As Milestone Nears, an Early Investigator Reflects on Lessons of Imatinib

This month, more than 30,000 people from all over the world will land in Orlando, Florida, for the annual meeting of the American Society of Hematology (ASH) to hear what breakthrough treatments are in store for blood cancers, which can silently roil patients from within before appearing as an odd bruise or unexplained fatigue.

ASH has seen so many advances in blood and bone marrow cancer treatments that one can forget how today’s “treatable” diagnoses were only recently a death sentence. Twenty-five years ago this month, the ASH audience witnessed a breakthrough that many still find worthy of the Nobel Prize—the groundbreaking work on STI-571, later known as imatinib.

In his December 2000 presentation, Brian Druker, MD, a physician at Oregon Health & Science University, showed how a pill—the first targeted therapy—had brought complete hematologic responses in 53 of 54 patients taking the 300 mg daily dose, typically within 4 weeks. These were patients who had not responded to interferon-α, a treatment that was not only less effective but also caused severe adverse events, whereas imatinib’s reactions were mostly nausea and diarrhea.¹

This was not the first presentation on STI-571, but it was the one that would change everything: The New England Journal of Medicine published results in April 2001,¹ and the FDA approved imatinib a month later.² Sold as Gleevec by Novartis, these “magic bullets” were heralded on the cover of TIME magazine.³

Jorge Cortes, MD, who will transition in April from the Georgia Cancer Center at Augusta University to the University of Alabama at Birmingham Division of Hematology and Oncology,⁴ had a front-row seat for everything: As a young physician, he left his native Mexico to work with Moshe Talpaz, MD, at the University of Texas MD Anderson Cancer Center in Houston; Talpaz was one of Druker’s fellow investigators on the imatinib trials. In an interview earlier this fall with The American Journal of Managed Care, Cortes recalled how chronic myeloid leukemia (CML) once offered a grim prognosis, and how quickly the shift happened.

CML, he said, “is not as explosive as acute leukemia, where someone who cannot be treated would have a life expectancy of just a few months. But chronic leukemia still had a median life expectancy of 3 to 4 years. So, when the median age [of diagnosis] is in the 50s or in the 60s, 3 to 4 years is not what you’re expecting to leave at.”

When Cortes started his career, treatment options were very limited. In Mexico, “We did not even have hydroxyurea,” he said. “It was very difficult, in part, because many of these patients had no symptoms—you just found out that the white cells were elevated. It’s very hard for somebody to accept that.”

Cortes vividly recalled the elation of doctors and patients when suddenly, there was a potential cure. There were very different reactions from those who realized they landed in the control arm of the phase 2 trial.

“I remember seeing these patients with these remarkable responses, when you had nothing else to offer them just a few months before,” Cortes said. “I still remember Dr Talpaz coming out of rooms and saying, ‘Wow, this thing works!’ He had this expression of wonder—of the big change that it was representing.”
At the end of 1999, the first phase 1 data were ready to be presented at ASH,⁵ with phase 2 trials getting underway. Word was spreading.

“We had many, many patients flying to these centers, to MD Anderson and to the other centers,” Cortes said. “Everybody wanted to get this drug.”

But the next study would be a randomized trial comparing the study drug with interferon-α, the standard of care. Because the trial was open-label (the drugs had different methods of delivery), patients knew which one they were receiving.

“It was a remarkable contrast,” he said. “Patients came to the study, [and] they wanted imatinib, but it was randomized.… The patients who would get imatinib—they would be very happy and excited—cheering. And patients who were getting interferon, sometimes they would cry, because what they were expecting was to get imatinib from the start, not interferon.”

Like others who treated patients with CML before imatinib was approved, Cortes still thinks about those who just missed out on the drug. One, he said, “was the mother of one of my best friends in medical school in Mexico.” The mother had been diagnosed a few years before the pivotal trial; Cortes was able to get her enrolled in a later study, “but she had already progressed to the blast phase.” Imatinib helped some, but it was not enough at that point.
“You feel so badly knowing where we are now,” Cortes said.

Changing the Treatment Paradigm
The early wave of excitement over imatinib only meant there was more work to do. Some patients reacted very well to the drug, but some didn’t, while others eventually developed resistance. Cortes has spent more than 20 years examining all these questions. He’s been an investigator or coinvestigator in developing second- and third-generation drugs in CML, including dasatinib and nilotinib, and in finding therapeutic combinations.^6,7

Just as important, Cortes insists, has been the work to change the way cancer treatment is managed—from monitoring to sequencing to evaluating individual patient characteristics for treatment decisions.⁸

A generation ago, these considerations were barely part of cancer care. “This was completely new,” he said. “There was a lot of learning about the [adverse events], the monitoring of the patients—it changed completely how we manage the patient.”

Cancer care was no longer just about the drugs—everything around the disease was new, including a shift away from the “save the best for last” mentality with new therapies.

Take the work going on involving a new CML therapy, asciminib (Scemblix; Novartis).⁹ Studies showed it had a different mechanism of action on the tyrosine kinase protein, while other CML drugs “bind in a remote place of that same protein,” Cortes said. Studies found a complementary effect of combining the drugs without elevating toxicity—unlike the effect of combining 2 chemotherapy drugs, for example.

But for which patients? “Not every patient has to take a combination, but what are settings where a combination may be valuable?” Cortes said he is working with colleagues in Germany on this question, evaluating which patients have a subset of genetic mutations indicating a poor outcome for a single tyrosine kinase inhibitor vs the combination.

Making a Difference in Quality of Life
As a medical student, Druker had been determined to find ways to treat cancer more humanely. He told the Journal of the National Cancer Institute, “My most vivid memory was when we learned about chemotherapy. I thought, ‘My God, this stuff works, but it’s horrible.’”¹⁰

In the 1970s and 1980s, the medical establishment was skeptical about the idea of genetics driving cancer, much less the concept of targeted therapy. This was despite the fact that the first scientific steps toward imatinib had already occurred: Scientists found that 1 of 46 chromosomes among patients with CML was abnormally short; they named it the Philadelphia chromosome after the city of its discovery.¹¹ Later, as DNA research techniques improved, others showed that the Philadelphia chromosome forms when 2 chromosomes break and the pieces trade places; a National Cancer Institute team then found that when the chromosome forms, a pair of separated genes fuse together. This is called the BCR-ABL hybrid, and it would prove crucial to developing imatinib.¹¹

The idea of targeting the BCR-ABL oncoprotein, a tyrosine kinase that causes CML, with a molecule that binds to the kinase and stops the signals that cause cancer to grow—while also killing cancer cells—was nothing short of revolutionary. Cortes said the patient outcomes in CML are to be celebrated, but this is the real story.

“CML has been a fascinating disease because it’s led the way in many aspects,” he said. “It was the first disease where it was discovered that there was an abnormality in the chromosomes that was linked to the disease.”
Druker deserved credit, Cortes said, not just for his scientific work but also for his persistence—he had to convince a pharmaceutical partner to develop a molecule to go after the target—which, at that time, was not a sure path to success. “I’m surprised he hasn’t gotten the Nobel Prize. But he has it in my mind,” Cortes said.

The approach spares patients many of the adverse events seen with traditional chemotherapy. This has changed the approach to treatment—with the idea being that all new therapies should aim to be less toxic, so patients can stay on them longer and continue to work and live normal lives. To Cortes, improving tolerability is just one step to the ultimate goal—finding treatments that can be stopped at some point. Cortes is active in the International CML Foundation, which he said is actively engaged in this question.

“How do we stop therapy [for] patients? Right now, we can do it, but it’s a reality for about a quarter of the patients,” he said. Although the percentage is better than it once was, “That’s not enough.”

Today, with CML highly treatable, those who are newly diagnosed will sometimes tell Cortes they have “the good cancer.” But Cortes quickly dismisses this.

It only takes reading the devastating essay in The New Yorker by Tatiana Schlossberg, the granddaughter of President John F. Kennedy, to be reminded how much we don’t know about cancer.

Schlossberg revealed on November 22 that she is dying of acute myeloid leukemia, made worse by the rare, aggressive mutation known as inversion 3.12 Her cancer is resistant despite a pair of stem cell transplants and other state-of-the-art treatments, and Schlossberg took aim at the massive cuts to scientific research under the direction of her cousin, HHS Secretary Robert F. Kennedy Jr.¹² The American Association for Cancer Research and other groups have decried the cuts to funding and related attacks on higher education.¹³

Cortes is optimistic that, in time, the United States will restore research funding. “ The US has been the leader in scientific development in so many areas, and we cannot afford to lose that,” he said.

Yet despite the progress he has seen over a generation, Cortes said nothing can be taken for granted. “I also want to emphasize that we still need to respect cancer,” he said. “Because anytime you give cancer a chance, if you lower your guard, it’s going to come and hit you.”

References

1. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344(14):1031-1037. DOI: 10.1056/NEJM200104053441401
2. Cohen MH, Williams G, Johnson JR et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8(5):935-942.
3. Lemonick M, Park. New hope for cancer. TIME. May 28, 2001. Accessed November 27, 2025. https://time.com/archive/6678138/new-hope-for-cancer/
4. UAB O’Neal Cancer Center welcomes Dr. Jorge E. Cortes to the Division of Hematology and Oncology. News release. O’Neal Cancer Center. October 14, 2025. Accessed November 26, 2025. https://www.onealcanceruab.org/news-and-events/news/cortes-ad-translation-commitment/
5. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105(7):2640–2653. DOI:10.1182/blood-2004-08-3097.
6. Kantarjian H, Shah NP, Hochhaus A, et al. N Engl J Med 2010;362(24):2260-2270. DOI: 10.1056/NEJMoa1002315.
7. Mauro MJ, Hehlmann R, Williams LA, et al. Five-year molecular response and overall survival with first- and second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a prospective, observational study - SIMPLICITY. Leuk Lymphoma. 2025;66(9):1615-1624. doi: 10.1080/10428194.2025.2495369.
8. García-Gutiérrez V, Breccia M, Jabbour E, Mauro M, Cortes JE. A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase. J Hematol Oncol. 2022;15(1):90. doi: 10.1186/s13045-022-01309-0.
9. Jain AG, Cortes JE. Asciminib: the tyrosine kinase inhibitor with a unique mechanism of action. Expert Opin Pharmacother. 2025;26(6):677-684. doi: 10.1080/14656566.2025.2480762.
10. Vastag B, Leukemia drug heralds molecularly targeted era, JNCI: J Natl Cancer Inst. 2000;92(1):6–8, https://doi.org/10.1093/jnci/92.1.6
11. Pray L. Gleevec: the breakthrough in cancer treatment. Nature Educ. 2008;1(1):37.
12. Schlossberg T. A battle with my blood. The New Yorker. November 22, 2025. Accessed November 22, 2025. https://www.newyorker.com/culture/the-weekend-essay/a-battle-with-my-blood
13. Caffrey M. AACR panelists call on scientists to stand up against cuts that threaten progress, patients, and future discoveries. AJMC. April 27, 2025. Accessed November 26, 2025. https://www.ajmc.com/view/aacr-panelists-call-on-scientists-to-stand-up-against-cuts-that-threaten-progress-patients-and-future-discoveries