Episode 289 - Treating Leukemias: Past and Present With Hagop Kantarjian

It's Healthcare Unfiltered, and it's your host, Shadi Nabhan. Thank you for tuning in to this episode of Healthcare Unfiltered, folks. Thank you for supporting this podcast going on close to 7 years now. Healthcare Unfiltered every Tuesday, week in and week out. I appreciate your support.

Thank you.

As you know, we cover everything from clinical advances to healthcare policy, book authors, a lot of things in healthcare that we have covered over the years. And last year we've launched Healthcare Unfiltered Express. Healthcare Unfiltered Express focuses specifically on advances in clinical oncology, new papers, new findings. It's shorter format, about 10 to 15 minutes, that allows you to really get in touch with a lot of things that are happening right away. So check out both Healthcare Unfiltered and Healthcare Unfiltered Express. Express. You can subscribe to both shows. They are available on all platforms from Amazon to Apple to Spotify, YouTube. And you can follow me on Twitter @ShadiNabhan and check out my Facebook page, my YouTube page, and my website, shadinabhan.com. Today's podcast is very special because I really host a legend, Dr. Hagop Kantarjian. There's probably no one that is watching this show or listening to this show that does not know who Dr. Hagop Kantarjian is arguably one of the most influential figures in oncology and hematology and has really transformed how we treat malignant hematological disorders, specifically leukemias. Hagop has been the chair of the Department of Leukemia at MD Anderson Cancer Center, has held many leadership positions, and has won numerous awards. I really will not have time to list all of the awards that that he won at ASCO and other societies. But needless to say, the first time I met Dr. Kantarjian was in 2002, and I was preparing for the Hematology Oncology Board, the George Washington Board. And I recall listening to a lecture that he gave. I believe the lecture he gave was on AML, or it could have been CML. I don't really remember exactly. But it was so clear, it was so obvious, it was so easy to follow, so easy to understand. And I was always dreaming, I'm thinking like, I wish I can one day give a lecture similar to the way Dr. Hagop Kantarjian delivers his lectures. And fast forward, I have been fortunate to learn a lot from Dr. Kantarjian, as so many of people who are listening here and who have really followed his work, as well as learned from him how we treat leukemia. So I've asked Dr. Kantarjian to come on the show to really simplify how we approach leukemias actually, which is not easy because we have so many types of leukemias. But interestingly, he suggested to me that he can actually cover that in less than 45 minutes. And he's going to look at this from the risk stratification perspective into favorable, less favorable, and not favorable leukemias. And he's going to lump all of these together under the leukemic disorders category. I am going to have Dr. Kantarjian in the future to come on the show and talk about his career path. and about leadership, mentorship. There's so much to learn from this legend in hematology, Dr. Hagop Kantarjian. I think we are so fortunate and so grateful to have someone like Dr. Kantarjian who has really dedicated his life to helping patients treated with leukemia and to mentoring many people who are interested in hematological malignancies. I don't think I've given enough— I've given Dr. Kantarjian justice in terms of introducing him, but I am certain and confident that everybody who is watching this show or listening to this show know exactly who I am talking about. Without further ado, the myth and the legend, Dr. Hagop Kantarjian on Healthcare Unfiltered. Well, folks, it's really a very Important day for me because not only that this is the first time Dr. Hagop Kantarjian comes on my show, Healthcare Unfiltered, but everybody knows who Dr. Kantarjian is, and I have been a big fan for 25 years. He has mentored a lot of us who are interested in malignant hematology. So, Hagop, it's truly an honor to have you on my humble show.

Likewise, Dr. Nava.

حلو لما تقول لي دكتور نبهان، هذا مهم جداً. بس، قبل أن نبدأ، هاجوب، قلت لك قليلاً عنك فيما جعلك، دعونا نذهب لمماري لين لثلاثين سنة.

ما جعلك تدخل في الليكيميا، في المالغنتي الهيماتولوجيا؟ فكما تعرفون، كنت أتعلم في جامعة أمريكا في بيروت في لبنان، وهذا هو المكان الذي يتعلمون العلم ثم يتعلمونه. I came for an elective fellowship at MD Anderson in 1978. And this is where I discovered that perhaps 90% of the knowledge in cancer will be obsolete 10 years later. And MD Anderson allowed individuals in training to expand with their vision and to take chances. You do high risk, but also high benefit approaches to therapy. And many of those fail, but ultimately some of them will become the new standards of care. And having an approach of innovation allows a faster pace of cancer research. At MD Anderson, I met Dr. Emil J. Freireich, Drs. MacReady, Keating, and many of the giants in leukemia research. And I decided to come back and stay at MD Anderson. So that's what I did. In '81, I came and trained as a fellow at MD Anderson, and then I stayed on faculty from 1983 till the present time.

You're a lifer. You're a lifer at MD Anderson. And it's amazing to see what has happened in the treatment of leukemia. And that's really the subject of today's podcast. We wanted to talk about the evolution of leukemia treatment and leukemia research, how things were 40 years ago, 1981, when you first started, and now we are 2026. So let's just start by how, when you first started, how were things? How was your thinking process? How was research at the time? And then how did things evolve?

Right. So just as a background, when we think of leukemias, we divide them in our mind into the acute and chronic leukemia, and that's based on the course of the diseases if untreated. So acute leukemias, patients lived 2 years untreated— patients lived about 1 to 2 months if untreated. The chronic leukemias, they lived about a couple of years. And then we divide them by the cell of origin. So in simple ways, myeloid versus lymphoid. So you have 4 main kinds of leukemia, acute myeloid leukemia, Acute lymphocytic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. And then you have subsets like APL and core binding factor acute myeloid leukemia as part of AML, and hairy cell leukemia, which is a cousin of chronic lymphocytic leukemia. But I like to divide them based on how the research has advanced from 1981 till now. So if you think about them in 1981, most of the leukemias were in what is called unfavorable category, meaning their 5-year survival was less than 30%. There was one intermediate leukemia, acute promyelocytic leukemia, and that's because anthracyclines were discovered in the '70s. So with anthracyclines, acute promyelocytic leukemia had a 5-year survival of about 40%. And then there were no favorable leukemias. There were no leukemias where you could say that the 5 or 10-year survival is above 70%. So when I started in 1981, the 2 acute leukemias, AML and ALL, were curable at a rate of 20% with intensive chemotherapy. These are the adult ALL. In the chronic leukemia, both CML and CLL were incurable, and the 5-year survival was about also 10% to 20%. You fast forward to today, most of the leukemias have shifted to the favorable category, meaning we expect their survival to be over 70% or 80% at 5 to 10 years. Then we have an intermediate group of leukemia where also there are substantial subsets. And now we have seen that among the unfavorable leukemia, there's only 2 simple categories, the older patients with AML and patients with maybe TP53 and MYCN. So if you like, I could take you through the progress in each of these entities and going from the most favorable to the least favorable, but also to show that there's no one path for curing cancer. A lot of it is trial and error, and also much of it is deciphering the pathophysiology of particular leukemias and then developing drugs that target those pathophysiologies.

I would love to do that. And before we do it, Hagop, I was going to— what was the rate-limiting— what was the catalyst event that you think led to this acceleration in change? Is it the genomic sequencing? I mean, what was it, you think?

I think deciphering the pathophysiology. We started Actually, around the mid-'80s, when people started talking about cancer genes or oncogenes, starting with the MYC and with the other oncogenes. And then in the 2000s, with actually deciphering the whole human genome and then looking at cancer genomes and finding abnormalities. So to give you a few examples, when in acute myeloid leukemia, when they developed the first leukemia genome, they identified maybe 2 or 3 abnormalities. It was IDH1. TP53 was well known, and maybe there was a third mutation. Now we know that there's a whole spectrum of more than 100 mutations, and many of those mutations are targetable. And this is what led, for example, to develop FLT3 inhibitors, IDH inhibitors, menin inhibitors, the development of venetoclax as a BCL-2 inhibitor. So all these were derived by understanding the pathophysiologic mechanisms of particular leukemias, either through their metabolic functioning or through particular mutations.

Amazing. Okay, let's pick your leukemia of choice and just go through how this transformed from unfavorable to favorable, maybe?

So what I'm going to do for simplicity is start with the best leukemias, the most favorable today. And I'm going to outline 7 of them with different modalities that led to their high potential cure. Then I'll go to the intermediate leukemias, and then we'll leave the unfavorable till the last. So when you think of the favorable leukemias, these are leukemias where the 5- to 10-year survival is over 80%. The simplest example is hairy cell leukemia. And the discovery was empirical because cladribine was developed for the treatment of T-cell malignancies. But then there was one patient on the Phase 1 study with hairy cell leukemia who received the treatment and went home to die because of lack of response. And that patient came back 6 months later incomplete remission. So one—

Wow.

Empiric discovery in the clinic led to the potential cure of hairy cell leukemia. So now the way we treat hairy cell leukemia is with 5 days of cladribine. Then we use the CD20 antibody rituximab. We give it weekly for 8 times, and the 10-year progression-free survival is 90 to 95%. So this is a leukemia that is easier to treat than even a pneumonia, because pneumonias, you need a longer course of antibiotic, more toxicity, and a higher mortality. So that's one example of a simple kind of leukemia that has a high cure rate and where we cannot do better than this. And the interesting point is the pathophysiology was discovered after those findings. So now we know that they are related to the BRAF mutation and people are developing BRAF inhibitors, but the train has left the station. There's nothing better than cladribine and rituximab as frontline curative therapy. The second leukemia, which is highly curable, is actually a subset of acute myeloid leukemia. Acute promyelocytic leukemia. So in 1981, a third of the patients died during the induction from DIC, and the cure rate with chemotherapy was 40%. The Chinese in the late 1980s started reporting on 2 drugs which were not chemotherapy. One was ATRA, which is a vitamin A analog, and the other one was arsenic trioxide, which is a poison. And when those studies came out of China, we decided at MD Anderson in 2000 to combine these agents as a non-chemotherapy regimen for leukemia. And people thought we were crazy because when we presented the data at the beginning, the APL aficionados thought that using a regimen without idarubicin and ATRA was criminal.

Yeah.

As the data evolved, then the same APL experts took the MD Anderson regimen, ATRA arsenic trioxide, compared it in a randomized trial 12 years later to ATRA idarubicin. And they found that the non-chemotherapy regimen developed at MD Anderson was better, highly curative with a 10-year survival of 90%. And this is now called the Lococo regimen after the person who did the randomized trial. Now, the third kind of highly curable leukemia is core-binding factor acute myeloid leukemia. So these are patients with translocation or inversion . And here, the curative approach was in 2 steps. The first step was the discovery of high-dose RAC. as opposed to standard RRC. That increased the cure rate from 30% to 50%. And then the discovery and the implementation of gemtuzumab, the CD133 antibody, which increased the cure rate from 50% to 80%. So in core binding factor leukemia, we did not make major targeted discoveries. We just collected 2 kinds of therapies in a synergistic fashion That led to the cure rate of 80% in these patients.

Amazing stories, by the way. The cladribine story with that one patient, the APL one, and this one as well. Just the stories behind the science. Amazing.

Now, the next 2 leukemias are very interesting because these 2 leukemias were driven by deciphering the pathophysiology of these leukemias. And these include CML and CLL. So in chronic myeloid leukemia, before 2000, we treated the patients with allogeneic transplant or with interferon, and the average survival was about 5 years. In 2000, Dr. Brian Druker, collaborating with Novartis, developed the first BCR-ABL tyrosine kinase inhibitors, imatinib. And following that, because we saw that patients were developing resistance to imatinib with mutations in the ABL kinase domain, we developed the more potent second-generation TKIs. So disatinib, bosutinib, nilotinib. And then we developed the third-generation TKIs, which were even more potent and could also suppress the T315I clones. So now you have all these TKIs, which we're implementing in the frontline. And now patients with chronic myeloid leukemia are expected to have a normal lifespan.

Yeah.

So the 10-year survival increased from 10% to 90%. And we are working on strategies to be able to stop the therapy in most of the patients, what we call treatment-free remission or a molecular cure. So today, in 100 patients with CML, we expect probably 90 to 95 of them to live their normal life. And we expect about 30 to 40% to be able to stop therapy after 5 years of a complete molecular cure. Now, how— and they don't have to be treated for years. They have to be treated for about 5 to 7 years, not for a lifetime. Now, where are we going to make progress in CML? Personally, I think that if we develop, instead of BCR-ABL inhibitors, if we develop BCR-ABL degraders and combine them with the BCR-ABL inhibitors, then potentially we could develop a combined regimen that's given for a year in the form of pills that would cure Most of the patients with CML.

What would be the difference? Like, in degraders, they just basically get rid of the domain completely?

No. So the inhibitors suppress the signal, but the cells that have the signal can remain dormant in a small proportion. And when you stop the TKI, it comes back. The degraders get into the BCR-ABL and destroy it. So they can destroy dormant cells which are resistant to BCR-ABL inhibitors. And this is not science fiction. So to get you back to the evolution of cancer research, at the beginning we had the first option, which was surgery. Then came radiation therapy. Then came chemotherapy.

Yep.

Then came the targeted therapies in the form of antibodies or the first BCR-ABL kinase inhibitor. And then we had the checkpoint inhibitors, a form of immunotherapy, and then the CAR-T cells. And now I think the 6th arm of cancer therapy are going to be degraders, tumor target degraders. So the example is in chronic lymphocytic leukemia, for example, where we know that the BCR— that the Bruton tyrosine kinase degraders may be more potent than the BTK inhibitors, and they could replace them and be more effective. So that's the story in CML that I would like to see with the development of BCR-ABL degraders that we could add to BCR-ABL inhibitors and perhaps cure chronic myeloid leukemia at a high percentage. Amazing. The other chronic leukemia is, of course, chronic lymphocytic leukemia. And today, when you read the textbooks, people say that chronic lymphocytic leukemia is still incurable. I personally think CLL is curable if you consider cure, meaning that the patient gets a treatment, the disease disappears, and it never comes back in the rest of the lifetime of the patient. So where did the breakthrough come from? It came in 2014 after we understood the role of the BTK and the BCL-2 in prolonging the survival of the CLL cells. So BTK inhibitors were developed. Venetoclax was developed at MD Anderson. We combined both of them for 2 years of therapy. And the first study was with ibrutinib, venetoclax given for 2 years. And we have treated over 200 patients. And with all the patients being off therapy for a minimum of 5 years, we have only 20 patients who have relapsed with a 5-year survival of 97%.

Amazing.

So again, CLL is the 6th form of favorable leukemias where the 5- to 10-year survival is over 70%.

The only thing though, Hagop, is we classify CLL as lymphoma. You got to be careful here.

It used to be classified as lymphoma until Michael Keating discovered the activity of fludarabine. So we stole them from the lymphoma people and developed FC and FCR and now the BTK inhibitors. So we think of CLL as a leukemia rather than a lymphoma at MD Anderson.

Yeah, I know that. I had to say it, though.

So then there are 2 additional leukemias that became very favorable as of, I would say, 2010, 2017. And these are the 2 subsets of ALL, adult ALL. So as you know, in childhood ALL, you give 3 years of intensive chemotherapy and you cure about 80% of the children. But that's really not manageable in poorer countries and in the community setting. In adult ALL, using the same 3 years of intensive chemotherapy, we were able to have a 5-year survival of about 50%. In 2000, we started in Philadelphia-positive ALL to add the BCR-ABL kinase inhibitors to chemotherapy. Yeah. So that was the first inflection point. In 2017, we found that blinatumomab was better than chemotherapy. And we had by then developed ponatinib, which is a very potent BCR-ABL kinase inhibitor. So in 2017 at MD Anderson, we combined ponatinib with blinatumomab in a simultaneous schedule. And now we're reporting a 5-year survival of 90% without intensive chemotherapy and with less than 5% of the patients requiring an allogeneic transplant. So that was—

How long is this regimen? 2 years?

So the regimen is given for 5 courses of belantamab. And unfortunately, today we have to give 5 years of ponatinib because we want both the PCR and the NGS MRD to be negative. And we're starting to do like CML. After 5 years of a complete molecular response, we're starting to stop therapy. And in about 17 patients where we did this, 0 of the 17 have relapsed. So the treatment is going to be about 5 years. Now, we can improve on this because so far we have not used the CAR-T cells instead of allogeneic transplant. So it is possible that in the future, We'll do the ponatinib or a better BCR-ABL kinase inhibitor. We'll do the 5 courses of Blinna, and then we will do a consolidation with CAR T-cell, which may allow us to discontinue the ponatinib sooner rather than after 5 years. So that's the plan for chronic— for Philadelphia-positive acute lymphocytic leukemia. But if you think about it, before 2000, Philadelphia-positive ALL was a fatal disorder. It was a death sentence. Today, it's the easiest of— one of the easier leukemias to treat. Now, another subset is B-cell ALL, where we developed both belinatumumab and inotuzumab. We added them to the chemotherapy, and now we have 5-year survivals which are very close to the 5-year survival in childhood ALL. So 85%. And this is with about half of the chemotherapy, but with the addition of those 2 antibodies. Personally, I think 5 years from now, we may treat ALL like lymphomas with 6 courses of chemotherapy with belinatumumab, inotumumab, followed by the CAR-T cells. and then stop the treatment. So rather than 3 years of intensive chemotherapy, about 6 to 7 months of milder chemotherapy with the targeted therapies with a potentially very high cure rate.

Amazing. So these are the 7, right? We did the 3 APL, hairy cell, core binding factor. We did CML, CLL, and then we did the last one, which is the— so these are the 7 favorable leukemias.

These are the 7-fiber. The intermediate have 2 categories. The older patients with ALL, we're using mini-CVD ponatinib lenalidomide. We have now a 5-year survival of 50%. And then the younger patients with AML, where instead of 3+7, we're using a more intensive therapy, the FLAG-ida venetoclax or the CLLA venetoclax. And we are having 5-year survival rates of 70%. But these patients still require allogeneic transplant in remission. And we're starting to add the targeted therapies. So the FLT3 inhibitors, the IDH inhibitors, the menin inhibitors, of course, on top of the venetoclax in addition to the chemotherapy. So these are the 2 intermediate leukemias, older ALL and younger AML. where actually the 5-year survival has exceeded 40%. And in the younger AML, it's about 70% in our hands. Now, the last—

There's a quick question. The menin inhibitors are being incorporated into frontline as part of trials, or are they right now ready for primetime in frontline?

No. So today they are part of trials. Because we have not incorporated them yet into the community to be added to the chemotherapy.

Yeah.

And the question is, do you add them to 3+7? Do you add them to clear venetoclax, or do you add them to the lower-intensity regimens that we use in older AML, like cladribine, low-dose aracytine, venetoclax, or azacitidine, venetoclax? So this is where there's a bit of a struggle in terms of implementing safe regimens in acute myeloid leukemia where you pile up more targeted therapies onto the intensive chemotherapy venetoclax. So now there's a group of leukemia doctors who are saying, why do we need the intensive chemotherapy at all?

Correct.

Can we use lower intensity therapy as we do in older AML with hypomethylating agent and the venetoclax to which we add the targeted therapies. I prefer cladribine, low-dose RAC, venetoclax because it's better than azacitidine, venetoclax. It is a low-intensity regimen and we can add those targeted therapies to that. So you're going to see a broad range of research in AML where different investigators do different things, either adopting intensive chemotherapy with targeted therapy or using ezacitidine venetoclax in triplet or quadruplet regimens, or at MD Anderson pushing for the cladribine lodosa-aracivin etoclax, to which we add a regimen in a quadruplet fashion such as cladribine lodosa-aracivin etoclax with the FLT3 inhibitor with an IDH inhibitor, with a menin inhibitor, either simultaneously or in a sequential fashion.

So now this takes us to the poor ones.

So let's talk about the poor ones. So the poor ones are patients over the age of 60 with acute myeloid leukemia.

Any acute myeloid leukemia?

No. So we excluded APL, we excluded core binding factor acute myeloid leukemia. So these are the older patients with acute myeloid leukemia. And you see the leukemia experts twisting themselves around trying to find which patients would be unfit for intensive chemotherapy to give them HMA venetoclax. But if you look at the SEER data, it's very simple. The mortality with any form of chemotherapy, if you're under 60, is about 10% during the induction. If you are 60 to 75, it goes to 30%. And if you are over 75, it goes to 50%. This is the 4-week mortality in community practice by the SEER data. Now, of course, in cancer centers, the mortalities are less, but this— they still range between, say, 10 or 15% during the induction.

Mm-hmm.

So what we need to do is come up with regimens where the mortality is very low and where you can add things to increase the cure rate. So people started with the hypomethylating agent. We had them since 2006, minimal benefit. In 2017, the HMA venetoclax regimen was developed and became a new standard of care. But when we look at the long-term follow-up with ezacitidine venetoclax in older unfit patients, the 3-year survival is only 25%. So then we are working on 2 strategies. The first one are triplet regimens with an HMA, and I prefer oral decitabine because then you can have a total oral therapy with decitabine venetoclax. and the third targeted therapy, or you can do cladribine, low-dose RAC, venetoclax.

What's an attractive third target in your opinion in this situation?

So the third target when you do, say, ezacitidine, lorcitabine, venetoclax will be a FLT3 inhibitor if the patient is FLT3 mutated, an IDH inhibitor if they are IDH1 or 2 mutated, And a menin inhibitor if they have, if they have a translocation 11q23 abnormality. But also there are other rearrangements that can benefit from the menin inhibitors, or possibly the possibility of what we call a menin signature, meaning an overexpression of particular cytokines that could respond to menin inhibitors. Now, we also found that menin inhibitors synergize with FLT3 inhibitors, and they synergize with venetoclax. So now instead of using triplet therapy, we're trying to advocate for safe quadruplet therapy where we use the FLT3 inhibitors even in FLT3 wild type. If they have a FLT3-like signature. And we add the venetoclax and possibly the menin inhibitor as indicated by the signature. So there's this signature called MYC1 signature that indicates that MYC1 overexpression could be sensitive to menin inhibitors. So these are the triplet regimens or quadruplet regimens that we're testing in older AML. And these may find a foothold in the younger patients in the future, as was shown by Dr. Amir Fathi when he compared ezacitidine venetoclax to 3+7 and showed the very exciting data at the ASH meeting.

I actually love the fact that you looked at the leukemias this way. I honestly haven't thought of it this way because you kind of combine the ALL, AML, CML, CLL, all of them together under one big umbrella. And we're defining them based on the risk category. It's almost like a different way of looking at leukemic disorders, myeloid disorders, if you will.

Correct. And actually, this way of classification may be more pertinent because then you start thinking of subsets of leukemia. Rather than the umbrella of acute versus chronic and myeloid versus lymphoid. So you talk about leukemia, what is the pathophysiology, and what can we add to the treatment that will increase the potential cure rate?

There's one leukemia you didn't address a little bit. Maybe we can spend a minute or 2 on it, which is secondary leukemia or treatment-related leukemia.

I presume obviously this fits in the high risk unless things have No, actually, the 3 leukemias where we need something urgently are TP53 acute myeloid leukemia. Nothing has worked, and that's about 10% to 15% of AML. MECOM rearranged leukemias. So these are patients with translocation 3q26 with a rearrangement. These are not common. These are about 1% to 2%, but they have a horrible outcome. And then what you mentioned, the treated secondary AML. So patients with either MDS or myeloproliferative neoplasms who are treated and progress to AML. These 3 categories of acute myeloid leukemia, we have nothing in our armamentarium that works so far. So what we need to do is develop either targeting strategies or strategies which are agnostic to the pathophysiology So for example, if you develop NK cellular therapy for minimal residual disease or possibly some form of immune therapy that eradicates residual disease. But we do not have yet good clues as to how to treat those 3 terrible leukemias that nothing has worked on so far.

Well, no retirement, Hagop, until you figure this out. So My question to you is, if we're having this conversation maybe a couple of years from now, are you— what's your futuristic look on leukemia? Are you optimistic? Do you sometimes look— I mean, I'm pragmatic and I'm realistic. There are times where you think we've done all we can. I'm not really sure we're going to be able to find something for TP53 unless you literally have a target against the TP53, which we tried. I think I remember there's several molecules that were hypothesized to target the TP53, but they really never pulled that off.

CD47.

Yeah. I mean, what's your futuristic look? How are we heading in the next couple of years?

So I think in the more favorable leukemias, we are going to be able to do much better. I think CML, if we discover a BCR-ABL degrader that's effective and safe, we will cure CML maybe with 1 year of combined therapy. In the CLL, we have better BTK inhibitors. We have the BTK degraders. We have better BCL-2 inhibitors coming along. So I think CLL will be potentially highly, highly curable with maybe 1.5 to 2 years of those combinations. In ALL, both Philadelphia-positive and the B-cell ALL, I think by adding additional antibodies like CD20 bispecific T-cell engagers or safer TKIs than ponatinib, for example, olverambatinib, we're going to be able to increase the chance of a cure in both B-cell ALL and PB-ALL. And don't forget, we're starting to use the CAR T-cells as a consolidation rather rather than allogeneic transplant. In acute myeloid leukemia, we need to discover more targets and better targeted therapies. So for example, if we discover one good pan-RAS inhibitor, this will be a major breakthrough because a lot of the patients with AML who relapse, relapse with the RAS pathway mutation. And now we know that there's a very effective KRAS inhibitor in pancreatic cancer. So if we have a good pan-RAS inhibitor that we can export to acute myeloid leukemia, it will elevate the potential cure rate across all AMLs. I do not know what will work in TP53, but there is already one molecule, an antibody that targets the TP53 with the mutation at 220, and it's working very well. But there are more, about 90 mutations along the TP53 molecule. So I don't know that we can develop one inhibitor for each of those mutations. We have to have a better approach to TP53. With the MEK/ERK, we are working on the pathophysiology, and we think We have something that might work. And with the treated secondary AML, that's also a big problem that we need to tackle.

Yeah, but the advances are historic. I mean, and this is not an easy thing to do. I mean, when I was a fellow, I could not treat ALL. I tried, it was impossible. And I was at a university setting and it was my biggest nightmare when I had to take care an ALL patient, not because things were not working. It was because you still had to do so much treatment and very intensive therapy, and the outcome was so dismal. And it's just amazing to see this. Hagop, any other questions I should have asked you pertaining to the treatments of leukemias? You did promise you're going to come back where we're going to talk about mentorship, leadership, and other aspects, not science, because a lot of people could learn from you and your journey. But anything about leukemias that we should have talked about that I forgot asking you about?

No, I think we pretty covered it much. Actually, I have an ASCO Post editorial that I co-wrote with Dr. Freireich, the late Dr. Freireich. It came out this month, so people who are interested can look at it. And it essentially goes in summary form through what we talked about.

Yeah, if you send me a link, I will put it in the notes because this will— we're taping this just for listeners and viewers. This is being taped before ASCO, but it's not going to cut. It's going to come out probably early July. So we'll be close enough to SOHO. So this will strategically put for SOHO. And how many years now you've been doing SOHO, Hagop?

So SOHO started under a different name. It was started by Michael Keating. He called it Leukemia: The Next Question. And this was like maybe 20 years ago. And then we made it Hematologic Malignancies, the next questions. And then we changed it to the Society of Hematologic Oncology, which started in 2012, I think. Well, congratulations. So we are in our 13th or 14th year now.

Congratulations. I will try to visit with you guys in Houston. It just happens around Labor Day and it's like You need to make the meeting around my schedule.

I insist that you come to Soho because you'll be able to interview so many people.

Yes, I'm going to be— we have to form a collaboration between Soho and Healthcare Unfiltered.

God willing.

Dr. Hagop Kantarjian, the myth, the legend, the master of leukemia in the flesh here on Healthcare Unfiltered. Thank you so much for coming on.

Very kind of you to invite me.

Thank you, folks. Thank you so much for listening. I appreciate you tuning in, and thank you, Hagop, for coming on the show. It means a lot to me that you gave Healthcare Unfiltered this exclusive. Folks, you can follow me on Instagram, Shadi underscore Healthcare Unfiltered. On YouTube, on X, or formerly known as Twitter, and let me know what you think. You can also suggest ideas, topics, and absolutely be engaged and follow all of the progress on Healthcare Unfiltered. And don't forget to check out also Healthcare Unfiltered Express and let your friends, colleagues know about both shows. Drop a brief review. This allows a lot of people to discover. This podcast and always let me know how I'm doing. Before I let you go, I'm going to leave you with a saying by a Lebanese poet, Khalil Gibran: Out of suffering have emerged the strongest souls. The most massive characters are seared with scars. Until next time, take care.