WEBVTT
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It's Healthcare Unfiltered, and it's your host, Shadi Nabhan.
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Thank you for tuning in to this episode of Healthcare Unfiltered, folks.
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Thank you for supporting this podcast going on close to seven years now.
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Healthcare Unfiltered every Tuesday, week in and week out.
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I appreciate your support.
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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.
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And last year we've launched Healthcare Unfiltered Express.
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Healthcare Unfiltered Express focuses specifically on advances in clinical oncology, new papers, new findings.
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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.
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So check out both Healthcare Unfiltered and Healthcare Unfiltered Express.
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You can subscribe to both shows.
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They are available on all platforms from Amazon to Apple to Spotify, YouTube, and you can follow me on Twitter at ChaddyNabhan.
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And check out my Facebook page, my YouTube page, and my website, chattinabhan.com.
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Today's podcast is very special because I really host a legend, Dr.
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Hagob Kintargian.
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There's probably no one that is watching this show or listening to this show that does not know who Dr.
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Hagob Kintargian is.
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Arguably one of the most influential figures in oncology and hematology, and has really transformed how we treat malignant hematological disorders, specifically leukemias.
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Hagob has been the chair of the Department of Leukemia at MD Anderson Cancer Center, has held many leadership positions, and has won numerous awards.
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I really will not have time to list all of the awards that he won at ASCO and other societies.
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But needless to say, the first time I met Dr.
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Kantargian was in 2002, and I was preparing for the hematology oncology board, the George Washington board.
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And I recall listening to a lecture that he gave.
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I believe the lecture he gave was on AML, or uh it could have been CML.
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I don't really remember exactly.
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But it was so clear, was so obvious, was so easy to follow, so easy to understand.
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And I was always dreaming, I'm thinking, like, I wish I can one day give a lecture similar to the way Dr.
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Hagob Kantarjan delivers his lectures.
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And uh fast forward, I have been uh fortunate to learn a lot from Dr.
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Kantarjan, as so many of people who are listening here and who have really followed his work, as well as learn from him how we treat leukemia.
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Um, so I've asked Dr.
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Kantarjan 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.
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And he's gonna look at this from the risk stratification perspective into favorable, less favorable, and not favorable leukemias.
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And he's gonna lump all of these together under the leukemic disorders category.
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I am going to have Dr.
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Kantarjan in the future to come uh on the show and talk about his career path and about leadership, mentorship.
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There's so much to learn from this legend in hematology, Dr.
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Hagob Kantarjan.
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I think we are so fortunate and so grateful to have someone like Dr.
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Kantarjan, who has really dedicated his life to helping patients treat with leukemia and to mentoring many people who are interested in uh hematological malignancies.
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I don't think uh I I've given enough, I've given Dr.
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Kantarjan 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.
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Without further ado, the myth and the legend, Dr.
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Hagob Kantarjan on Healthcare Unfiltered.
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Well, folks, uh it's really a very um important day for me because not only that this is the first time Dr.
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Hagob Kantarjan comes on my show, Healthcare Unfiltered, but um everybody knows who Dr.
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Cantarjan is, and I have been a big fan for 25 years.
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He has mentored a lot of us uh who are interested in malignant hematology.
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So, Hagob, it's uh truly an honor to have you on my humble show.
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Likewise, Dr.
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Naban.
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Uh when you tell me Dr.
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Nabhan, that's very interesting.
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But um, before we get started, Hagob, uh um a bit about you in terms of what got you, take us through memory lane for 30 years.
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What got you into leukemia, into malignant hematology?
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So, as you may know, I was uh trained at the American University of Beirut in Lebanon, and this is where people absorb knowledge and then they apply it.
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I came for an elective uh fellowship at MD Anderson in 1978.
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And this is where I discovered that perhaps 90% of the knowledge in cancer will be obsolete 10 years later.
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And MD Anderson allowed individuals in training to expand with their vision and to take chances.
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Uh uh, you do high-risk uh but also high-benefit uh approaches to therapy.
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And many of those fail, but ultimately some of them will become the new standards of care.
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And having an approach of innovation uh allows a faster pace of cancer research.
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Uh at MD Anderson I met Dr.
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Emil J.
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Freyrak, uh Dr.
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McCready Keating, and many of the giants in leukemia research, and I decided to come back and stay at MD Anderson.
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So that's what I did.
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In 81, I came and trained as a fellow at MD Anderson, and then I stayed on faculty from 1983 till the present time.
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You're a lifer, you're a lifer at MD Anderson.
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And um it's amazing to see what has happened uh in the treatment of leukemia.
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And that's really the subject of today's podcast.
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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.
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So let's just start by how when you first started, how how were things?
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How was your thinking process?
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How was research at the time, and then how did things evolve?
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Right.
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So, just as um 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.
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So acute leukemias, patients lived two years untreated, uh, two two patients lived about one to two months if untreated.
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The chronic leukemias, they lived about uh a couple of years, and then we divide them by the cell of origin, so in simple ways, myeloid versus lymphoid.
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So you have four 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.
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But I I like to divide them based on how the research has advanced from 1981 till now.
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So if you think about them, in 1981, most of the leukemias were in what is called unfavorable category, meaning their five-year survival was less than 30%.
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There was one intermediate leukemia, acute promyelostic leukemia, and that's because uh ensacyclines were discovered in the 70s.
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So with anthracyclines, acute bromyostic leukemia had a five-year survival of about 40%.
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And then there were no favorable leukemias.
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There were no leukemias where you could say that the five or 10-year survival is uh above uh 70%.
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So when I started in 1981, the two acute leukemias, AML and ALL, were curable at a rate of 20% with intensive chemotherapy.
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Uh, these are the adult ALL.
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In the chronic leukemia, both CML and CLL were incurable, and the five-year survival was about also um 10 to 20 percent.
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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 five to ten years.
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Then we have an intermediate group of leukemia where also there are substantial subsets.
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And now we uh have seen that among the unfavorable leukemia, there's only two simple categories: the older patients with AML and patients with maybe TP53 and MECO.
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So, if you like, I could take you through the progress in each of these entities and uh going from the most favorable to the least favorable, but also to show that there's no one path for curing cancer.
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A lot of it is trial and error, and also much of it is deciphering the pasophysiology of particular leukemias and then developing drugs that target those pasophysiologists.
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I would love to do that.
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Um, and before we do it, Hagob, uh, I was gonna what was the rate limited?
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What was the catalyst event that you think led to this acceleration in um in change?
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Is it uh the uh you know genomic sequencing?
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I mean, what what was it you think?
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I think deciphering the pathophysiology, we started actually around uh the mid-80s when people started talking about cancer genes or oncogenes, starting with the MEC and with the other oncogenes.
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And then in the 2000s, uh, with actually deciphering the whole um uh human genome and then looking at cancer genomes and finding abnormalities.
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So, to give you a few examples, um, when in acute myelid leukemia, when they developed the first leukemia genome, they identified maybe two or three abnormalities.
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It was IDH1, uh, TP53 was well known, and maybe there was a third mutation.
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Now we know that there's a whole spectrum of uh more than 100 mutations, and many of those mutations are targetable.
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And this is what led, for example, to develop FLIP-3 inhibitors, IDH inhibitors, menine inhibitors, the development of venetoclax as a BCL2 inhibitor.
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So all these were derived by understanding the pathophysiologic mechanisms of particular leukemias, uh, either through their metabolic functioning or through particular mutations.
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Amazing.
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Okay, let's uh let's pick uh your leukemia of choice and just go through uh how this transformed from unfavorable to a favorable, maybe.
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Right.
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So, what I'm gonna do for simplicity is start with the best leukemias, the most favorable today, and I'm gonna outline seven of them with different uh modalities that led to their high potential cure.
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Then I'll go to the intermediate leukemias and then we'll leave the unfavorable till the last.
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So when you think of the favorable leukemias, these are leukemias where the five to ten year survival is over 80%.
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The simplest example is hairy cell leukemia, and the discovery was empirical because gladribine was developed for the treatment of T cell malignancies.
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But then there was one patient on the phase one study with hairy cell leukemia who received the treatment and went home to die because of lack of response, and that patient came back six months later in complete remission.
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So one empirical recovery in the clinic led to the potential cure of hairy cell leukemia.
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Uh, so now uh the way we treat hairy cell leukemia is for with five days of cladribine, then we use the CD20 antibody retoxima, we give it weekly four or eight times, and the 10-year progression-free survival is 90 to 95 percent.
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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.
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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.
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And the interesting point is the pathophysiology was discovered after uh those findings.
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So now we know that they are related to the BRF mutation, and people are developing BRF inhibitors, but uh the uh train has left the state the station.
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There's nothing better than cladarbine and retoximab as frontline curative syrup.
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The second leukemia, which is highly curable, is actually a subset of acute myeloid leukemia, acute promyelotic leukemia.
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So in 1981, a third of the patients died during the induction from DIC, and the cure rate with chemotherapy was 40%.
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The Chinese in the late 1980s started reporting on two drugs which were not chemotherapy.
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One was ATRA, which is a vitamin A analog, and the other one was arsenic trioxide, which is a poison.
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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.
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And people thought we're crazy because when we presented the data at the beginning, the uh the APL officionados thought that uh using a regimen without Iderubicin and ATRA was criminal.
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Yeah, yeah.
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As the data evolved, then the same APL experts took the MD Henderson regimen, atra arsenic trip side, compared it in a randomized trial 12 years later to Atra-Idarubicin, and they found that the non-chemotherapy regimen developed at MD Henderson was better, highly curative, with a 10-year survival of 90%.
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And this is now called the Lococo regimen after the person who did the randomized trial.
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Now, the third kind of highly curable leukemia is core binding factor acute myeloid leukemia.
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So these are patients with translocation A21 or inversion 16.
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And here the uh curative approach was in two steps.
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The first step was the discovery of high-dose RRC as opposed to standard RRC, that increased the cure rate from 30 to 50 percent, and then the discovery and the implementation of Gem2zumar, the CD133 antibody, which increased the cure rate from 50 to 80 percent.
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So, in core binding factor leukemia, we did not make major targeted discoveries, we just collected two kinds of therapies in a synergistic fashion that led to the cure rate of 80 percent in these patients.
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Amazing stories, by the way, the cladribine story with that one patient, the APL one, and this one as well.
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Just the stories behind the science, amazing.
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Now, the next two leukemias are very interesting because these two leukemias were driven by deciphering the pathophysiology of these leukemias.
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And these include CML and CLN.
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So, in chronic myeloid leukemia, before 2000, we treated the patients with allogenic transplant or with interferon, and the average survival was about five years.
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In 2000, Dr.
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Brian Drucker, collaborating with Novartis, developed the first BCR able tyrosine kinase inhibitors, ematin.
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And following that, because we saw that patients were developing resistance to EMATNIB with mutations in the able kinasal domain, we developed the more potent second generation TKIs, so desatineb, bosutineb, nilotinib, and then we developed the third generation TKIs, which were even more potent and could also uh suppress the T3015 I clones.
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So now you have all these TKIs which were implementing in the front line, and now patients with chronic myeloid leukemia are expected to have a normal lifespan.
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So the 10-year survival increased from 10% to 90%, and uh we are working on strategies to uh be able to stop the therapy in most of the patients, what we call treatment fear emission or a molecular cure.
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So today, in 100% patients with CMN, we expect probably 90 to 95 of them to live their normal life, and we expect about 30 to 40 percent to be able to stop therapy after five years of complete molecular cure.
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Now, how and and they don't have to be treated for years, they have to be treated for about five to seven years, not for a lifetime.
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Now, what where are we going to make progress in CML?
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Personally, I think that if we develop instead of BCR inhibit BCR-able inhibitors, if we develop BCR-able degraders and combine them with the BCR-able 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.
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What would be the difference?
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Like in degrading degraders, they just basically get rid of the domain completely?
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No.
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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.
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The degraders get into the BCR able and destroy it.
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So they can destroy dormant cells which are resistant to BCR able inhibitors, and this is not science fiction.
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So to get you back to uh the evolution of cancer research, at the beginning we had the first uh option, which was surgery, then came radiation therapy, then came chemotherapy, then came the targeted therapies in the form of antibodies or the first BCR able kinase inhibitor, and then we had the checkpoint inhibitors, a form of immunotherapy, and then the CART cells.
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And now I think the sixth arm of cancer therapy are going to be degraders, tumor target degraders.
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So the example is in chronic lymphocytic leukemia, for example, where we know that the BCR uh that the bruton tyrosine kinase degraders may be more potent than the BTK inhibitors, and they could replace them and be more effective.
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So that's the story in CML that I would like to see with the development of BCR-able degraders that we could add to BCR-able inhibitors and perhaps cure chronic myeloid leukemia at a high percentage.
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The other chronic leukemia is, of course, chronic lymphocytic leukemia.
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And today, when you read the textbooks, people say that chronic lymphocytic leukemia is still incurable.
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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.
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So, where did the breakthrough come from?
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It came in 2014, after we understood the role of the BTK and the BCL2 in prolonging the survival of the CLL cells.
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So BTK inhibitors were developed, the netoclex was developed.
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At MD Anderson, we combined both.
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Of them for two years of therapy, and the first study was with um uh a brutin and venetoclax given for two years, and we have treated over 200 patients, and with uh all the patients being off therapy for a minimum of five years, we have only 20 patients who have relapsed with a five-year survival of 97 percent.
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So, again, CLL is the sixth form of favorable leukemias where the five to ten year survival is over 70 percent.
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The only thing though, Hagob is we usually we classify CL as lymphoma.
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You gotta be careful here.
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It used to be classified as lymphoma until Michael Keating discovered the activity of fluerabine.
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So we stole them from the lymphoma people and we developed FC and FCR, and now the BTK inhibitors.
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So we think of CLL as a leukemia rather than a lymphoma at MD Anders.
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Yeah, uh yeah, I know that.
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That's I had to say it though.
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So then there are two additional leukemias but that became very favorable as of I would say 2010-2017.
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And these are the two subsets of ALL, adult ALL.
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So, as you know, in childhood ALL, you give three 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.
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In adult ALL, using the same three years of intensive chemotherapy, we were able to have a five-year survival of about 50 percent.
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In 2000, we started in Philadelphia positive ALL to add the BCR-able kinase inhibitors to chemotherapy.
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So that was the first inflection point.
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In 2017, we found that blinatumal was better than chemotherapy, and we had by then developed ponatineib, which is a very potent BCR-able kinase inhibitor.
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So in 2017 at MD Anderson, we combined ponatinib with blinatumumal in a simultaneous schedule, and now we're reporting a five-year survival of 90% without intensive chemotherapy and with less than 5% of the patients requiring an allogenic transplant.
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So that was how long is this regimen?
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Two years?
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So the regimen is given for five courses of blinatumad.
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And unfortunately, today we have to give five years of ponatinem because we want both the PCR and the NGSMRD to be negative.
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And we're starting to do like CML.
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After five years of a complete molecular response, we're starting to stop therapy.
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And in about 17 patients where we did this, zero of the 17 have relapsed.
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So the treatment is going to be about five years.
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Now we can improve on this because so far we have not used the CART cells instead of allogenic transplant.
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So it is possible that in the future we'll do the uh ponatineib or a better BCR-able kinase inhibitor.
00:25:23.119 --> 00:25:36.319
We'll do the five uh courses of Blinna, and then we will do a consolidation with CART cell, which may allow us to discontinue the uh ponetinib sooner rather than after five years.
00:25:36.480 --> 00:25:43.359
So that's the plan for chronic my uh for uh Philadelphia positive acute lymphocyth leukemia.
00:25:43.519 --> 00:25:51.279
But if you think about it, before 2000, uh uh Philadelphia positive ALL was a fatal disorder.
00:25:51.359 --> 00:25:52.799
It was a death sentence.
00:25:53.119 --> 00:25:58.319
Today it's the easiest of one of the easier leukemia to treat.
00:25:58.559 --> 00:26:06.079
Now, another subset is B cell ALL, where we developed both uh blinatumumab and inotuzumab.
00:26:06.240 --> 00:26:18.160
We added them to the chemotherapy, and now we have five-year survivals, which are very close to the five-year survival in childhood ALL, so 85 uh percent.
00:26:18.799 --> 00:26:24.960
And this is with about half of the chemotherapy, but with the addition of those two antibodies.
00:26:25.119 --> 00:26:40.000
Uh, personally, I think five years from now we may treat ALL like lymphomas with six courses of chemotherapy with blinatumumumab inotumumab, followed by the CART cells, and then stop the treatment.
00:26:40.160 --> 00:26:50.960
So rather than three years of intensive chemotherapy, about six to seven months of milder chemotherapy with the targeted therapies with a potentially very high Q rate.
00:26:51.680 --> 00:26:52.160
Amazing.
00:26:52.400 --> 00:26:53.680
So these are the seven, right?
00:26:53.759 --> 00:27:06.880
We did the we did the three APL, hairy cell, core binding factor, we did CML, CLL, and then we did the uh the last uh so these are the seven favorable leukemias.
00:27:07.200 --> 00:27:08.640
These are the seven favorable.
00:27:09.200 --> 00:27:11.359
The intermediate have two categories.
00:27:11.519 --> 00:27:19.839
The older patients with ALL where using mini CVD, Ponatineblina, we have now a five-year survival of 50%.
00:27:20.640 --> 00:27:36.160
And then the younger patients with AML, where instead of three plus seven, we're using a more intensive therapy, the FLAG IDA venetoclax or the CLIA venetoclax, and we are having five-year survival rates of 70%.
00:27:36.799 --> 00:27:43.920
But these patients still require allogenic transplant and remission, and we're starting to add the targeted therapies.
00:27:44.079 --> 00:27:56.160
So the FLIT-3 inhibitors, the um uh IDH inhibitors, the menin inhibitors, of course, on top of the venetoclax, uh, in addition to the chemotherapy.
00:27:56.240 --> 00:28:05.920
So these are the two intermediate leukemias, older ALL and younger AML, where actually the five-year survival has exceeded 40%.
00:28:06.559 --> 00:28:11.039
And in the younger AML, it's about 70% in our hands.
00:28:11.599 --> 00:28:23.200
Now the last quick question the men inhibitors are um are being incorporated into frontline as part of trials, or are they right now ready for prime time in frontline?
00:28:23.759 --> 00:28:35.680
Uh no, so today they are part of trials uh because we have not incorporated them yet into the community to be added to the chemotherapy.
00:28:35.839 --> 00:28:39.039
And the question is: do you add them to 3 plus 7?
00:28:39.279 --> 00:28:52.720
Do you add them to CLIA venetoclax, or do you add them to the lower intensity regimens that we use in older AML, like Ladribine, Lodos RSC venetoclax, or isacytidine venetoclax?
00:28:53.119 --> 00:29:09.039
So this is where there's a bit of a struggle in terms of implementing safe regimens in uh acute myeloid leukemia, where you pile up more targeted therapies onto the intensive chemotherapy venetoclax.
00:29:09.279 --> 00:29:15.680
So now there's a group of leukemia doctors who are saying, why do we need the intensive chemotherapy at all?
00:29:16.000 --> 00:29:26.960
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?
00:29:27.519 --> 00:29:34.400
I prefer cladribine lodos RS venetoclax because it's better than azocitidine venetoclax.
00:29:34.559 --> 00:29:39.440
It is a low intensity regimen, and we can add those targeted therapies to that.
00:29:39.599 --> 00:30:18.640
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 azocitine venetoclax in triplet or quadruplate regimens, or at MD Anderson pushing for the cladribine lodos RSC venetoclax, to which we add a regimen in a quadruplate fashion, such as cladribine lodos RSE venetoclax with a FLIT3 inhibitor, with an IDH inhibitor, with a menine inhibitor, either simultaneously or in a sequential fashion.
00:30:19.599 --> 00:30:21.680
So now this takes us to the poor ones.
00:30:22.319 --> 00:30:24.000
So let's talk about the poor ones.
00:30:24.160 --> 00:30:29.839
So the poor ones are patients over the age of 60 with acute myelid leukemia.
00:30:33.279 --> 00:30:38.720
No, so we excluded APL, we excluded core binding factor, acute myelid leukemia.
00:30:38.960 --> 00:30:42.799
So these are the older patients with acute myelid leukemia.
00:30:43.279 --> 00:30:56.000
And um you see the leukemia experts twisting themselves around trying to find which patients would be unfit for intensive chemotherapy to give them HMA venetoclass.
00:30:56.240 --> 00:30:59.359
But if you look at the SEER data, it's very simple.
00:30:59.599 --> 00:31:06.960
The mortality with any form of chemotherapy, if you're under 60, is about 10% during the induction.
00:31:07.200 --> 00:31:10.720
If you are 60 to 75, it goes to 30 percent.
00:31:11.039 --> 00:31:14.480
And if you are over 75, it goes to 50 percent.
00:31:14.640 --> 00:31:19.920
This is the four-week mortality in community practice by this year data.
00:31:20.160 --> 00:31:29.839
Now, of course, in cancer centers, the mortalities are less, but this they still range between say 10 or 15 percent during the induction.
00:31:30.319 --> 00:31:40.640
So um 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 Q rate.
00:31:40.880 --> 00:31:44.400
So people started with the hypomethylating agent.
00:31:44.640 --> 00:31:48.319
We had them since 2006, minimal benefit.
00:31:48.559 --> 00:31:56.640
In 2017, the HMA venetoclux regimen was developed and became a new standard of care.
00:31:56.960 --> 00:32:06.240
But when we look at the long-term follow-up with isacytidine venetoclux, in all the unfit patients, the three-year survival is only 25%.
00:32:07.039 --> 00:32:10.480
So then we are working on two strategies.
00:32:10.960 --> 00:32:29.920
The first one are triplet regimens uh with an HMA, and I prefer all are decitabine because then you can have a total oral therapy with dicitabine, venetoclax, and the third targeted therapy, or you can do cladribine lodos RSC venetoclax.
00:32:30.240 --> 00:32:35.119
What's uh what's an attractive third target, in your opinion, in this situation?
00:32:35.519 --> 00:33:21.119
So the third target when you do, say, azacytobene, decytabine, venetoclax will be a flit 3 inhibitor if the patient is flithery mutated, an IDH inhibitor if they are IDH1 or 2 mutated, and a menin inhibitor if they have uh um uh if they have uh a translocation 11 Q23 uh abnormality, but also there are other uh rearrangements that uh can benefit from the menine inhibitors or possibly the possibility of what we call a menine signature, meaning uh an overexpression of particular cytokines that could respond to menine inhibitors.
00:33:21.279 --> 00:33:29.119
Now we also found that menine inhibitors synergize with FLIT3 inhibitors and they synergize with venetoclax.
00:33:29.440 --> 00:33:50.480
So now instead of using triplet therapy, we're trying to advocate for safe quadruplet therapy where we use the FLIT 3 inhibitors even in FLIT-3 wild type, if they have a FLIT-3-like signature, and we add the venetoclax and possibly the menon inhibitor as indicated by the signature.
00:33:50.640 --> 00:34:02.000
So there's a signature called MIS-1 signature that uh indicates that MIS-1 overexpression could be sensitive to menon inhibitors.
00:34:02.240 --> 00:34:15.280
So these are the triplet regimens or quadruplate 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.
00:34:15.599 --> 00:34:26.159
Amir Fatih when he combined when he compared isocitidine venetoclux to 3 plus 7 and showed the very exciting data at the Ash meeting.
00:34:27.039 --> 00:34:32.079
You know, I uh I actually love the fact that you looked at the leukemias this way.
00:34:32.239 --> 00:34:45.920
I honestly haven't thought of it this way because you cannot combine the ALL, AML, CML, CL, all of them together in under one big umbrella, and we're defining them based on the risk category.
00:34:46.320 --> 00:34:52.480
It's almost like a different way of looking at leukemic disorders, myeloid disorders, if you will.
00:34:53.920 --> 00:34:54.480
Correct.
00:34:54.639 --> 00:35:09.280
And and actually, this way of a classification may be uh more pertinent because then you start thinking of subsets of leukemia rather than the umbrella of acute versus chronic and myeloid versus lymphoid.
00:35:09.440 --> 00:35:18.239
So you talk about leukemia, what is the pathophysiology, and what can we add to the treatment that will increase the potential curate?
00:35:18.880 --> 00:35:21.440
There's one leukemia you didn't address a little bit.
00:35:21.519 --> 00:35:26.480
Maybe we can spend a minute or two on it, which is secondary leukemia or treatment-related leukemia.
00:35:26.559 --> 00:35:30.639
I presume obviously this fits in the high risk unless things have changed.
00:35:31.199 --> 00:35:39.599
No, actually, the three leukemias where we need something urgently are TP53, acute myeloid leukemia.
00:35:39.760 --> 00:35:44.239
Nothing has worked, and that's about 10 to 15 percent of AML.
00:35:44.639 --> 00:35:47.519
MECOM rearranged leukemias.
00:35:47.679 --> 00:35:53.440
So these are patients with translocation 3 to Q26 with a rearrangement.
00:35:53.599 --> 00:35:58.639
These are not common, that's these are about 1 to 2 percent, but they have a horrible outcome.
00:35:58.960 --> 00:36:02.639
And then what you mentioned, the treated secondary AML.
00:36:02.800 --> 00:36:09.840
So patients with either MDS or myeloproliferative neoplasms who are treated and progress to AML.
00:36:10.079 --> 00:36:18.079
These three categories of acute myelukemia, we have nothing in our armamentarium that works so far.
00:36:18.400 --> 00:36:27.360
So what we need to do is develop either targeting strategies or strategies which are agnostic to the pathophysiology.
00:36:27.599 --> 00:36:41.679
So, for example, if you develop uh N-K cellular therapy for minimal residual disease or possibly uh some form of immune therapy that eradicates residual disease.
00:36:41.920 --> 00:36:51.199
But we do not have yet good clues as to how to treat those three terrible leukemias that nothing has worked on so far.
00:36:51.599 --> 00:36:54.480
Well, no retirement, I guess, until you figure this out.
00:36:54.639 --> 00:37:05.280
Uh so um my question to you is uh if we're having this conversation maybe a couple of years from now, are you what's your futuristic look on leukemia?
00:37:05.360 --> 00:37:06.320
Are you optimistic?
00:37:06.480 --> 00:37:11.039
Do you sometimes look, I mean, I'm pragmatic and I'm realistic.
00:37:11.199 --> 00:37:14.000
There are times where you think, you know, we've done all we can.
00:37:14.159 --> 00:37:21.840
I'm not really sure we're gonna be able to find something for TP53 unless you literally have a target against the TP53, which we tried.
00:37:21.920 --> 00:37:29.119
I think I remember there's several molecules that were hypothesized to target the TP53, but they really never seen it.
00:37:29.280 --> 00:37:29.679
Yeah.
00:37:29.840 --> 00:37:31.840
Um, I mean, what's your futuristic look?
00:37:31.920 --> 00:37:33.920
How are we heading in the next couple of years?
00:37:34.320 --> 00:37:40.159
So I think in the more favorable leukemias, we are going to be able to do much better.
00:37:40.320 --> 00:37:52.719
I think CML, if we discover a BCR-able degrader that's effective and safe, we will cure CML maybe with one year of combined therapy and the CLL.
00:37:53.119 --> 00:38:01.599
We have better uh BTK inhibitors, we have the BTK degraders, we have better BCL2 inhibitors coming along.
00:38:01.760 --> 00:38:10.639
So I think CLL will be potentially highly, highly curable with maybe one and a half to two years of dose combinations.
00:38:11.119 --> 00:38:37.199
In ALL, both Philadelphia positive and the B cell ALL, I think by adding additional antibodies like CD20 by specific T cell engagers or safer uh TKIs uh than ponatinate, for example, or verambatinin, we're going to be able to increase the chance of a cure in both B cell ALL and uh pre-BALL.
00:38:37.280 --> 00:38:47.360
And don't forget, we're starting to use the CAR T cells as a consolidation rather than uh rather than allogenic transplant.
00:38:47.519 --> 00:38:56.239
In acute myeldochemia, we need to discover more targets and better targeted therapies.
00:38:56.400 --> 00:39:10.559
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 a RAS-based wave mutation.
00:39:10.800 --> 00:39:16.079
And now we know that there's a very effective KRAS inhibitor in pancreatic cancer.
00:39:16.320 --> 00:39:28.079
So if we have a good pan RAS inhibitor that we can export to acute myelogleukemia, it will elevate the potential cure rate across all AMS.
00:39:28.639 --> 00:39:42.559
I do not know what will work in TP53, but there is already one molecule, an antibody, that targets the uh TP53 with the mutation at 220, and it's working very well.
00:39:42.639 --> 00:39:48.880
But there are more, uh about 90 mutations along the TP53 molecule.
00:39:48.960 --> 00:39:54.480
So I don't know that we can develop one inhibitor for each of those mutations.
00:39:54.559 --> 00:39:57.920
We have to have a better approach to TP53.
00:39:58.079 --> 00:40:03.920
With the MECOM, we're working on the pathophysiology, and we think we have something that might work.
00:40:04.320 --> 00:40:10.800
And with the treated secondary AML, that's also a big problem uh that we need to tackle.
00:40:11.199 --> 00:40:13.119
Yeah, but the advances are historic.
00:40:13.199 --> 00:40:15.039
I mean, and this is not an easy thing to do.
00:40:15.199 --> 00:40:21.679
I mean, I I re you know, when I was a fellow, um I could not treat ALL.
00:40:21.760 --> 00:40:24.000
I tried, it was impossible.
00:40:24.079 --> 00:40:30.400
And and I was at a university setting, and it was my biggest nightmare when I had to take care of an ALL patient.
00:40:30.559 --> 00:40:39.039
Not because things were not working, it was because you still had to do so much treatment and very intensive therapy, and it and the outcome was so dismal.
00:40:39.519 --> 00:40:41.679
Uh, and it's just amazing to see this.
00:40:41.840 --> 00:40:47.519
Um, I go any other questions I should have asked you pertaining to the treatments of leukemias.
00:40:47.599 --> 00:40:57.440
You you did promise you're gonna come back where we're gonna talk about mentorship, leadership, and other aspects are not science, because a lot of people could learn from you and your your journey.
00:40:57.599 --> 00:41:02.079
But anything about leukemias that we should have talked about that I forgot asking you about?
00:41:02.800 --> 00:41:06.000
No, I think uh we pretty covered it much.
00:41:06.159 --> 00:41:12.880
Uh actually, I have an Asco Post uh editorial uh that I co-wrote with Dr.
00:41:12.960 --> 00:41:14.239
Freirach, the late Dr.
00:41:14.320 --> 00:41:14.960
Freyrak.
00:41:15.440 --> 00:41:25.039
It came out this month, so people who are interested can look at it and it's essentially goes in a summary form through what we talked about.
00:41:25.360 --> 00:41:32.079
Yeah, if you send me a link, I will uh put it in the notes because this will uh we're we're taping this just for listeners and viewers.
00:41:32.159 --> 00:41:38.000
This is being taped before ASCO, but it's not is not going to come, it's gonna come out probably early July.
00:41:38.079 --> 00:41:40.400
So uh we'll be close enough to Soho.
00:41:41.039 --> 00:41:44.400
Uh so this will be we'll strategically put it before Soho.
00:41:44.559 --> 00:41:47.039
And how many years now you've been doing Soho, Hagob?
00:41:47.599 --> 00:41:50.639
So Soho started under a different name.
00:41:50.800 --> 00:41:56.000
It was started by Michael Keating, he called it leukemia, the next question.
00:41:56.480 --> 00:42:12.320
Uh, and this was like uh 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.
00:42:12.880 --> 00:42:16.239
So we're gonna be our 13th or 14th year now.
00:42:16.639 --> 00:42:17.599
Congratulations.
00:42:17.760 --> 00:42:20.719
I uh I I I will try to visit with you guys in Houston.
00:42:20.800 --> 00:42:26.880
It just happens around Labor Day, and it had like you you need to uh you need to make the meeting around my schedule.
00:42:27.440 --> 00:42:34.480
I insist that you come to Soho because you'll you'll be able to interview so many people.
00:42:34.719 --> 00:42:40.159
Yes, I'm gonna be we have to we have to form a collaboration between Soho and Healthcare Unfiltered.
00:42:41.920 --> 00:42:42.800
God willing.
00:42:43.039 --> 00:42:43.360
Dr.
00:42:43.440 --> 00:42:51.039
Hagop Kantarjan, the myth, the legend, the master of leukemia in his in the flesh here on Healthcare Unfiltered.
00:42:51.119 --> 00:42:52.639
Thank you so much for coming on.
00:42:53.039 --> 00:42:54.800
Very kind of you to invite me.
00:42:54.960 --> 00:42:55.760
Thank you.
00:43:09.679 --> 00:43:14.639
It means a lot to me that you gave Healthcare Unfiltered this exclusive.
00:43:14.960 --> 00:43:25.360
Uh, 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.
00:43:25.519 --> 00:43:33.679
You can also suggest ideas, topics, and absolutely be engaged and uh follow all of the progress on Healthcare Unfiltered.
00:43:33.760 --> 00:43:40.239
And don't forget to check out also Healthcare Unfiltered Express and let your friends, colleagues know about both shows.
00:43:40.400 --> 00:43:41.679
Drop a brief review.
00:43:41.840 --> 00:43:48.159
This allows a lot of people to discover this podcast and always let me know how I'm doing.
00:43:48.400 --> 00:43:54.239
Before I let you go, I'm gonna leave you with a saying by Lebanese poet Khalil Jibran.
00:43:55.679 --> 00:44:04.079
Out of suffering have emerged the strongest souls, the most massive characters are seared with scars.
00:44:04.400 --> 00:44:05.599
Until next time.
00:00:12.240 --> 00:00:15.839
It's Healthcare Unfiltered, and it's your host, Shadi Nabhan.
00:00:16.079 --> 00:00:20.079
Thank you for tuning in to this episode of Healthcare Unfiltered, folks.
00:00:20.320 --> 00:00:24.480
Thank you for supporting this podcast going on close to seven years now.
00:00:24.719 --> 00:00:27.839
Healthcare Unfiltered every Tuesday, week in and week out.
00:00:27.920 --> 00:00:29.359
I appreciate your support.
00:00:29.519 --> 00:00:38.399
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.
00:00:38.640 --> 00:00:42.000
And last year we've launched Healthcare Unfiltered Express.
00:00:42.159 --> 00:00:49.520
Healthcare Unfiltered Express focuses specifically on advances in clinical oncology, new papers, new findings.
00:00:49.759 --> 00:00:57.280
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.
00:00:57.520 --> 00:01:01.759
So check out both Healthcare Unfiltered and Healthcare Unfiltered Express.
00:01:02.079 --> 00:01:03.600
You can subscribe to both shows.
00:01:03.679 --> 00:01:11.840
They are available on all platforms from Amazon to Apple to Spotify, YouTube, and you can follow me on Twitter at ChaddyNabhan.
00:01:12.560 --> 00:01:18.719
And check out my Facebook page, my YouTube page, and my website, chattinabhan.com.
00:01:18.879 --> 00:01:24.239
Today's podcast is very special because I really host a legend, Dr.
00:01:24.400 --> 00:01:25.920
Hagob Kintargian.
00:01:26.079 --> 00:01:32.239
There's probably no one that is watching this show or listening to this show that does not know who Dr.
00:01:32.400 --> 00:01:34.400
Hagob Kintargian is.
00:01:35.200 --> 00:01:50.400
Arguably one of the most influential figures in oncology and hematology, and has really transformed how we treat malignant hematological disorders, specifically leukemias.
00:01:50.719 --> 00:02:01.599
Hagob has been the chair of the Department of Leukemia at MD Anderson Cancer Center, has held many leadership positions, and has won numerous awards.
00:02:01.760 --> 00:02:08.479
I really will not have time to list all of the awards that he won at ASCO and other societies.
00:02:08.800 --> 00:02:11.759
But needless to say, the first time I met Dr.
00:02:11.919 --> 00:02:20.319
Kantargian was in 2002, and I was preparing for the hematology oncology board, the George Washington board.
00:02:20.479 --> 00:02:22.960
And I recall listening to a lecture that he gave.
00:02:23.120 --> 00:02:27.919
I believe the lecture he gave was on AML, or uh it could have been CML.
00:02:28.000 --> 00:02:30.159
I don't really remember exactly.
00:02:30.479 --> 00:02:35.840
But it was so clear, was so obvious, was so easy to follow, so easy to understand.
00:02:35.919 --> 00:02:42.000
And I was always dreaming, I'm thinking, like, I wish I can one day give a lecture similar to the way Dr.
00:02:42.159 --> 00:02:44.879
Hagob Kantarjan delivers his lectures.
00:02:45.360 --> 00:02:49.759
And uh fast forward, I have been uh fortunate to learn a lot from Dr.
00:02:49.840 --> 00:02:59.120
Kantarjan, as so many of people who are listening here and who have really followed his work, as well as learn from him how we treat leukemia.
00:02:59.280 --> 00:03:00.639
Um, so I've asked Dr.
00:03:00.719 --> 00:03:16.319
Kantarjan 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.
00:03:16.560 --> 00:03:24.560
And he's gonna look at this from the risk stratification perspective into favorable, less favorable, and not favorable leukemias.
00:03:24.639 --> 00:03:29.759
And he's gonna lump all of these together under the leukemic disorders category.
00:03:30.000 --> 00:03:31.199
I am going to have Dr.
00:03:31.280 --> 00:03:37.680
Kantarjan in the future to come uh on the show and talk about his career path and about leadership, mentorship.
00:03:37.759 --> 00:03:42.879
There's so much to learn from this legend in hematology, Dr.
00:03:43.039 --> 00:03:44.159
Hagob Kantarjan.
00:03:44.400 --> 00:03:48.000
I think we are so fortunate and so grateful to have someone like Dr.
00:03:48.080 --> 00:04:01.120
Kantarjan, who has really dedicated his life to helping patients treat with leukemia and to mentoring many people who are interested in uh hematological malignancies.
00:04:01.360 --> 00:04:04.879
I don't think uh I I've given enough, I've given Dr.
00:04:04.960 --> 00:04:14.960
Kantarjan 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.
00:04:15.120 --> 00:04:18.160
Without further ado, the myth and the legend, Dr.
00:04:18.319 --> 00:04:21.839
Hagob Kantarjan on Healthcare Unfiltered.
00:04:30.000 --> 00:04:37.839
Well, folks, uh it's really a very um important day for me because not only that this is the first time Dr.
00:04:37.920 --> 00:04:44.000
Hagob Kantarjan comes on my show, Healthcare Unfiltered, but um everybody knows who Dr.
00:04:44.160 --> 00:04:47.519
Cantarjan is, and I have been a big fan for 25 years.
00:04:47.600 --> 00:04:51.519
He has mentored a lot of us uh who are interested in malignant hematology.
00:04:51.680 --> 00:04:56.639
So, Hagob, it's uh truly an honor to have you on my humble show.
00:04:57.279 --> 00:04:58.319
Likewise, Dr.
00:04:58.480 --> 00:04:59.120
Naban.
00:04:59.920 --> 00:05:01.759
Uh when you tell me Dr.
00:05:01.839 --> 00:05:03.360
Nabhan, that's very interesting.
00:05:03.680 --> 00:05:13.920
But um, before we get started, Hagob, uh um a bit about you in terms of what got you, take us through memory lane for 30 years.
00:05:14.240 --> 00:05:17.600
What got you into leukemia, into malignant hematology?
00:05:18.079 --> 00:05:27.519
So, as you may know, I was uh trained at the American University of Beirut in Lebanon, and this is where people absorb knowledge and then they apply it.
00:05:27.759 --> 00:05:33.600
I came for an elective uh fellowship at MD Anderson in 1978.
00:05:34.160 --> 00:05:42.480
And this is where I discovered that perhaps 90% of the knowledge in cancer will be obsolete 10 years later.
00:05:42.639 --> 00:05:51.120
And MD Anderson allowed individuals in training to expand with their vision and to take chances.
00:05:51.279 --> 00:05:58.959
Uh uh, you do high-risk uh but also high-benefit uh approaches to therapy.
00:05:59.120 --> 00:06:04.959
And many of those fail, but ultimately some of them will become the new standards of care.
00:06:05.279 --> 00:06:11.680
And having an approach of innovation uh allows a faster pace of cancer research.
00:06:11.920 --> 00:06:14.319
Uh at MD Anderson I met Dr.
00:06:14.639 --> 00:06:15.279
Emil J.
00:06:15.439 --> 00:06:17.600
Freyrak, uh Dr.
00:06:17.839 --> 00:06:25.680
McCready Keating, and many of the giants in leukemia research, and I decided to come back and stay at MD Anderson.
00:06:26.000 --> 00:06:27.360
So that's what I did.
00:06:27.600 --> 00:06:36.480
In 81, I came and trained as a fellow at MD Anderson, and then I stayed on faculty from 1983 till the present time.
00:06:37.360 --> 00:06:39.839
You're a lifer, you're a lifer at MD Anderson.
00:06:40.959 --> 00:06:45.279
And um it's amazing to see what has happened uh in the treatment of leukemia.
00:06:45.360 --> 00:06:47.519
And that's really the subject of today's podcast.
00:06:47.680 --> 00:07:01.439
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.
00:07:02.240 --> 00:07:06.319
So let's just start by how when you first started, how how were things?
00:07:06.480 --> 00:07:07.920
How was your thinking process?
00:07:08.079 --> 00:07:12.000
How was research at the time, and then how did things evolve?
00:07:12.399 --> 00:07:12.959
Right.
00:07:13.279 --> 00:07:26.560
So, just as um 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.
00:07:26.639 --> 00:07:35.040
So acute leukemias, patients lived two years untreated, uh, two two patients lived about one to two months if untreated.
00:07:35.279 --> 00:07:46.079
The chronic leukemias, they lived about uh a couple of years, and then we divide them by the cell of origin, so in simple ways, myeloid versus lymphoid.
00:07:46.160 --> 00:08:09.680
So you have four 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.
00:08:10.000 --> 00:08:18.079
But I I like to divide them based on how the research has advanced from 1981 till now.
00:08:18.639 --> 00:08:31.519
So if you think about them, in 1981, most of the leukemias were in what is called unfavorable category, meaning their five-year survival was less than 30%.
00:08:32.320 --> 00:08:41.440
There was one intermediate leukemia, acute promyelostic leukemia, and that's because uh ensacyclines were discovered in the 70s.
00:08:41.600 --> 00:08:48.399
So with anthracyclines, acute bromyostic leukemia had a five-year survival of about 40%.
00:08:49.360 --> 00:08:51.919
And then there were no favorable leukemias.
00:08:52.080 --> 00:09:00.480
There were no leukemias where you could say that the five or 10-year survival is uh above uh 70%.
00:09:01.759 --> 00:09:11.919
So when I started in 1981, the two acute leukemias, AML and ALL, were curable at a rate of 20% with intensive chemotherapy.
00:09:12.080 --> 00:09:14.080
Uh, these are the adult ALL.
00:09:14.559 --> 00:09:26.240
In the chronic leukemia, both CML and CLL were incurable, and the five-year survival was about also um 10 to 20 percent.
00:09:26.720 --> 00:09:40.559
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 five to ten years.
00:09:40.799 --> 00:09:48.320
Then we have an intermediate group of leukemia where also there are substantial subsets.
00:09:48.720 --> 00:10:02.399
And now we uh have seen that among the unfavorable leukemia, there's only two simple categories: the older patients with AML and patients with maybe TP53 and MECO.
00:10:03.039 --> 00:10:19.759
So, if you like, I could take you through the progress in each of these entities and uh going from the most favorable to the least favorable, but also to show that there's no one path for curing cancer.
00:10:20.240 --> 00:10:33.360
A lot of it is trial and error, and also much of it is deciphering the pasophysiology of particular leukemias and then developing drugs that target those pasophysiologists.
00:10:33.679 --> 00:10:34.799
I would love to do that.
00:10:34.879 --> 00:10:40.399
Um, and before we do it, Hagob, uh, I was gonna what was the rate limited?
00:10:40.639 --> 00:10:48.960
What was the catalyst event that you think led to this acceleration in um in change?
00:10:49.200 --> 00:10:52.399
Is it uh the uh you know genomic sequencing?
00:10:52.480 --> 00:10:54.320
I mean, what what was it you think?
00:10:55.120 --> 00:11:09.200
I think deciphering the pathophysiology, we started actually around uh the mid-80s when people started talking about cancer genes or oncogenes, starting with the MEC and with the other oncogenes.
00:11:09.279 --> 00:11:22.000
And then in the 2000s, uh, with actually deciphering the whole um uh human genome and then looking at cancer genomes and finding abnormalities.
00:11:22.159 --> 00:11:34.159
So, to give you a few examples, um, when in acute myelid leukemia, when they developed the first leukemia genome, they identified maybe two or three abnormalities.
00:11:34.320 --> 00:11:41.360
It was IDH1, uh, TP53 was well known, and maybe there was a third mutation.
00:11:41.519 --> 00:11:50.320
Now we know that there's a whole spectrum of uh more than 100 mutations, and many of those mutations are targetable.
00:11:50.399 --> 00:12:02.000
And this is what led, for example, to develop FLIP-3 inhibitors, IDH inhibitors, menine inhibitors, the development of venetoclax as a BCL2 inhibitor.
00:12:02.240 --> 00:12:15.600
So all these were derived by understanding the pathophysiologic mechanisms of particular leukemias, uh, either through their metabolic functioning or through particular mutations.
00:12:16.399 --> 00:12:17.039
Amazing.
00:12:17.200 --> 00:12:26.240
Okay, let's uh let's pick uh your leukemia of choice and just go through uh how this transformed from unfavorable to a favorable, maybe.
00:12:26.639 --> 00:12:26.799
Right.
00:12:27.039 --> 00:12:39.519
So, what I'm gonna do for simplicity is start with the best leukemias, the most favorable today, and I'm gonna outline seven of them with different uh modalities that led to their high potential cure.
00:12:39.679 --> 00:12:45.120
Then I'll go to the intermediate leukemias and then we'll leave the unfavorable till the last.
00:12:45.279 --> 00:12:52.320
So when you think of the favorable leukemias, these are leukemias where the five to ten year survival is over 80%.
00:12:53.120 --> 00:13:03.679
The simplest example is hairy cell leukemia, and the discovery was empirical because gladribine was developed for the treatment of T cell malignancies.
00:13:03.919 --> 00:13:18.320
But then there was one patient on the phase one study with hairy cell leukemia who received the treatment and went home to die because of lack of response, and that patient came back six months later in complete remission.
00:13:18.639 --> 00:13:25.919
So one empirical recovery in the clinic led to the potential cure of hairy cell leukemia.
00:13:26.080 --> 00:13:42.799
Uh, so now uh the way we treat hairy cell leukemia is for with five days of cladribine, then we use the CD20 antibody retoxima, we give it weekly four or eight times, and the 10-year progression-free survival is 90 to 95 percent.
00:13:43.039 --> 00:13:56.080
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.
00:13:56.399 --> 00:14:05.200
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.
00:14:05.600 --> 00:14:12.399
And the interesting point is the pathophysiology was discovered after uh those findings.
00:14:12.480 --> 00:14:22.960
So now we know that they are related to the BRF mutation, and people are developing BRF inhibitors, but uh the uh train has left the state the station.
00:14:23.120 --> 00:14:28.240
There's nothing better than cladarbine and retoximab as frontline curative syrup.
00:14:28.799 --> 00:14:38.240
The second leukemia, which is highly curable, is actually a subset of acute myeloid leukemia, acute promyelotic leukemia.
00:14:38.320 --> 00:14:46.320
So in 1981, a third of the patients died during the induction from DIC, and the cure rate with chemotherapy was 40%.
00:14:47.120 --> 00:14:54.720
The Chinese in the late 1980s started reporting on two drugs which were not chemotherapy.
00:14:54.879 --> 00:15:01.519
One was ATRA, which is a vitamin A analog, and the other one was arsenic trioxide, which is a poison.
00:15:01.759 --> 00:15:13.679
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.
00:15:13.840 --> 00:15:28.240
And people thought we're crazy because when we presented the data at the beginning, the uh the APL officionados thought that uh using a regimen without Iderubicin and ATRA was criminal.
00:15:28.480 --> 00:15:28.960
Yeah, yeah.
00:15:29.440 --> 00:15:53.840
As the data evolved, then the same APL experts took the MD Henderson regimen, atra arsenic trip side, compared it in a randomized trial 12 years later to Atra-Idarubicin, and they found that the non-chemotherapy regimen developed at MD Henderson was better, highly curative, with a 10-year survival of 90%.
00:15:54.720 --> 00:16:00.000
And this is now called the Lococo regimen after the person who did the randomized trial.
00:16:00.399 --> 00:16:06.879
Now, the third kind of highly curable leukemia is core binding factor acute myeloid leukemia.
00:16:07.039 --> 00:16:11.840
So these are patients with translocation A21 or inversion 16.
00:16:12.240 --> 00:16:17.679
And here the uh curative approach was in two steps.
00:16:17.840 --> 00:16:38.399
The first step was the discovery of high-dose RRC as opposed to standard RRC, that increased the cure rate from 30 to 50 percent, and then the discovery and the implementation of Gem2zumar, the CD133 antibody, which increased the cure rate from 50 to 80 percent.
00:16:38.639 --> 00:16:54.320
So, in core binding factor leukemia, we did not make major targeted discoveries, we just collected two kinds of therapies in a synergistic fashion that led to the cure rate of 80 percent in these patients.
00:16:54.720 --> 00:17:00.240
Amazing stories, by the way, the cladribine story with that one patient, the APL one, and this one as well.
00:17:00.320 --> 00:17:02.799
Just the stories behind the science, amazing.
00:17:03.919 --> 00:17:13.839
Now, the next two leukemias are very interesting because these two leukemias were driven by deciphering the pathophysiology of these leukemias.
00:17:13.920 --> 00:17:17.359
And these include CML and CLN.
00:17:17.519 --> 00:17:28.400
So, in chronic myeloid leukemia, before 2000, we treated the patients with allogenic transplant or with interferon, and the average survival was about five years.
00:17:28.720 --> 00:17:30.000
In 2000, Dr.
00:17:30.079 --> 00:17:38.240
Brian Drucker, collaborating with Novartis, developed the first BCR able tyrosine kinase inhibitors, ematin.
00:17:39.119 --> 00:18:05.599
And following that, because we saw that patients were developing resistance to EMATNIB with mutations in the able kinasal domain, we developed the more potent second generation TKIs, so desatineb, bosutineb, nilotinib, and then we developed the third generation TKIs, which were even more potent and could also uh suppress the T3015 I clones.
00:18:06.079 --> 00:18:16.240
So now you have all these TKIs which were implementing in the front line, and now patients with chronic myeloid leukemia are expected to have a normal lifespan.
00:18:16.720 --> 00:18:35.039
So the 10-year survival increased from 10% to 90%, and uh we are working on strategies to uh be able to stop the therapy in most of the patients, what we call treatment fear emission or a molecular cure.
00:18:35.359 --> 00:18:52.400
So today, in 100% patients with CMN, we expect probably 90 to 95 of them to live their normal life, and we expect about 30 to 40 percent to be able to stop therapy after five years of complete molecular cure.
00:18:52.720 --> 00:19:01.039
Now, how and and they don't have to be treated for years, they have to be treated for about five to seven years, not for a lifetime.
00:19:01.359 --> 00:19:05.039
Now, what where are we going to make progress in CML?
00:19:05.200 --> 00:19:29.920
Personally, I think that if we develop instead of BCR inhibit BCR-able inhibitors, if we develop BCR-able degraders and combine them with the BCR-able 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.
00:19:30.240 --> 00:19:31.119
What would be the difference?
00:19:31.200 --> 00:19:36.319
Like in degrading degraders, they just basically get rid of the domain completely?
00:19:36.640 --> 00:19:36.880
No.
00:19:37.039 --> 00:19:48.240
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.
00:19:48.480 --> 00:19:53.039
The degraders get into the BCR able and destroy it.
00:19:53.839 --> 00:20:01.920
So they can destroy dormant cells which are resistant to BCR able inhibitors, and this is not science fiction.
00:20:02.160 --> 00:20:31.359
So to get you back to uh the evolution of cancer research, at the beginning we had the first uh option, which was surgery, then came radiation therapy, then came chemotherapy, then came the targeted therapies in the form of antibodies or the first BCR able kinase inhibitor, and then we had the checkpoint inhibitors, a form of immunotherapy, and then the CART cells.
00:20:31.759 --> 00:20:40.240
And now I think the sixth arm of cancer therapy are going to be degraders, tumor target degraders.
00:20:40.559 --> 00:20:57.200
So the example is in chronic lymphocytic leukemia, for example, where we know that the BCR uh that the bruton tyrosine kinase degraders may be more potent than the BTK inhibitors, and they could replace them and be more effective.
00:20:57.440 --> 00:21:12.000
So that's the story in CML that I would like to see with the development of BCR-able degraders that we could add to BCR-able inhibitors and perhaps cure chronic myeloid leukemia at a high percentage.
00:21:13.839 --> 00:21:18.240
The other chronic leukemia is, of course, chronic lymphocytic leukemia.
00:21:18.480 --> 00:21:24.400
And today, when you read the textbooks, people say that chronic lymphocytic leukemia is still incurable.
00:21:24.880 --> 00:21:39.200
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.
00:21:39.519 --> 00:21:41.519
So, where did the breakthrough come from?
00:21:41.680 --> 00:21:52.880
It came in 2014, after we understood the role of the BTK and the BCL2 in prolonging the survival of the CLL cells.
00:21:53.039 --> 00:21:57.440
So BTK inhibitors were developed, the netoclex was developed.
00:21:57.599 --> 00:21:59.759
At MD Anderson, we combined both.
00:22:00.319 --> 00:22:24.480
Of them for two years of therapy, and the first study was with um uh a brutin and venetoclax given for two years, and we have treated over 200 patients, and with uh all the patients being off therapy for a minimum of five years, we have only 20 patients who have relapsed with a five-year survival of 97 percent.
00:22:25.359 --> 00:22:35.279
So, again, CLL is the sixth form of favorable leukemias where the five to ten year survival is over 70 percent.
00:22:35.599 --> 00:22:39.359
The only thing though, Hagob is we usually we classify CL as lymphoma.
00:22:39.440 --> 00:22:40.799
You gotta be careful here.
00:22:41.920 --> 00:22:48.640
It used to be classified as lymphoma until Michael Keating discovered the activity of fluerabine.
00:22:49.039 --> 00:22:56.960
So we stole them from the lymphoma people and we developed FC and FCR, and now the BTK inhibitors.
00:22:57.119 --> 00:23:01.440
So we think of CLL as a leukemia rather than a lymphoma at MD Anders.
00:23:01.920 --> 00:23:03.359
Yeah, uh yeah, I know that.
00:23:03.440 --> 00:23:05.279
That's I had to say it though.
00:23:06.079 --> 00:23:14.799
So then there are two additional leukemias but that became very favorable as of I would say 2010-2017.
00:23:15.440 --> 00:23:19.039
And these are the two subsets of ALL, adult ALL.
00:23:19.200 --> 00:23:34.240
So, as you know, in childhood ALL, you give three 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.
00:23:34.720 --> 00:23:44.000
In adult ALL, using the same three years of intensive chemotherapy, we were able to have a five-year survival of about 50 percent.
00:23:44.960 --> 00:23:53.440
In 2000, we started in Philadelphia positive ALL to add the BCR-able kinase inhibitors to chemotherapy.
00:23:53.599 --> 00:23:56.319
So that was the first inflection point.
00:23:56.720 --> 00:24:08.960
In 2017, we found that blinatumal was better than chemotherapy, and we had by then developed ponatineib, which is a very potent BCR-able kinase inhibitor.
00:24:09.119 --> 00:24:28.640
So in 2017 at MD Anderson, we combined ponatinib with blinatumumal in a simultaneous schedule, and now we're reporting a five-year survival of 90% without intensive chemotherapy and with less than 5% of the patients requiring an allogenic transplant.
00:24:28.720 --> 00:24:30.640
So that was how long is this regimen?
00:24:30.799 --> 00:24:31.200
Two years?
00:24:32.160 --> 00:24:37.519
So the regimen is given for five courses of blinatumad.
00:24:38.160 --> 00:24:48.480
And unfortunately, today we have to give five years of ponatinem because we want both the PCR and the NGSMRD to be negative.
00:24:48.640 --> 00:24:50.880
And we're starting to do like CML.
00:24:51.039 --> 00:24:56.079
After five years of a complete molecular response, we're starting to stop therapy.
00:24:56.400 --> 00:25:02.559
And in about 17 patients where we did this, zero of the 17 have relapsed.
00:25:02.640 --> 00:25:05.759
So the treatment is going to be about five years.
00:25:05.920 --> 00:25:13.599
Now we can improve on this because so far we have not used the CART cells instead of allogenic transplant.
00:25:13.759 --> 00:25:22.960
So it is possible that in the future we'll do the uh ponatineib or a better BCR-able kinase inhibitor.
00:25:23.119 --> 00:25:36.319
We'll do the five uh courses of Blinna, and then we will do a consolidation with CART cell, which may allow us to discontinue the uh ponetinib sooner rather than after five years.
00:25:36.480 --> 00:25:43.359
So that's the plan for chronic my uh for uh Philadelphia positive acute lymphocyth leukemia.
00:25:43.519 --> 00:25:51.279
But if you think about it, before 2000, uh uh Philadelphia positive ALL was a fatal disorder.
00:25:51.359 --> 00:25:52.799
It was a death sentence.
00:25:53.119 --> 00:25:58.319
Today it's the easiest of one of the easier leukemia to treat.
00:25:58.559 --> 00:26:06.079
Now, another subset is B cell ALL, where we developed both uh blinatumumab and inotuzumab.
00:26:06.240 --> 00:26:18.160
We added them to the chemotherapy, and now we have five-year survivals, which are very close to the five-year survival in childhood ALL, so 85 uh percent.
00:26:18.799 --> 00:26:24.960
And this is with about half of the chemotherapy, but with the addition of those two antibodies.
00:26:25.119 --> 00:26:40.000
Uh, personally, I think five years from now we may treat ALL like lymphomas with six courses of chemotherapy with blinatumumumab inotumumab, followed by the CART cells, and then stop the treatment.
00:26:40.160 --> 00:26:50.960
So rather than three years of intensive chemotherapy, about six to seven months of milder chemotherapy with the targeted therapies with a potentially very high Q rate.
00:26:51.680 --> 00:26:52.160
Amazing.
00:26:52.400 --> 00:26:53.680
So these are the seven, right?
00:26:53.759 --> 00:27:06.880
We did the we did the three APL, hairy cell, core binding factor, we did CML, CLL, and then we did the uh the last uh so these are the seven favorable leukemias.
00:27:07.200 --> 00:27:08.640
These are the seven favorable.
00:27:09.200 --> 00:27:11.359
The intermediate have two categories.
00:27:11.519 --> 00:27:19.839
The older patients with ALL where using mini CVD, Ponatineblina, we have now a five-year survival of 50%.
00:27:20.640 --> 00:27:36.160
And then the younger patients with AML, where instead of three plus seven, we're using a more intensive therapy, the FLAG IDA venetoclax or the CLIA venetoclax, and we are having five-year survival rates of 70%.
00:27:36.799 --> 00:27:43.920
But these patients still require allogenic transplant and remission, and we're starting to add the targeted therapies.
00:27:44.079 --> 00:27:56.160
So the FLIT-3 inhibitors, the um uh IDH inhibitors, the menin inhibitors, of course, on top of the venetoclax, uh, in addition to the chemotherapy.
00:27:56.240 --> 00:28:05.920
So these are the two intermediate leukemias, older ALL and younger AML, where actually the five-year survival has exceeded 40%.
00:28:06.559 --> 00:28:11.039
And in the younger AML, it's about 70% in our hands.
00:28:11.599 --> 00:28:23.200
Now the last quick question the men inhibitors are um are being incorporated into frontline as part of trials, or are they right now ready for prime time in frontline?
00:28:23.759 --> 00:28:35.680
Uh no, so today they are part of trials uh because we have not incorporated them yet into the community to be added to the chemotherapy.
00:28:35.839 --> 00:28:39.039
And the question is: do you add them to 3 plus 7?
00:28:39.279 --> 00:28:52.720
Do you add them to CLIA venetoclax, or do you add them to the lower intensity regimens that we use in older AML, like Ladribine, Lodos RSC venetoclax, or isacytidine venetoclax?
00:28:53.119 --> 00:29:09.039
So this is where there's a bit of a struggle in terms of implementing safe regimens in uh acute myeloid leukemia, where you pile up more targeted therapies onto the intensive chemotherapy venetoclax.
00:29:09.279 --> 00:29:15.680
So now there's a group of leukemia doctors who are saying, why do we need the intensive chemotherapy at all?
00:29:16.000 --> 00:29:26.960
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?
00:29:27.519 --> 00:29:34.400
I prefer cladribine lodos RS venetoclax because it's better than azocitidine venetoclax.
00:29:34.559 --> 00:29:39.440
It is a low intensity regimen, and we can add those targeted therapies to that.
00:29:39.599 --> 00:30:18.640
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 azocitine venetoclax in triplet or quadruplate regimens, or at MD Anderson pushing for the cladribine lodos RSC venetoclax, to which we add a regimen in a quadruplate fashion, such as cladribine lodos RSE venetoclax with a FLIT3 inhibitor, with an IDH inhibitor, with a menine inhibitor, either simultaneously or in a sequential fashion.
00:30:19.599 --> 00:30:21.680
So now this takes us to the poor ones.
00:30:22.319 --> 00:30:24.000
So let's talk about the poor ones.
00:30:24.160 --> 00:30:29.839
So the poor ones are patients over the age of 60 with acute myelid leukemia.
00:30:33.279 --> 00:30:38.720
No, so we excluded APL, we excluded core binding factor, acute myelid leukemia.
00:30:38.960 --> 00:30:42.799
So these are the older patients with acute myelid leukemia.
00:30:43.279 --> 00:30:56.000
And um you see the leukemia experts twisting themselves around trying to find which patients would be unfit for intensive chemotherapy to give them HMA venetoclass.
00:30:56.240 --> 00:30:59.359
But if you look at the SEER data, it's very simple.
00:30:59.599 --> 00:31:06.960
The mortality with any form of chemotherapy, if you're under 60, is about 10% during the induction.
00:31:07.200 --> 00:31:10.720
If you are 60 to 75, it goes to 30 percent.
00:31:11.039 --> 00:31:14.480
And if you are over 75, it goes to 50 percent.
00:31:14.640 --> 00:31:19.920
This is the four-week mortality in community practice by this year data.
00:31:20.160 --> 00:31:29.839
Now, of course, in cancer centers, the mortalities are less, but this they still range between say 10 or 15 percent during the induction.
00:31:30.319 --> 00:31:40.640
So um 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 Q rate.
00:31:40.880 --> 00:31:44.400
So people started with the hypomethylating agent.
00:31:44.640 --> 00:31:48.319
We had them since 2006, minimal benefit.
00:31:48.559 --> 00:31:56.640
In 2017, the HMA venetoclux regimen was developed and became a new standard of care.
00:31:56.960 --> 00:32:06.240
But when we look at the long-term follow-up with isacytidine venetoclux, in all the unfit patients, the three-year survival is only 25%.
00:32:07.039 --> 00:32:10.480
So then we are working on two strategies.
00:32:10.960 --> 00:32:29.920
The first one are triplet regimens uh with an HMA, and I prefer all are decitabine because then you can have a total oral therapy with dicitabine, venetoclax, and the third targeted therapy, or you can do cladribine lodos RSC venetoclax.
00:32:30.240 --> 00:32:35.119
What's uh what's an attractive third target, in your opinion, in this situation?
00:32:35.519 --> 00:33:21.119
So the third target when you do, say, azacytobene, decytabine, venetoclax will be a flit 3 inhibitor if the patient is flithery mutated, an IDH inhibitor if they are IDH1 or 2 mutated, and a menin inhibitor if they have uh um uh if they have uh a translocation 11 Q23 uh abnormality, but also there are other uh rearrangements that uh can benefit from the menine inhibitors or possibly the possibility of what we call a menine signature, meaning uh an overexpression of particular cytokines that could respond to menine inhibitors.
00:33:21.279 --> 00:33:29.119
Now we also found that menine inhibitors synergize with FLIT3 inhibitors and they synergize with venetoclax.
00:33:29.440 --> 00:33:50.480
So now instead of using triplet therapy, we're trying to advocate for safe quadruplet therapy where we use the FLIT 3 inhibitors even in FLIT-3 wild type, if they have a FLIT-3-like signature, and we add the venetoclax and possibly the menon inhibitor as indicated by the signature.
00:33:50.640 --> 00:34:02.000
So there's a signature called MIS-1 signature that uh indicates that MIS-1 overexpression could be sensitive to menon inhibitors.
00:34:02.240 --> 00:34:15.280
So these are the triplet regimens or quadruplate 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.
00:34:15.599 --> 00:34:26.159
Amir Fatih when he combined when he compared isocitidine venetoclux to 3 plus 7 and showed the very exciting data at the Ash meeting.
00:34:27.039 --> 00:34:32.079
You know, I uh I actually love the fact that you looked at the leukemias this way.
00:34:32.239 --> 00:34:45.920
I honestly haven't thought of it this way because you cannot combine the ALL, AML, CML, CL, all of them together in under one big umbrella, and we're defining them based on the risk category.
00:34:46.320 --> 00:34:52.480
It's almost like a different way of looking at leukemic disorders, myeloid disorders, if you will.
00:34:53.920 --> 00:34:54.480
Correct.
00:34:54.639 --> 00:35:09.280
And and actually, this way of a classification may be uh more pertinent because then you start thinking of subsets of leukemia rather than the umbrella of acute versus chronic and myeloid versus lymphoid.
00:35:09.440 --> 00:35:18.239
So you talk about leukemia, what is the pathophysiology, and what can we add to the treatment that will increase the potential curate?
00:35:18.880 --> 00:35:21.440
There's one leukemia you didn't address a little bit.
00:35:21.519 --> 00:35:26.480
Maybe we can spend a minute or two on it, which is secondary leukemia or treatment-related leukemia.
00:35:26.559 --> 00:35:30.639
I presume obviously this fits in the high risk unless things have changed.
00:35:31.199 --> 00:35:39.599
No, actually, the three leukemias where we need something urgently are TP53, acute myeloid leukemia.
00:35:39.760 --> 00:35:44.239
Nothing has worked, and that's about 10 to 15 percent of AML.
00:35:44.639 --> 00:35:47.519
MECOM rearranged leukemias.
00:35:47.679 --> 00:35:53.440
So these are patients with translocation 3 to Q26 with a rearrangement.
00:35:53.599 --> 00:35:58.639
These are not common, that's these are about 1 to 2 percent, but they have a horrible outcome.
00:35:58.960 --> 00:36:02.639
And then what you mentioned, the treated secondary AML.
00:36:02.800 --> 00:36:09.840
So patients with either MDS or myeloproliferative neoplasms who are treated and progress to AML.
00:36:10.079 --> 00:36:18.079
These three categories of acute myelukemia, we have nothing in our armamentarium that works so far.
00:36:18.400 --> 00:36:27.360
So what we need to do is develop either targeting strategies or strategies which are agnostic to the pathophysiology.
00:36:27.599 --> 00:36:41.679
So, for example, if you develop uh N-K cellular therapy for minimal residual disease or possibly uh some form of immune therapy that eradicates residual disease.
00:36:41.920 --> 00:36:51.199
But we do not have yet good clues as to how to treat those three terrible leukemias that nothing has worked on so far.
00:36:51.599 --> 00:36:54.480
Well, no retirement, I guess, until you figure this out.
00:36:54.639 --> 00:37:05.280
Uh so um my question to you is uh if we're having this conversation maybe a couple of years from now, are you what's your futuristic look on leukemia?
00:37:05.360 --> 00:37:06.320
Are you optimistic?
00:37:06.480 --> 00:37:11.039
Do you sometimes look, I mean, I'm pragmatic and I'm realistic.
00:37:11.199 --> 00:37:14.000
There are times where you think, you know, we've done all we can.
00:37:14.159 --> 00:37:21.840
I'm not really sure we're gonna be able to find something for TP53 unless you literally have a target against the TP53, which we tried.
00:37:21.920 --> 00:37:29.119
I think I remember there's several molecules that were hypothesized to target the TP53, but they really never seen it.
00:37:29.280 --> 00:37:29.679
Yeah.
00:37:29.840 --> 00:37:31.840
Um, I mean, what's your futuristic look?
00:37:31.920 --> 00:37:33.920
How are we heading in the next couple of years?
00:37:34.320 --> 00:37:40.159
So I think in the more favorable leukemias, we are going to be able to do much better.
00:37:40.320 --> 00:37:52.719
I think CML, if we discover a BCR-able degrader that's effective and safe, we will cure CML maybe with one year of combined therapy and the CLL.
00:37:53.119 --> 00:38:01.599
We have better uh BTK inhibitors, we have the BTK degraders, we have better BCL2 inhibitors coming along.
00:38:01.760 --> 00:38:10.639
So I think CLL will be potentially highly, highly curable with maybe one and a half to two years of dose combinations.
00:38:11.119 --> 00:38:37.199
In ALL, both Philadelphia positive and the B cell ALL, I think by adding additional antibodies like CD20 by specific T cell engagers or safer uh TKIs uh than ponatinate, for example, or verambatinin, we're going to be able to increase the chance of a cure in both B cell ALL and uh pre-BALL.
00:38:37.280 --> 00:38:47.360
And don't forget, we're starting to use the CAR T cells as a consolidation rather than uh rather than allogenic transplant.
00:38:47.519 --> 00:38:56.239
In acute myeldochemia, we need to discover more targets and better targeted therapies.
00:38:56.400 --> 00:39:10.559
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 a RAS-based wave mutation.
00:39:10.800 --> 00:39:16.079
And now we know that there's a very effective KRAS inhibitor in pancreatic cancer.
00:39:16.320 --> 00:39:28.079
So if we have a good pan RAS inhibitor that we can export to acute myelogleukemia, it will elevate the potential cure rate across all AMS.
00:39:28.639 --> 00:39:42.559
I do not know what will work in TP53, but there is already one molecule, an antibody, that targets the uh TP53 with the mutation at 220, and it's working very well.
00:39:42.639 --> 00:39:48.880
But there are more, uh about 90 mutations along the TP53 molecule.
00:39:48.960 --> 00:39:54.480
So I don't know that we can develop one inhibitor for each of those mutations.
00:39:54.559 --> 00:39:57.920
We have to have a better approach to TP53.
00:39:58.079 --> 00:40:03.920
With the MECOM, we're working on the pathophysiology, and we think we have something that might work.
00:40:04.320 --> 00:40:10.800
And with the treated secondary AML, that's also a big problem uh that we need to tackle.
00:40:11.199 --> 00:40:13.119
Yeah, but the advances are historic.
00:40:13.199 --> 00:40:15.039
I mean, and this is not an easy thing to do.
00:40:15.199 --> 00:40:21.679
I mean, I I re you know, when I was a fellow, um I could not treat ALL.
00:40:21.760 --> 00:40:24.000
I tried, it was impossible.
00:40:24.079 --> 00:40:30.400
And and I was at a university setting, and it was my biggest nightmare when I had to take care of an ALL patient.
00:40:30.559 --> 00:40:39.039
Not because things were not working, it was because you still had to do so much treatment and very intensive therapy, and it and the outcome was so dismal.
00:40:39.519 --> 00:40:41.679
Uh, and it's just amazing to see this.
00:40:41.840 --> 00:40:47.519
Um, I go any other questions I should have asked you pertaining to the treatments of leukemias.
00:40:47.599 --> 00:40:57.440
You you did promise you're gonna come back where we're gonna talk about mentorship, leadership, and other aspects are not science, because a lot of people could learn from you and your your journey.
00:40:57.599 --> 00:41:02.079
But anything about leukemias that we should have talked about that I forgot asking you about?
00:41:02.800 --> 00:41:06.000
No, I think uh we pretty covered it much.
00:41:06.159 --> 00:41:12.880
Uh actually, I have an Asco Post uh editorial uh that I co-wrote with Dr.
00:41:12.960 --> 00:41:14.239
Freirach, the late Dr.
00:41:14.320 --> 00:41:14.960
Freyrak.
00:41:15.440 --> 00:41:25.039
It came out this month, so people who are interested can look at it and it's essentially goes in a summary form through what we talked about.
00:41:25.360 --> 00:41:32.079
Yeah, if you send me a link, I will uh put it in the notes because this will uh we're we're taping this just for listeners and viewers.
00:41:32.159 --> 00:41:38.000
This is being taped before ASCO, but it's not is not going to come, it's gonna come out probably early July.
00:41:38.079 --> 00:41:40.400
So uh we'll be close enough to Soho.
00:41:41.039 --> 00:41:44.400
Uh so this will be we'll strategically put it before Soho.
00:41:44.559 --> 00:41:47.039
And how many years now you've been doing Soho, Hagob?
00:41:47.599 --> 00:41:50.639
So Soho started under a different name.
00:41:50.800 --> 00:41:56.000
It was started by Michael Keating, he called it leukemia, the next question.
00:41:56.480 --> 00:42:12.320
Uh, and this was like uh 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.
00:42:12.880 --> 00:42:16.239
So we're gonna be our 13th or 14th year now.
00:42:16.639 --> 00:42:17.599
Congratulations.
00:42:17.760 --> 00:42:20.719
I uh I I I will try to visit with you guys in Houston.
00:42:20.800 --> 00:42:26.880
It just happens around Labor Day, and it had like you you need to uh you need to make the meeting around my schedule.
00:42:27.440 --> 00:42:34.480
I insist that you come to Soho because you'll you'll be able to interview so many people.
00:42:34.719 --> 00:42:40.159
Yes, I'm gonna be we have to we have to form a collaboration between Soho and Healthcare Unfiltered.
00:42:41.920 --> 00:42:42.800
God willing.
00:42:43.039 --> 00:42:43.360
Dr.
00:42:43.440 --> 00:42:51.039
Hagop Kantarjan, the myth, the legend, the master of leukemia in his in the flesh here on Healthcare Unfiltered.
00:42:51.119 --> 00:42:52.639
Thank you so much for coming on.
00:42:53.039 --> 00:42:54.800
Very kind of you to invite me.
00:42:54.960 --> 00:42:55.760
Thank you.
00:43:09.679 --> 00:43:14.639
It means a lot to me that you gave Healthcare Unfiltered this exclusive.
00:43:14.960 --> 00:43:25.360
Uh, 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.
00:43:25.519 --> 00:43:33.679
You can also suggest ideas, topics, and absolutely be engaged and uh follow all of the progress on Healthcare Unfiltered.
00:43:33.760 --> 00:43:40.239
And don't forget to check out also Healthcare Unfiltered Express and let your friends, colleagues know about both shows.
00:43:40.400 --> 00:43:41.679
Drop a brief review.
00:43:41.840 --> 00:43:48.159
This allows a lot of people to discover this podcast and always let me know how I'm doing.
00:43:48.400 --> 00:43:54.239
Before I let you go, I'm gonna leave you with a saying by Lebanese poet Khalil Jibran.
00:43:55.679 --> 00:44:04.079
Out of suffering have emerged the strongest souls, the most massive characters are seared with scars.
00:44:04.400 --> 00:44:05.599
Until next time.
