Adaptation Is Key to Advancing Care for Adult Patients With Leukemia

Jorge E. Cortes, MD

It would be difficult to look at data involving practice-changing agents for patients with leukemia and miss the name Jorge E. Cortes, MD. An investigative leader for nearly 30 years, Cortes has led the development of numerous leukemia treatments, including trials for the second-generation tyrosine kinase inhibitor (TKI) bosutinib (Bosulif), which is widely used for chronic myeloid leukemia (CML); omacetaxine mepesuccinate (Synribo), a drug approved for patients with CML when TKIs have stopped working; the third-generation TKI ponatinib (Iclusig), another CML treatment; and glasdegib (Daurismo), a smoothened inhibitor approved for the treatment of older patients with acute myeloid leukemia (AML) and complications like heart or kidney disease that preclude use of intensive induction chemotherapy.

Today, Cortes is leading something even larger than drug trials: the Georgia Cancer Center at Augusta University, which named him its director in 2019, following a 20-plus year career at The University of Texas MD Anderson Cancer Center in Houston. Working to make Georgia Cancer Center a world-class facility and continuing with as much research as possible keeps Cortes busy, but he has still found time to cochair the 26th Annual International Congress on Hematologic Malignancies^® hosted by Physicians’ Education Resource^® (PER^®), LLC.

The hybrid interactive conference will be held from Thursday, February 24, 2022, to Sunday, February 27, 2022, at the Eden Roc in Miami Beach, Florida. The 4-day event will focus on leukemias, lymphoma, and myeloma. Its presentations and panels will cover the latest developments in chimeric antigen receptor (CAR) T-cell therapy, the most pivotal new trial results, the use of genomics and molecular testing in hematological cancers, and how to cope with the emerging value based–care landscape.

At MD Anderson—where he rose from a fellow to the deputy chair of the Department of Leukemia— Cortes established himself as one the world’s leading leukemia researchers and the coauthor of more than 1000 published papers. At Georgia Cancer Center, he has less time for research, but he has still managed to launch another multicenter trial of an experimental CML treatment.

“[Cortes] is truly a world expert on all things leukemia, has peerless clinical experience, and is an undisputed leader in the field. He has been instrumental in a very large number of trials that have led to drug approvals, and he ranks among the most published authors in the scientific world,” Alexander E. Perl, MD, MS, said. Perl is an associate professor of medicine at Perelman School of Medicine at the University of Pennsylvania and a member of the leukemia program in the Abramson Cancer Center in Philadelphia, who has worked with Cortes on trials of FLT3 inhibitors.

“He’s an excellent speaker as well,” Perl added, “and will make a great chair for the conference.”

Courtney D. DiNardo, MD, MSCE, a clinical researcher in the Department of Leukemia at MD Anderson Cancer Center, said the key to Cortes’ success is a level of drive that is unusual even in a world of highly driven people.

“He’s always moving; he’s always thinking. He’s kind of like the Energizer Bunny. He just keeps going and going,” she said.

The agenda for the International Congress on Hematologic Malignancies^® features dozens of presentations and panels, and most of them are followed directly by question-and-answer sessions with thought leaders. The other program cochairs are Andre H. Goy, MD, physician in chief at Hackensack Meridian Health Oncology Care Transformation Service, chairman and chief physician officer at John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology at Hackensack Meridian School of Medicine, and professor of medicine at Georgetown University in Hackensack, New Jersey, and Sagar Lonial, MD, FACP, chief officer of Winship Cancer Institute of Emory University in Atlanta, Georgia.

The key topics for discussion will include the following:

• current and emerging biomarkers to determine risk and choose therapy for patients with hematologic malignancies;
• key clinical data on current treatment approaches;
• recent clinical trial results on emerging therapeutic approaches;
• and approaches to mitigate and manage treatment-related adverse events.

A MODERN LANDSCAPE

Cortes recently sat down for an in-depth interview with OncologyLive^® to preview the conference and share his thoughts about the major trends in leukemia treatment.

“When I started, leukemia treatment was easy,” Cortes said. “[Individuals] with AML got 7 plus 3 [cytarabine continuously for 7 days and an anthracycline on each of the f irst 3 days of a treatment cycle]. Patients with CML would get interferon. And individuals with a model of proliferative neoplasms got hydroxyurea. And that was it. It was very easy. Unfortunately, the results were terrible.

“Nowadays, there’s a lot more complexity in our understanding of the biology. There’s not one AML, there’s not one ALL [acute lymphoblastic leukemia]. There are a lot more challenges in classifying the cancer, and the same is true in treatment. We have a lot more treatment options, but the increase in treatment options means that it’s a lot harder to pick the right one. How do I select when I have 3 or 4 options? How do I combine them? What is the relative value? The answers to all these questions are evolving very rapidly because there [are] a lot of data coming out.”

Among the biggest topics of conversation at the hematology conference will be recent trial results for CAR T-cell therapy. In October, the FDA approved brexucabtagene autoleucel (Tecartus) for adults with relapsed or refractory B-cell precursor ALL. The approval was based on results from the ZUMA-3 trial (NCT02614066), in which 71 patients were enrolled and underwent leukapheresis. The CAR T-cell therapy was then successfully manufactured for 65 of those patients and administered to 55. At the median follow-up of 16.4 months, 31 (56%) patients reached complete remission (CR). The median duration of remission was 12.8 months (95% CI, 8.7 months-not estimable [NE]). Median relapse-free survival was 11.6 months (95% CI, 2.7-15.5), and median overall survival (OS) was 18.2 months (95% CI, 15.9 months-NE). Among responders, median OS was not reached at the time of analysis.¹

A few days before that approval, Kite submitted a supplemental biologics license application to the FDA to expand the current indication of the CAR T-cell therapy axicabtagene ciloleucel (Yescarta) to include the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma. The application was based on findings from the phase 3 ZUMA-7 trial (NCT03391466), which showed improved event-free survival compared with standard of care after a median follow-up of 2 years. Among the 359 patients who were randomized 1:1 to CAR T-cell therapy or standard of care, patients in the experimental group experienced a 60% reduction in events.²

“We will present a lot of data on CAR T-cell therapy,” Cortes said. “This is a rapidly emerging field, with a large number of new trial results, not just in acute lymphoblastic leukemia but, increasingly, in other areas as well, and we dedicate a whole section of the conference to the understanding of CAR T-cells. This is something that was addressed last year, but we will do it again because new information keeps coming, and now there’s the new indication in acute lymphoblastic leukemia.”

Cortes said that studies with venetoclax (Venclexta) in AML will also be discussed. “We will present [findings] from the initial phase 1 and phase 2 trials and then the randomized phase 3 studies that cemented venetoclax as the standard of care in a short period of time.”

Results of the phase 3 Viale-A (NCT02993523) trial led to venetoclax being adopted as the standard treatment in older patients with previously untreated AML. The trial randomized 286 patients to receive azacitidine plus venetoclax and 145 patients to receive azacitidine plus placebo. At a median follow-up of 20.5 months, the median OS was 14.7 months in the azacitidine/venetoclax group vs 9.6 months in the control group (HR for death, 0.66; 95% CI, 0.52-0.85; P < .001). Participants were also more likely to experience CR (36.7% vs. 17.9%; P < .001) and composite CR (66.4% vs 28.3%; P < .001). Serious adverse events occurred in 83% of patients in the experimental arm vs 73% of patients in the control arm.³ These data, as well as data from the phase 3 VIALE-C trial (NCT03069352), supported the FDA decision in October 2020 to grant regular approval to venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of adults 75 years and older with newly diagnosed AML.^4,5

Another major focus of conversation will be research indicating that many patients with CML who have responded completely to TKI treatment and gone several years with no evidence of disease can safely discontinue treatment.

“We have [an] increasing amount of trial data on this issue,” Cortes said. “We want to present the data from The LAST Study [NCT02269267] and elsewhere and put those trials in context and explore which patients are good candidates for treatment discontinuation and how we can do it right to minimize the risk for patients.”

EXPANDING HORIZONS

Cortes credits his career in medicine to his uncle. “When I was in high school, I wanted to be a dentist for some reason, but my uncle, whom I was very close with, asked me why I wanted to limit myself to treating the mouth when I was a good enough student to become a doctor and treat the whole body. Eventually he convinced me that medicine was probably a better path for me,” he said.

The decision to specialize in leukemia treatment and research also happened more by chance than by design. Cortes attended medical school and did his residency in his native Mexico before arriving in Houston for a hematology fellowship at The University of Texas Health Science Center. A portion of his rotation was held across the street at MD Anderson Cancer Center, where he met the team working on leukemia. Impressed by the investigators in the laboratory and the work they were doing, Cortes switched his program to focus on leukemia. More than 1000 papers later, his focus remains unchanged.

“Remember, we’re talking about almost 30 years ago, so in those days, [treating leukemia] was very, very challenging,” Cortes said. “There were very few new therapies available in leukemia, but there was a good opportunity to study because access to tissue is readily available. You also got the outcomes very quickly, so the clinical trials could be conducted rapidly.”

Location was also important to fueling his research. “[Houston] was a very active environment for research,” Cortes said. “There were lots of clinical trials, lots of academic discussions and interaction, so I thought it was a field that was very ripe for discoveries, and sure enough, a lot of new things have happened since then. Some of them, I’ve been a part of, and some of them, I’ve been a witness to, but it’s been a very rapid development.”

Cortes’ interest in and experience with TKIs dates all the way back to the beginning. He was investigating CML with Moshe Talpaz, MD; Hagop M. Kantarjian, MD, a 2014 Giants of Cancer Care® award winner in the leukemia category; and others at MD Anderson when the initial phase 1 trials of imatinib (Gleevec) began. He saw the incredible efficacy of the drug in those first patients and realized the great potential of targeted medications, specifically with TKIs.

The potential has been recognized in recent years in the expansion of targeted agents and a growing number of assays. Strategies for selecting the best therapies will be a major topic of conversation at the International Congress on Hematologic Malignancies^®.

“We will have an outstanding presentation on the increasing complexity and the molecular diversity of acute lymphoblastic leukemia, which is a rapidly evolving area. It’s become very complex, but also very specific, so this presentation will discuss how to use that information to manage patients,” Cortes said. “We will have the same sort of presentation for acute myeloid leukemia because again, it’s become a necessity to assess your patient to understand how to proceed with treatment.

“There will also be information on these molecular abnormalities in individuals that do not have leukemia but do [have] predisposing factors, these CHIPs—or clonal hematopoiesis of indeterminate potential. We have analyses of what these clonal entities mean, and we need to continue discussing them as we try to understand how they should affect our approach.”

SHAPING THE NEXT GENERATION

You could say that Cortes enjoys being in the weeds of drug development, having a hand in the process from start to finish. He enjoys the complexity of running large drug trials, analyzing early-stage data to construct late-stage protocols, assembling research teams, and working with both drug companies and the FDA.

“Drug development is a very complex endeavor,” he said. “Having a drug that works is obviously very important, but you have to design the trials in such a way that you get not only the academic answers and the clinical answers that you want, but also the data you need for regulatory approval. You also need to work with a lot of different groups— investigators, sponsors, regulatory authorities, and most importantly, you have to work with patients. You need to recruit and enroll them.”

Cortes noted that one of the key challenges is adapting opinions about drugs as new information becomes available and modifying trial design accordingly.

“Even when the drugs look good initially, you also have to acknowledge that you know very little, and sometimes you learn things that that you didn’t expect,” he said, citing his experience with the agent ponatinib. “It looked like a wonderful, very effective drug, but we learned that ponatinib had risk of arterial occlusive events—heart attacks, strokes, and things like that—which was completely unexpected. The [challenge] was how to react to that. How do you balance the risk-benef it ratio? How do you [work] with the sponsor, the regulator agencies, and the patients?”

Cortes’ strategy for managing these adverse effects secured ponatinib its 2012 FDA approval—albeit with a black box warning—for the treatment of adults with CML and Philadelphia chromosome–positive ALL. Last year, the FDA expanded the indication. Both approvals were supported by data from the phase 2 PACE trial (NCT01207440)6; the second indication was also supported by data from the phase 2 OPTIC trial (NCT02467270).⁷

“When we talk about what it takes to run a good trial, it all sounds straightforward, almost to the point of being obvious, but it’s not,” DiNardo said. “Doing good clinical research is a challenge, and some people are much better at it than others. I worked with Dr Cortes on several trials when I was new to the leukemia team at MD Anderson, and I am very happy I got a chance to learn from the best.”

LOOKING BEYOND THE CURVE

Among the discussion of new trial results and new diagnostic tests, the International Congress on Hematologic Malignancies® will also explore a relatively new concern: weighing the relative value of various potential treatments beyond their statistical significance.

“You’re looking to maximize value for the patient,” Cortes said. “In a randomized trial, you [are looking to] get an improvement in survival that has a statistical value. But statistical significance may or may not mean something clinically. If [the survival benefit] is just a few weeks and the toxicity profile is harsh, how much of that extra time is spent in the hospital or suffering because of adverse effects? The survival benefit can be somewhat diluted by what kind of lifestyle you have. You’re alive, but are you living a normal life or at least close-to-normal life? And then, you know, how much are you paying for each week or month of extended survival? These are all things you need to consider, and we’re seeing more interest in thinking about how to balance them.”

Cortes has taken a particular interest in improving quality of life for older patients and those with comorbidity that made traditional treatments hard to tolerate. “Age alone doesn’t make you less able to tolerate treatment, but it is more common that older patients will not be able to tolerate treatment,” he said.

Cortes’ interest in investigating treatments for older patients helped inspire his work to develop glasdegib. The agent was approved in November 2018 in combination with low-dose cytarabine for patients with newly diagnosed AML who are 75 years or older with comorbidities that preclude intensive induction chemotherapy.⁸ That approval was supported by data from the BRIGHT AML 1003 trial (NCT01546038), in which 115 patients were randomized to receive low-dose cytarabine with or without glasdegib. After a median follow-up of 20 months, median OS was 8.3 months (95% CI, 4.4-12.2) in the investigative arm vs 4.3 months (95% CI, 1.9-5.7) in the control arm (HR, 0.46; 95% CI, 0.300.71; P = .0002).

“[Older patients] have more comorbidities; they frequently take other medications, so you have to consider drug-drug interactions,” Cortes said. “There is also a tendency to give up—patients give up on themselves, doctors are more likely to give up on [finding treatments]—and you need to avoid that. Life expectancy is much longer now than it was 30 years ago. For trial [design] purposes, we used to consider patients over 55 [years] as elderly. We wouldn’t even [enroll them to] stem cell trials. Nowadays that sounds ridiculous. We realize that it’s just as important to combat cancer in these patients as it is in patients of any other age.”

CARVING OUT A CORNER OF CARE

To relax and recharge, Cortes naturally enjoys something that keeps him moving full speed ahead: long-distance running. “I love to run. I have done 8 marathons so far. I’ve run them in Chicago, Boston, New York, and Houston. I’ll be doing Houston again [in 2022], and hopefully that will qualify me to return to Boston,” said Cortes, whose best marathon time is 3 hours and 30 minutes.

Why running? Part of the allure is the chance to get away from stuffy indoor spaces and spend long periods outside. He even enjoys bad-weather days because he likes making himself endure conditions that would send others to the treadmill.

“The challenge is the point of long-distance running. It’s demanding. The race is demanding. The training is demanding. But it gives you a feeling of accomplishment,” he said. “I also like that it’s an individual sport. If I have a bad day, I’m not hurting any teammates. Running lets you run your race, at your own pace. You set your goals, and it’s fun to meet them. But if you don’t, you just try again.”

References

1. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S01406736(21)01222-8
2. Efficacy of axicabtagene ciloleucel compared to standard of care therapy in subjects with relapsed/refractory diffuse large B cell lymphoma (ZUMA-7). ClinicalTrials.gov. Updated October 14, 2021. Accessed October 26, 2021. https://clinicaltrials. gov/ct2/show/NCT03391466
3. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
4. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. FDA. October 16, 2020. Accessed October 26, 2021. bit.ly/3o0CBPl
5. Venclexta. Prescribing information. AbbVie Inc; 2021. Accessed October 26, 2021. bit.ly/3jZqqSz
6. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393-404. doi:10.1182/blood-2016-09-739086
7. Kantarjian HM, Deininger MW, Abruzzese E, et al. Efficacy and safety of ponatinib (PON) in patients with chronic-phase chronic myeloid leukemia (CP-CML) who failed one or more second-generation (2G) tyrosine kinase inhibitors (TKIs): analyses based on PACE and Optic. Blood. 2020;136(suppl 1):43-44. doi:10.1182/ blood-2020-133922
8. FDA approves glasdegib for AML in adults age 75 or older or who have comorbidities. FDA. Updated December 14, 2018. Accessed October 26, 2021. bit.ly/3vOy3jb