How the Study of Leukemias Inspired a Decades-Long Career

Jorge E. Cortes, MD, is the director
of the Georgia Cancer Center and cochair
of the 26th Annual International Congress on Hematologic Malignancies, hosted by Physicians’ Education Resource, LLC (PER®).

Q: Can you discuss what you believe is the most significant research of your career?

A: [Over the course of my career, I’ve always worked on] some research in leukemia specifically, and have mostly focused on product development, particularly early product development. I think some of the most important contributions that I’ve made have been in CML [chronic myeloid leukemia]. I’ve been working on the development of some of the TKIs, and I’ve led the research that ended up in the approval of 3 of the drugs that we use today: ponatinib [Iclusig], bosutinib [Bosulif], and omacetaxine [Synribo]. [The latter is a drug] we don’t use that much, but it’s still a drug that was approved, and it helps a few patients.

I’ve done a lot of work [not only with] clinical trials, but also understanding the disease, the prognostic factors, the management of adverse effects [AEs]. I’ve also done a lot of work in AML [acute myeloid leukemia] and multiple trials with PI3K inhibitors. I also led the clinical trial that ended up leading to the approval of gilteritinib [Xospata], a hedgehog inhibitor for AML.¹ Those are some of the most important contributions that I think I have been a part of.

Q: How did you decide that leukemia was going to be your focus of research?

A: It was a little bit by chance. I am originally from Mexico, and I had done my training there. However, I came to Houston to repeat my training, particularly in hematology. In Mexico, hematology and oncology are separated, so I came to repeat my training in hematology with a focus on thrombosis and hemostasis. [I went] to a sister institution of MD Anderson [Cancer Center], University of Texas Health Science Center across the street, because they had a good thrombosis and coagulation program there. The malignancy part of the rotation of that fellowship was at MD Anderson.

When I started my rotation, I started there in leukemia. I met wonderful mentors, in particular Susan O’Brien, MD. Looking at the research, the care, and the patients made me switch my program and the focus of my career. I had a lot of opportunities working with other departments and with her and Hagop M. Kantarjian, MD, and Moshe Talpaz, MD, and many others. That convinced me to change [my career] and I am very happy I did.

Q: What is it about leukemias that you found particularly interesting?

A: Remember, we’re talking about almost 30 years ago. In those days, it was very challenging [to treat] with very few new therapies available, but there was a good opportunity to study because the access to tissue was readily available. You get the outcomes very quickly. The clinical trials could be conducted rapidly. Again, the city where I was [located] was a very active environment for research with lots of clinical trials, academic discussions, and interaction. I thought it was a field that was ripe for preclinical research. Sure enough, since then a lot of new things have happened. Some of them I have been a part of, some of them I’ve been witnessing, but it’s been a rapid development.

Q: What drew you to research in TKIs?

A: I was working [on treating] CML already with Talpaz and Kantarjian. It started with the development of what in those days was called CGP-571, which ended up being imatinib [Gleevec].

There was a collaboration with Brian Druker, MD, from Oregon; I was working in the clinic with Talpaz, who was the principal investigator at MD Anderson. I was a witness to those early patients who went into phase 1 trials. It became very impressive to see the response of these patients and the efficacy of the drug, knowing that it was so molecularly targeted. I had the opportunity very early on to meet Druker, and it was the start of the era of targeted therapy with good understanding of the biology and drugs that were specifically developed for that. You may remember the famous cover of Time magazine about “magic bullets.” I was there, [and working] with these mentors made it a very attractive field. I started getting involved myself, leading some of these trials, and seeing one drug better than another led to the incredible improvements in something that was, up until then, very difficult to see.

Q: What were the biggest challenges in the development of bosutinib and ponatinib?

A: It is a very complex endeavor. You have to design trials in such a way that will not only give you the academic and clinical answers that you want, but will also meet the regulatory requirements for getting approval. It’s a complex interaction, so you have to work with investigators, sponsors, and regulatory authorities. Most importantly, you have to work with patients to recruit and enroll them.

The drugs [may look] good initially, [but] you have to acknowledge that you know very little and sometimes you learn things that you didn’t expect. For example, we had a wonderful drug, a very effective drug, and a great development, but then we learned that it had this risk of arterial occlusive events, [such as] heart attacks and strokes,
and these things were completely unexpected. How do you react to that? You have very effective growth, but you have AEs that you didn’t expect and don’t want. The balance of what to do with that risk-benefit ratio and how you deal with the sponsor, the regulatory authorities, and, of course, the patients [is complex].

Q: Can you discuss challenges of treating older patients? How can we treat them better?

A: It’s a complex scenario because, number 1, leukemias are more frequent in older patients and the older population is complex. Age does make you less able to tolerate treatment. It is more common that older patients will not be able to tolerate treatments and you cannot treat them as aggressively. They take many other medications frequently, so there is the complexity of drug interactions, and they take many other medications frequently, so there is the complexity of drug interactions, and [the doctor or patients have] a tendency to give up.

I remember when I started, there were studies about treatments of AML in the elderly, and the age cutoff was 55 years. We wouldn’t do stem cell transplants in patients aged 50 or 55 years or older. Nowadays that sounds ridiculous, but it reflected how toxic the therapy was, how different the perceptions were of age and life expectancy, and how [you should decide] what to do with these patients. Today, we recognize that these patients need special attention and special considerations, but they are as interested in defeating cancer as any other patient of any other age.

Reference

Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688