I was getting scared.
The drug initiated a new era in cancer care, where characteristics of the tumor – rather than its original location – determined what treatment a patient would get.
“It revolutionized the way physicians and scientists began to think about how to treat cancer said Louis DeGennaro, president and CEO of The Leukemia & Lymphoma Society. “It was the birth of precision medicine: the right drug to the right patient at the right time.”
Although Gleevec remains one of the most powerful of these targeted therapies, approved for treating 11 kinds of cancer including Mann’s type of leukemia, many similar drugs have followed, transforming treatment for lung cancer and other tumor types.
DeGennaro, who was a pharmaceutical executive back then, said the impact of Gleevec was almost immediate. “Even from where I sat, this was a game-changer. It gave us a whole new way to think about how to develop drugs,” he said.
Fifteen years ago, it was typical for one or two drugs to be approved annually to treat leukemia. “One year there were three and I was dancing on my desk,” DeGennaro said. Since 2017, thanks to the explosion of precision medicines and immune therapies, there have been 81 drug approvals for blood cancers, he said, 68 of which were at least partially funded by his society.
In addition to working well, Gleevec also can be delivered by a daily pill, instead of hours in an infusion center with terrible side effects.
“Today, a patient doesn’t get a death sentence from their physician, they get a prescription,” DeGennaro said. “They treat their cancer by taking two pills a day and live a long, healthy productive life.”
Gleevec and other targeted therapies aren’t cures and they don’t work for everyone. Most of the drugs stop working after a while.
But for some patients, including Mann, Gleevec is the only drug they’ll ever need to block their cancer. Some people are able to pause the drug for periods of time – DeGennaro recalls a young patient who took two breaks to have babies – while some can eventually stop it altogether.
The fact that it’s a long-term therapy means drug companies can make a lot of money, even on relatively rare diseases, said Dr. George Demetri, director of the Sarcoma Center at Dana-Farber Cancer Institute in Boston, who treats relatively rare solid tumors and proved that Gleevec worked for gastrointestinal stromal tumors.
“It changed the economic incentive for biotech,” he said.
The quick time-frame for approval, with trials started in 1998 and the drug approved in 2001, sped up the pace by which science could help patients, Demetri said.
“I never could have done that in the 90s. Never,” he said. “It used to take 20 years to figure out if you had a drug.”
Before Gleevec, doctors didn’t understand why a drug stopped working in a particular patient. But by focusing on a specific target like the enzyme that Gleevec attacked, it was easier to see when and why a drug became ineffective, Demetri said.
“By fundamentally understanding the mechanism, we can be engineers,” he said. “Otherwise, you’re just trial and erroring it.”
Plus, by showing that cancer care could truly extend a patient’s life, rather than just making them miserable with chemotherapy, Demetri said the drug had an “ongoing inspirational impact,” encouraging many more talented doctors and researchers to enter the field.
Mann, now 64, tried going off Gleevec, but his cancer threatened to return, so now he’s on it for life.
Although some people suffer worse side effects, for Mann the only symptoms are puffy eyes and some fatigue and muscle aches, which he manages by drinking a lot of water and continuing to run nearly every day.
Demetri laughs thinking about his gastrointestinal stromal tumor patients complaining now that they don’t tan as well while taking the drug, compared to the horrible prognosis he used to talk to them about.
“It’s been transformational,” he said.
Mann found out he was sick at 37, when he went to an Army doctor complaining of back pain. An MRI indicated something was wrong with his bone marrow and a blood test showed his white blood count was through the roof.
Mann, then a major working on future weapons systems, said he simply couldn’t accept his death sentence. His daughter Patrice was still in kindergarten. “Her being 5 gave me a reason to live,” he said.
About 18 months into his diagnosis, while running a bone marrow drive, he met a man diagnosed with a different type of leukemia. The man told him about clinical trials and said he needed to get himself to MD Anderson in Houston.
Mann did, and was in one trial that didn’t help much. As his white blood cell count climbed in early 1998, Mann was getting worried. “I was totally out of options,” he said, and more than three years out from his diagnosis.
Wasn’t there anything else to try? The doctor said there was one trial he was optimistic about, but it hadn’t started yet. Mann wasn’t sure he’d survive long enough, but when he got the call that summer, he signed on. He swallowed his first dose on Aug. 3, 1998.
As the months went by, Mann wasn’t seeing much change in himself, but he kept bumping into other trial patients who had joined later and were getting higher doses. They seemed to be thriving. By December, his doctor convinced the company running the trial to give Mann a higher dose. He was lucky to have made it that far. Others didn’t last long enough.
“It definitely was my life saver,” Mann said.
Brian Druker remembers the first patient who ever received Gleevec. Bud Romine, a retired railroad engineer, had reached out to Druker in 1996 after an article ran in the local paper touting the lab research and volunteered.
He was started on an even lower dose than Mann, and it didn’t work. But luckily, Romine also lived long enough, and by 1999, Druker was able to convince Novartis to let him increase the dose. “He responded beautifully,” Druker said, and years later died of something other than cancer.
Before Gleevec, treating chronic myeloid leukemia was a challenge for doctors, too. Druker would tell patients they had about three years to live, but wouldn’t tell them how anxious he’d be every time they came in for a checkup.
If their leukemia had switched from the chronic to an acute phase, “it was a time bomb. Game over,” Druker said. “At some point it was going to take off and there was nothing you could do to prevent that.”
In the early 1990s, treating leukemia patients at Dana-Farber, Druker hoped his research could help improve that outlook.
He was studying a family of enzymes called kinases that drove cell growth. Druker was hopeful that if he could just turn off the one abnormal kinase that was driving chronic myeloid leukemia, he could cut off the fuel supply feeding the cancer and change the outlook for his patients.
But there were 500 such enzymes, and Druker’s peers thought if he shut off one he’d shut off them all and kill the patient.
His career was going nowhere, so he moved to Oregon Health & Science University, in Portland.
Almost immediately, good luck struck. In Druker’s first days on the West Coast he had reached out to a colleague at a drug company to see if he had any new drug in development that might inhibit the kinase. He did, and Druker showed it worked amazingly well. It killed cancer cells in a lab dish, leaving healthy cells untouched.
But it wasn’t so easy to turn a successful lab experiment into a treatment.
Druker is credited with the success of Gleevec in part because of what came next: years of lobbying and arm-twisting to get the drug company, now known as Novartis, to bring the drug to market.
On Friday afternoon, Druker and Mann reunited for the first time in nearly four years.
“I’m so glad to meet my life-saving hero,” Mann said to the box on the Zoom screen.