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In this Oncology, Etc. episode, hosts Patrick Loehrer and David Johnson interview hematologist-oncologist and scientist Dr. David Steensma, who currently serves as Head of Global Hematology at Novartis. In Part One of the episode, Dr. Steensma shares about his career journey from astronomy to medicine, and from academia to industry. We’ll also learn about the discovery and significance of a new pre-malignant condition - Clonal Hematopoiesis of Indeterminate Potential (CHIP).

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TRANSCRIPT

Dave Johnson: Hello, everyone, I'm Dave Johnson at UT Southwestern, in Dallas.

Pat Loehrer: And I'm Pat Loehrer from Indiana University, in the Center of Global Oncology in Indianapolis.

Dave Johnson: And this is another episode of Oncology, Etc.

Pat Loehrer: Yeah. Before I get started, I'm going to ask you a quiz. Do you know what a myrmecologist is, Dave?

Dave Johnson: Is that somebody who studies snails and conches, or no?

Pat Loehrer: No. Not even close.

Dave Johnson: Okay.

Pat Loehrer: Do you know what a philatelist is?

Dave Johnson: I thought it was maybe a small cardiologist.

Pat Loehrer: Someone who studies mermaids - no, no. A myrmecologist, actually, is a subject of this book that I just read called, Scientist, it's a story about E.O. Wilson. It's a biography of him. And I didn't know that much about him.

Dave Johnson: Oh, ants.

Pat Loehrer: Yes. Yeah. Richard Rhodes wrote this book. Actually, it's a great read. I mean, he grew up in Alabama, at the age of seven, he was fishing. And fishing, the hook got caught in his eye, he kept on fishing. He didn't seek medical attention. And later on, he ended up losing his vision in that eye, and his other eye was perfect. So, he used that to focus on little things - he loved ants and butterflies, and at the age of 18, he discovered the first colony of fire ants in the United States, eventually, went to Harvard. He was instrumental in creating the Encyclopedia of Life in which they're basically doing this global database for 1.9 million species. He was a bit of a controversial, but a very proactive person with conservation. He said basically that destroying the rainforest for economic gain is like burning a Renaissance painting to cook a meal. And he's talked about the Brazilian rainforest in which less than 1% of it is now present as it was compared to 100 years ago.

It's really quite amazing. His study of ants, the best quote I have from that is he said, "Karl Marx was right." He says, "Socialism works, it's just that he picked the wrong species." So, that's my book today, but I'm gonna turn it over to you, Dave, to introduce our speaker.

Dave Johnson: Well, we're very fortunate today to have David Steensma on this episode of Oncology, Etc.

Dr. Steensma is a highly accomplished physician-scientist, and an internationally recognized expert in the diagnosis and management of myelodysplastic syndromes. He has numerous academic accomplishments, ranging from characterization of the prevalence of JAK 617F mutations in MDS, first description of the involvement of the IR3G in human neoplasia, and more recently, the initial definition of Clonal Hematopoiesis of Indeterminate Potential, or CHIP - more about that later.

Dr. Steensma is a graduate of The University of Chicago Pritzker School of Medicine. He obtained his Internal Medicine and his Hematology-Oncology fellowship training at the Mayo Clinic in Rochester. In the early 2000s, he served as a post-doctoral research fellow and visiting scholar in the molecular biology hematology laboratories of Dr. Douglas Higgs, and Richard Gibson at Oxford University. He has served the medical community in many ways, including on the FDA ODAC Committee, a fun activity if there ever was one, Educational Chair of the 2015 ASH annual meeting, and also as a member of the ABIM Hematology Examination Committee, as well as many others.

He is currently the Global Hematology Head at Novartis Institute for Biological Research, where he oversees early-phase development of malignant and non-malignant hematology drugs within Novartis. Prior to moving to industry, he served as the Edward P. Evans Chair in MDS Research at Dana-Farber Cancer Institute in Boston. He's an enthusiastic philatelist. We'll talk about that a little bit more later in the podcast.

So, David, welcome to Oncology, Etc, and thank you so much for joining us.

Dr. David Steensma: Thank you for having me. Honored to be here.

Dave Johnson: Well, why don't we start by asking you just to tell us a little about yourself. Give us a little of your background, where you grew up, about your family, and very importantly, what and who influenced you to pursue Medicine as a career.

Dr. David Steensma: Yeah. So, my family is mostly in Michigan. My parents live there now, my sister, you know, extended family - my wife is from there. And when the Dutch came to the US during the great immigration wave around the turn of the 19th into the 20th century, a lot of them settled in Western Michigan-

Pat Loehrer: Dave Johnson was there.

Dr. David Steensma: -watching this happen? So, a lot of them settled in Western Michigan. I think it reminded them of home, you know, flat, sandy, big body of water to the left, similar kind of climate, and that's really my origin as Dutch immigrant community on both sides. I grew up in New Jersey though, partly because of the Vietnam war. And my dad getting a low number when he was drafted and having to move there, and then they stayed there for decades, and that's where I grew up.

I went to college thinking I wanted to do Physics and Astronomy - was fascinated by Astronomy, Astrophysics. Thought that that was gonna be my career, had a job as an undergraduate, working as an observatory assistant, to this day, probably the best job I've ever had. And then, I finished all the courses for my major, I took a course in Cell Biology just for fun, and I thought, "Wow, this is really interesting," and started thinking about going to medical school instead, and took Organic Chemistry over the summer between my junior and senior years of college, and one thing led to another, I ended up applying to medical school instead.

I don't have any doctors in my family. My grandfather worked for Roche as a chemist, his whole career. That's the closest we get to Medicine in previous generations. My father was an Aerospace engineer, my mom, a school teacher. You never know what pathways life is going to take you down.

Dave Johnson: Actually, I majored in Mechanical Engineering and I love Physics, so I get it. I mean, there were answers there. Medicine has always been a little more puzzling where they create these different words that you have to memorize. But I love people who have gone through the sciences like this.

Again, you've had a terrific career in academics, and now you've moved to industry. Tell us a little bit about that transition. What was the attraction, and what have you found to be the differences between the academics and your role now in Novartis?

Dr. David Steensma: I love being an academic, and you know, I envisioned that I would retire as such, but you know, things changed a little bit in 2020. It was a very unsettled time, I think, a lot of us thinking about what we were going to do for the next stage of our career. I was also turning 50 at the end of that year, so, milestones like that tend to make us think about where are we going. And Jay Bradner, the head of Novartis's Research Institute, called and said, "You know, we could really use a hematologist for leading our Early Development." And I initially said, "No." I didn't think about it. Although, tremendous respect for Jay, he had been a colleague at Dana-Farber, brilliant guy. I had first met him as a medical student at The University of Chicago some decades earlier, and then he called back and said, "Well, just come out and visit and see what we're all about."

And the research institute's just based in Cambridge, Ma. So, it was an easy visit, and one thing led to another, and a few months later, I was leading Hematology Development for Novartis. It really has been a fun transition. I think one of the big attractions for me was being able to do things at a different scale, and I loved Dana-Farber, but I was really getting frustrated with all of the staffing shortages. Clinical trials were really moving slowly, and so, the ability to work with a large range of centers around clinical development was very attractive. And there's a lot of great people at Novartis's Research Institute, it's like a biotech within a larger pharmaceutical company. It's been fun for me also, not just to have that narrow focus on CHIP and myelodysplasia, like I had before, but to be able to be involved in drug development, and lymphoma, and in CAR T, and in sickle cell gene therapy and all kinds of other really fun programs.

So, one of the things I've been a little bit shocked by is actually how similar life as an early drug developer is compared to academia. I mean, the biggest difference is not seeing patients, although Novartis would've let me, Dana-Farber did not. So, I've stopped seeing patients, at least for now. But there's a level of emphasis on science, and on careful clinical trial development that I really appreciate. And in many ways, academia has become a little bit more corporate. You know, greater proportion of the funding comes from industry. There are companies that are spinning off all the time from academic institutions. I like to say my Conflicts of Interest declaration has gotten much easier now because there's only one company to declare compared to before. It was, you know, anyone who you'd done a trial with or an advisory board participation. So, it's more similar than it is different.

I think it would be different-- People have different roles within companies, and I think if I was in late-stage development, really focused on what's gonna be the big value return for the company, that would be a different type of job, and I'd have to think more about the financial implications and the regulatory to a greater degree than I do. I get to work with scientists who are coming up with new molecular glue degraders and calling and saying, "Hey, where's the disease where this might be applicable?" And talking to the chemists about engineering out different liabilities that might be an issue for our patients, and you know, that really is energizing.

Pat Loehrer: You're one of the pioneers in CHIP. Can you talk a little bit about it, and what it means to the average clinician or to the patient?

Dr. David Steensma: CHIP is one of the coolest discoveries in the biology of aging, I think in the last 20 years. And we had long had the sense that as people age, the number of hematopoietic stem cells that they have is reduced. In the late '60s, early '70s, there really seems to be a bottleneck, when in childhood, in young adulthood, we have thousands of different hematopoietic stem cells contributing in our blood cell production. And then, there's like a colony collapse that happens and, you know, at age 75, it's a much smaller number, 10 to 12 in most people. In some people hematopoiesis is dominated by a single clone. But we really didn't have an understanding of the mechanism of why that happened. Until 2014, several groups, including Ben Ebert’s, led by Sid Jaiswal, a young investigator who's now at Stanford, found that somatic mutations that are common in MDS and leukemia, like TET2 and DNMT3A, these are actually common in aging people with totally normal blood counts.

And similar to monoclonal gammopathy of undetermined significance, there's just a portion of the older population that has these somatic mutations. And so, we kind of needed to name for it, and I feel a little bit like what my mentor, from Mayo, Bob Kyle, just one of my personal heroes, you know, he had taken an observation in plasma cell disorders that Jan Waldenström made, that was being called ‘benign gammopathy’, and didn't really have a good name. And he called it MGUS, Monoclonal Gammopathy of Undetermined Significance, a name that, now for more than 50 years, has been part of the medical lexicon.

And so, we did that with CHIP. I wasn't the guy who discovered CHIP, clonal hematopoiesis; it was somebody else's discoveries, but we came up with a definition for it, and a term for it, and it really took off. I mean, that paper has been cited a couple of thousand times already, and it's part of the new World Health Organization classification of hematologic diseases that just debuted this summer. So, that's been a fun world to be involved with, and it has clinical implications. And so, with Irene Ghobrial, who has a special interest in MGUS and smoldering myeloma and their progression to overt myeloma, I founded a clinic at Dana-Farber for patients with CHIP and other related precursor conditions.

So, the most interesting thing about CHIP, I think, is that it not only predisposes the human malignancy, but because these cells, these clonal cells, circulate, they interact with the vascular endothelium in different ways. It's a risk factor for cardiovascular events, it's a risk for death from cardiac cause, it's a risk factor for worse gout, worse COPD, but it protects, mechanisms that we don't fully understand yet against dementia. And we think that what's happening is these cells are getting in the brain and they are replacing some of the microglia that just undergo attrition with aging. So, that's fascinating. Somatic mosaicism has been described in lots of different tissues now; the esophagus, the liver, the gut, the skin. You know, these mutations that we normally think of as associated with malignancy can be found in many different tissues as we age. It's just part of life, as part of the entropy of existence. But in the blood, it's special because there's no anatomical constraints on that tissue in the way that there is with a clonal proliferation in the esophagus. And so, the circulation of the blood is what really makes that special.

Dave Johnson: So, I'd like to go back just for a moment and talk about your corporate life, if I may. I think many of, if not the majority of our listeners, come from the academic world. And so, they're familiar with the day-to-day activities of an academic such as yourself, but perhaps, less so with what do you do during the day as someone who is responsible for early-phase drug development in industry, what does your day look like? Do you come in every morning and meet with the basic scientist, or is there a corporate meeting? How does your day-to-day activity go?

Dr. David Steensma: That's a great question. It's one I get a lot actually, Dave, and I think, you know, because all of us train in academic medical centers, that's a life that's very familiar to us. And what happens in these other arenas - government, industry, biotech - is maybe a little bit less familiar. So, there's a lot of meeting that takes place; meeting with clinical trial teams, meeting with basic scientists, meeting with different operational experts and program managers. So that might involve, "Okay, we have a molecule that this is the safety profile of it. We have two other similar molecules that could go into the same indication, their safety profile is a little bit different. Which one is the one that is most likely to be tolerated and beneficial for patients?"

It might then be submitting packages for regulatory consideration by FDA and other health authorities around the world, and then responding to their feedback when they come and say, "Hey, we're not ready to give you this investigational new drug designation and let you start on clinical trials until you do ABC, and then we have to think about how we're going to do ABC.

It can involve business development, we call it, which is, "Okay, this is our portfolio, but we really need an X or we really need a Y, and biotech company A has these. Are they willing to talk?" And sometimes they come to us and say, "Hey, we've come up with this compound, we really need the power of a big company to take that forward and do a full development. Are you interested in partnering with us?"

I meet with my team members quite regularly in one-on-one meetings, both to talk about specific projects, but also their career development - make sure they're happy and you know, just as in academia, people want to progress to different roles; that's true in the industry world too. You know, connecting people to others and helping them think about what's their next promotion, what's their next role going to look like.

And then, there's a lot of governance meetings. So, these are meetings where we say, "Okay, this clinical trial, should we go forward with this or not? It's gonna be $100,000,000 investment, this is the data we have to this point, you know, should we do this? What are the considerations?" That's a big part of it.

There is travel, you know, during the COVID pandemic era, been much less so. The one thing I always heard people in industry complain about before I made this switch was the travel. There's been a lot less of that, so it's made me happy because it's been a more balanced lifestyle, that's for sure. But there is still some of that; travel to investigative sites, travel to the big meetings like the ASCO annual meeting, EHA, the ASH annual meeting, and some smaller meetings. So, it's a real mix of things.

Dave Johnson: So, let me just follow up with one further question. Do you find that your reading has changed?

Dr. David Steensma: I think that my reading has changed a little bit, but mostly because of the breadth of programs that I am now responsible for. So, in the past, I was very heavily focused, at least within Medicine, on the myeloid world and trying to keep track of developments outside of that.

But now, I really have to pay attention to new findings in lymphoma, and myeloma, and non-malignant hematology to a greater extent than I was. My reading of things outside of Medicine has also been a little bit broader and there's more time for it because there's not the, you know, staying three hours at night and finishing your Epic EMR inbox. One of the things I've really been impressed by is that in industry, there's not a lot of time wasting. A lot of things that we were asked to do in academic medical centers are things that doctors really don't need to be doing. So, I get to read lots of other things too.

Pat Loehrer: Let me follow up on Dave's question. This is a confession on my part. There's so many things that I have done that I don't feel like I'd really qualified to do. There's this imposter syndrome that we talk about. You're now the Head of Global Hematology. Was there a sense as you're taking these steps that, "Wait a minute, this is really a job really too big for me, and I'll try it," or do you just have this innate confidence? How was that?

Dr. David Steensma: I am definitely affected by that, it's a major transition. I'd never done anything like this, and even with the assurance of knowing a number of the people at the research institute that I was going to, being confident in Jay Bradner's leadership, and that of Alice Shaw, who is our Translational Clinical Oncology leader, a wonderful colleague, this was still unlike anything that I'd ever done. And so, I was anxious about it.

You know, ironically, sometimes the things that we complain about become the best preparation for what's coming in life. And about six years ago, Dana-Farber affiliated with a community-based practice in the Brighton neighborhood in Boston, called St. Elizabeth's Hospital and provided hematology oncology services there, and they really needed somebody to go out for heme malignancies.  And talk about taking me out of my comfort zone, instead of having a very narrow clinic where I was seeing marrow failure, and MDS, and leukemia, and MPN, and CHIP, patients with these conditions where I really had a comfort level, I was treating patients with HIV-associated lymphoma, and myeloma, and calling a lot of my colleagues back at Dana-Farber for advice.

And I grumbled about being the guy that was asked to do this, but it turned out to be terrific preparation for what I'm doing now because my myeloma knowledge is not obsolete from fellowship 20 years ago. It's up-to-date, I've prescribed, you know, a lot of the newer agents and seeing what the adverse events were, and same with lymphoma, and seeing where the patients' needs were. So, I'm actually really grateful for that experience now, in retrospect. At the time it felt like a nuisance. I had to leave the site and go to the other site, and I had patients in two hospitals, which is not easy, but I'm glad it happened.

Pat Loehrer: I think that's an interesting observation. I, too, was at one point in my career spending time between two facilities, with essentially a private practice that was broad and general, versus the more narrow practice I had at the university. And it was challenging, but I think, like you say, it's so rewarding in many ways, and helped me in my transition from being an oncologist to a Chair of Medicine of a major department, in my later years.

Dave Johnson: Well, this will wrap up part one of our interview with hematologist, oncologist, and researcher, Dr. David Steensma. In the second part of this episode, we'll ask David about an article he wrote on key opinion leaders, published in the JCO a few years ago - very provocative paper to be sure. We'll also explore how he got into and stayed passionate about stamps; a subject about which he's written extensively.

Thank you to all of our listeners for tuning in to Oncology, Etc. This is an ASCO Education podcast where we will talk about just about anything and everything. If you have an idea for a topic or a guest you'd like to hear on our show, please email us at: education@asco.org.

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