized trials. However, when you are in a land of research plenty, where you have multiple new drugs that you are trying to incorporate into your standard of care. In ALL, for example, blinatumomab, inotuzumab, possibly the new CD20 antibodies, possibly venetoclax, and possibly the CAR T-cells. I think in that setting, a Bayesian approach will be much more effective in getting you fastest to the ideal regimen the ideal regimen that you can then compare to whatever standard of care you want. But let's take the example of Philadelphia-positive ALF. So now we have studies with disatinib, blinatumomab, and with ponatinib, blinatumomab, which are giving a CMR rate close to 90% and the 4-year survival of 90%. So people want to randomize. What will be the control arm? Will it be hyper-CVAD imatinib? or hyper-CVAD desatinib. And if I tell the patient that the standard arm historically has a 4-year survival of 60% or 70%, will they agree to be randomized? So remember, Shadi, the essence of a randomized trial is what is called equipoise, meaning that you as a physician do not have any knowledge that tells you that perhaps arm A is better than arm B. So if you can go to the patient and say that you do have equipoise, so you tell the patient in all transparency, I really do not know in this trial whether ponatinib or disatinib lena is superior to hyper-CVAD imatinib, and therefore I'm going to randomize you. And if the patient, knowing the historical data, agrees to that, then it's fine. But this is the essence of a randomized trial. It implies equipoise, meaning that the physicians truly and honestly do not know which of the 2 arms is going to be superior or inferior.

And Shadi, in ASH, there was a presentation from the French group, Dr. Boissel, where he compared 2 cohort comparisons, not randomized trial, but he compared, for example, high-risk ALL who received induction therapy and standard consolidation in the past 2 recent ones where they have high-risk taking chemotherapy and Oblena, and he showed in a comparison that Oblena is superior. So essentially, this is the kind of things that everybody is using.

I can honestly talk to you guys for hours. I really— I'm very grateful. This is the best inaugural podcast I've done, the first episode. I mean, if folks don't listen to future episodes after this, They are foolish. How could they not when you start? But, you know, I feel bad for the future guests, to be honest. I mean, after this, I don't know. They have big shoes to fill. I'm very grateful for your time, Drs. Hagop Kantarjian and Elie Jabbour. Anything that you want to say? Final thoughts before I let you go back, Hagop, to painting and Elie to really doing leukemia stuff?

Good to reconnect with you, Shadi, and stay safe and We'll see you at ASH.

Shadi, I'll see you at ASH. You are very promising.