Get to Know ... Marina Konopleva, MD, PhD

Marina Konopleva, MD, PhD, Director of the Leukemia Program and Co-Director of the Blood Cancer Institute at the Albert Einstein College of Medicine, discusses her new role at Albert Einstein as well as highlights from her career at the MD Anderson Cancer Center and some of the pressing questions remaining in acute myeloid leukemia (AML) research.

Where did you grow up, and when did you know you wanted to be a physician? I was born in a small city in Georgia, which was a former Soviet Union Republic. Now it’s an independent state. My mother and grandfather were physicians.

I always thought I would be a physician because I saw my mom, who was an ophthalmologist, working in the clinic. I saw how hard she worked, but she got a lot of appreciation from her patients and a lot of love and recognition from her colleagues. I liked that component.

How did you choose hematologic oncology and AML specifically? I think that was serendipitous. When I was at the First Pavlov State Medical University in St. Petersburg, Russia, we had rotations in different specialties. I did like one other specialty, which was infectious disease. Then I had a great mentor, Professor Andrey Zaritskey, who was a hematologist giving a hematology class.

I think he really portrayed a passion for hematology. Even at that time, there was so much going on in the basic science of hematology, which I thought was ahead of other disciplines. I think what got me interested was when we were taking care of patients with leukemia. They were very sick—many died and were very ill. He told me, “Marina, these patients are really sick and complicated. We need somebody to take care of them. Somebody like you has to take care of them.”

That got to me, and I felt that I could really contribute and help heal them or at least help them survive. Although it was so difficult, at that time, we didn’t have many drugs. I decided to go into hematology right after medical school. Then I got the training in St. Petersburg, Russia. I did my training specialization in hematology.

Later, in 1996, when I came to the United States, I did research in the lab of Dr. Michael Andreeff, and his main topic was AML. That’s how I got to work on AML in the clinic as well.

Looking back on your long tenure at the University of Texas MD Anderson Cancer Center, what makes you most proud? I was there for 26 years—10 years were in the lab, and I spent about 16 years as a physician scientist (in the clinic and the lab). It’s hard to pinpoint one single thing. Professionally, the fact that we were able to—based in part on research in my lab—contribute to the development of venetoclax and get it to the clinic. It is now used throughout the world in AML patients.

Of course, it was by no means my discovery alone; there were many people who worked on it. The fact that I had some piece in that, and contributed to bringing that to clinic, every time now when I see a patient getting venetoclax, I’m proud of that. That was a drug we used in the lab that we were hoping would make it to clinic, but from the drugs we worked with in the lab, so many did not make it, or they did make it, but they didn’t show benefit.

Other than that, mentorship of junior faculty and people in the lab was really important for me. I’ve seen people grow, especially in the field of leukemia, junior faculty members who started as assistant professors at the time when I started working with them. I can see how much they have grown, they really became leaders in the field and people look up to them. They have high-profile publications and lead key clinical trials in the field. I had some small input into their development, but I’m also very happy to see them so successful and independent.

Of course, the work in the lab was very important. It was essentially my entire career. Taking care of patients was always very important for me, which is why I decided to go back to clinical medicine after being successful in the lab.

I just felt that it was missing the patient contact—the fact that you can really help them on a daily basis and make a difference. I think these interactions with patients were really important, seeing that you can change how they feel and how the disease is doing. Sometimes we can cure them, which is the best-case scenario. I always felt that I give a little piece of myself to all my patients because I’m just trying to feel what they’re going through.

Can you share about your new role at the Albert Einstein College of Medicine and some projects you’ll be working on? I am the director of the clinical leukemia program. I’m a co-director of the Translational Blood Cancer Institute, which is research-oriented. I will have essentially a very similar role that I had at MD Anderson. Being a physician scientist, I am hopeful to bring new clinical trials here to Einstein, especially in the leukemia space, and mentor the junior faculty.

I will continue working on the translational projects in acute leukemia. Targeting cell-death machinery will remain the focus of my lab. Plus, we have interests in oncometabolism and in immune-oncology.

I still have to see whether these projects will continue as they are right now, or whether I’ll get into some new areas, which I will be very excited about. What we are good at is trying to bring the drugs from the lab to clinic. We want to make sure that anything that goes into clinical trials has potential. In the meantime, we’re figuring out mechanisms of how the drugs work and how resistance may develop. That will still be the main direction conceptually for me.

What do you think are some of the most pressing questions in AML that still need to be addressed? In AML, we made some progress, but clearly, we are far from the cure. Even with the venetoclax combinations, if you look at the long-term results, we can cure only 20% to 30% of patients, but no more than that. These are all the patients who we think cannot tolerate intensive chemotherapy. We are far away from the goal of the cure. For younger patients, we generally do better if they can proceed to stem cell transplant.

There are a lot of new combination trials going on, with the hope that we can extend the duration of response, increase survival, and reduce resistance. These are with the small-molecule inhibitors, chemotherapy, and the immune therapeutic agents. I feel that some of them look really exciting, and hopefully we can make a difference.

Patients who have specific poor-risk features, like p53 mutations, we are still struggling with. We are hoping that some of the immune approaches that are agnostic toward the mutational status might be helpful. For example, there’s a lot of excitement about natural killer (NK) cell therapies, NK cell engagers, or other immune approaches, antibodies, monoclonal antibodies against leukemia-specific antigens.

I think some of these approaches are really promising. Finally, the induction of differentiation of the leukemia, basically tumors of bone marrows where the cells are undifferentiated and tumor-like, and then some of the new agents. Again, their responses are not curative on their own.

Understanding what happens, why the resistance happens, and how we can overcome that with combinations, or at least understanding the mechanism of resistance, will be our questions for the next 10 years or so.

What do you hope to see happen in this field? What do you think can happen in the next 20 years? I would like to see the cure rates in younger patients approach 70% to 80%, which is what we have with some of the better cytogenetics risk. I still don’t think we’re going to be at 100%, just because of the side effects of the drugs. There are still some very hard subsets. For older patients, if we can get to a five-year survival rate of 50%, that would be amazing, that is more than double what we have now.

Are we going to get there? I’m always optimistic. I think with the progress we have right now with the new agents, we should be able to get there, even though it has been slow in AML. There has been great progress in other leukemias, like acute lympho­blastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and others, but AML has been the toughest so far.

I think that is because it’s a very heterogenic disease with multiple clones. The drug that will affect one clone may eliminate that clone, but then there’s the next clone that will live through. The question is how we can get rid of all of them, without affecting the patient’s safety. That’s the challenge.

There are some approaches where we are starting to sequence the drugs. We are trying to understand what the genetic drivers of the disease are, and then perhaps sequencing drugs even before the patients relapse so we can use the drugs against specific mutations. Not many of those are available, but we do have some clinical tools there. I think in combination with immune therapy that will be helpful because these can work agnostic of mutations.

I don’t think any single agent will ever cure AML, but there are new things coming up that could make a difference—that’s my hope.

On a more personal note, could you discuss a bit about how your experience as an immigrant and non-native English speaker impacted your career path? When I arrived in Houston, Texas, in 1996, I was okay with English. Obviously, it was a totally different culture. It was a totally different environment. At that time, physicians in Russia were extremely poor. I came on the fellowship grant, which only paid $17,000 a year, which was for three months’ duration. I had very limited income. I was trying to save some money for my family back home.

There were a lot of constraints there, but people in the lab were very helpful. They realized that I was visiting only for a few months, and I was supposed to go back home. There was one woman in the lab named Angela who offered to let me to stay in her house temporarily, which I did. She had friends in the neighborhood who had a garage apartment who gave it to me for free. That was amazing—the way people really welcome you and help you out. In Houston, and Texas in general, people are extremely friendly and kind. I was coming from Russia, and people in Russia are also very kind, but they don’t show that. They’re very stoic.

I really felt liberated coming to this country and being able to do what I’ve done. I was able to go all the way from post-doctorate fellow to full professor. It’s just this American dream that people are talking about; when you live through that, you realize that it is a reality. It’s just your hard work and dedication plus support of people around you. I was very fortunate to have ongoing support from my first research mentor, Dr. Michael Andreeff, throughout my career, and Dr. Hagop Kantarjian, our leukemia department chair, through my clinical career steps.

What inspiration or recommendations can you give to younger physicians or trainees in the field? The main thing is to work hard. To be able to succeed, you have to work hard, and unfortunately that comes with a cost—a cost to your family and your personal time. If you want to make a difference, you have to accept that you have to be at work a lot, and perhaps you cannot give as much to your family. Otherwise, just follow your passion, and try to get there by learning and reading.

What was really important for me was learning from people—from my colleagues and collaborators. In my grants, I always have collaborators. All my papers have a lot of authors on them. It’s for a good reason, because you can help collect all the pieces of goodness and knowledge and share that, and people get excited to work together. I feel like this really becomes synergistic in some ways.

What is most important is to be a people person—to work with others and help them. If you help others, they will return that by helping you. I came to this country with essentially no lab experience, and I was able to learn a lot just because I was collegial and helpful to my colleagues.

What do you like to do outside of work? I recently became a grandma. That made a lot of people go, “Wow!” My granddaughter Sophia is 10 months old. That was one of the key reasons I decided to move to New York. Now I enjoy taking care of her, seeing her getting up, moving around, smiling, and chatting.

We like going to the Houston Opera, and I’m hoping to get a subscription here in New York as well.

Marina Konopleva, MD, PhD, is the Director of the Leukemia Program and Co-Director of the Blood Cancer Institute at the Albert Einstein College of Medicine in New York.