He also spent time staring at his office wall. When the phase I patients started responding to STI-571, Druker asked his group to send him photos of themselves doing the things they loved to do. “Let’s make this believable,” he told his patients. “Give me pictures I can show.” He tacked them up on his office wall as evidence to any visitor of what was happening. A patient who’d entered the study crippled by fatigue was gardening. Judy Orem sent a photo that showed her planting a tree. Another was surrounded by her grandchildren. Stuck once again with an excruciating wait, the wall gave Druker the will to persevere.
Finally, as promised, by the summer of 2000, enough of the drug had been produced to support full enrollment of the phase II study for chronic-stage patients. At last, the floodgates opened. And patients rushed through. The phase II study for chronic phase patients—those who typically had four to six years to live—enrolled 532. The phase II study for accelerated phase patients—with about one to two years to live—enrolled 235. The phase II for blast crisis patients—who had just months to live—enrolled 260. “Could it have happened faster? Sure,” Sawyers acknowledged. But Novartis “did the right thing in the end.”
SINCE DRUKER’S ARRIVAL in 1993, OHSU had gone from having a small cancer center where only people from the area sought care to a hub of leukemia care, with patients flying in from around the country and the world. With the three phase II studies now fully open, it was time to add another doctor to the overtaxed clinical team, which still consisted of Carolyn Blasdel, two other research nurses, and Michael O’Dwyer. Druker needed another clinician to handle the patient load, and Michael Mauro was the ideal candidate. A medical doctor just finishing up a fellowship at New York Presbyterian, Mauro was trying to figure out his next steps when he saw a job posting for a clinical hematologist. He knew of Druker’s work and had been in the audience at the 1999 plenary session at ASH. Mauro assumed that there would be scores of people like him vying for the chance to work with Druker on these trials, and was shocked to receive a call from Druker, who wanted to interview him for the position. “He just wanted to talk,” recalled Mauro. They discussed leukemia research, Mauro’s experience, and running, an interest they shared. He got the job.
By July 2000, Mauro and his wife, a designer, had moved to Portland. With barely a moment to take in his new surroundings, Mauro was immersed in the clinic. From the start, he was seeing trial patients, consulting with new patients about trials they could enroll in near their homes, monitoring all the test results for the clinical trials, and accepting invitations to lecture across the country and internationally. “And this was all in a matter of the first year or two,” said Mauro, a lithe man with wavy brown hair and green eyes. Less than two months after starting, he was submitting research to ASH. Like Druker and the rest of the team, he worked nights and weekends, doing everything he could to care for patients and spread the word about the drug. The relentless schedule was, as he puts it, “good stressful,” Mauro said. “I wouldn’t trade it for the world.”
Mauro already knew the unprecedented physical responses to STI-571 but wasn’t expecting the emotional response that patients had for it. The patients treated their medicine like gold. “They cherished it, they defended it with their life.” Mauro remembered one couple saying they’d taken the jewelry out of their safe to make room for the bottles of pills.
As Druker, Sawyers, and Talpaz had, Mauro began amassing his own inspiring stories. One patient he met early on had developed delirium from interferon and was being treated for a mental illness as well as cancer. She started taking STI-571 and underwent a complete reawakening. She returned to living independently and to being with her children and grandchildren.
The phase III trial did not lag far behind. Dubbed IRIS, short for “International Randomized Study of Interferon and STI-571,” this study was the first one to allow newly diagnosed patients who had not yet started any other treatment for CML access to STI-571. Even though the company could submit the drug for FDA review based on phase II, the randomized study comparing STI-571 with interferon had to get started. Novartis wanted the drug available to newly diagnosed patients as soon as possible if the evidence supported that use. The clinicians were equally eager because they knew that patients should have access to STI-571 the moment they’d been diagnosed, not after they’d suffered through interferon. By the fall of 2000, Novartis had the still-ongoing phase I trial, three phase II studies, and a large phase III trial open to enrollment of just over 1,000 patients.
But there was still more to go. After the phase II studies had reached their target accrual numbers, plenty of CML patients around the world were still taking interferon. Every CML patient whose disease had progressed on interferon wanted the drug. STI-571 was no longer considered an altruistic option to advance medical knowledge. It was a medication that was almost certain to help. But these patients would not be able to get into the phase III study because it was reserved for patients who had not taken any other medications for CML. Yet they couldn’t get in the phase II because all the study sites were full. Sawyers remembers returning to the office after a long day at the clinic to a stack of messages from people around the world wanting to get the drug. “You felt that it was your obligation to get them some [STI-571] because you knew it would help them,” he said.
Toward the end of 2000, the company launched yet another trial, this one called “expanded access.” This study allowed individuals with CML who’d stopped responding to interferon or could not take it at all and were ineligible for a bone marrow transplant to get STI-571 through one of the phase II investigators without enrolling in one of the previously established trials. The process was laborious; the paperwork required for each patient amounted to a mini–clinical trial for each enrollment. But now, almost any CML patient who wanted the drug could get it. The only restrictions were distance—patients still had to be willing to travel to one of the trial sites periodically—and the long amount of time it took for the staff to enroll each patient; they seemed to always be behind.
By the end of 2000, trial centers existed in twenty-eight centers across Europe and the United States—fourteen countries overall—and more than 3,000 CML patients were being treated with STI-571 worldwide. People from countries without an official trial site traveled long distances for an initial appointment with a study investigator, continuing treatment under the care of their local oncologist. The waiting lists were shrinking, and the responses were lasting. With more than 70,000 CML sufferers worldwide, there were still plenty of patients waiting to benefit from the drug, but the drug was still experimental. Some conservative-minded patients and doctors preferred to wait for FDA approval. Others still hadn’t heard about it. But by and large, STI-571 was making its way to those who wanted it.
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PUTTING IT IN WRITING
In late 1999, Judy Orem started the STI Gazette, a monthly newsletter that served as yet another glue for the OHSU phase I trial group. Orem was continuing to respond to the drug. She and her husband had decided to stay in Portland, where they’d both grown up, after her first three-month clinical trial commitment finished. But with others returning to their homes, the clubhouse atmosphere of the OHSU phase I group started to wane. “It was a sudden loss,” said Orem, who’d grown accustomed to long conversations with patients who’d started the trial around the same time she did.
The Gazette was a way to keep the information flowing and the family spirit alive. “I sent it out every month so that people, when they left the study, still would feel a part of it,” she said. Orem had taken on a kind of mother-hen role, organizing events and making sure people knew the latest news about the drug. Each issue had a personal message from Druker or another doctor with insights about how STI-571 had come to be, the expansion of the trials program, responses to questions from patients, and, later, the investigation of the drug in the treatment of other cancers. The newsletter, paid for and printed by the Leukemia and Lymphoma Societ
y, was also a place to collect patients’ stories and updates. By now there was a growing sense among the phase I enrollees that they were in the midst of something special. That was true for Druker’s patients, but also for people around the world who, through the newsletter, could express their sense that they were part of something bigger than themselves. Sending in a story to the newsletter wasn’t just a way to communicate how meaningful the drug was to each individual. It was a way to document a miracle.
A patient named Dori wrote of her week spent hiking in eastern Oregon. Another patient announced a long-awaited return to her pottery work. One issue included a recipe, another joked about a tattoo revealed during a bone marrow biopsy, and yet another wondered about the owner of an Arizona license plate that read “STI-571.” There was information about organizations that provided cheap or free flights to cancer patients needing to reach faraway treatment centers, other practical advice and insights, and an ongoing chronicle of the progress of the drug through the clinical trials system. Each otherwise mundane tidbit shared was tinged with the awareness that it would not have happened if not for the drug.
Then there were the personal histories. The newsletter printed first names only, but everyone knew who was who. Sandy, from London, had been diagnosed when she was already in the accelerated stage of the disease. She was about to get a bone marrow transplant when she was accepted on a trial. Three months later, the disease had reverted to the chronic stage.
Gerry had been diagnosed after inexplicable bruises suddenly appeared on his thighs. His white blood cells were 100 percent positive for the Philadelphia chromosome when he was diagnosed. After three years on interferon, he slept twenty-two hours a day. He entered the STI-571 trial as part of the 85-milligram cohort and returned later to treatment with 300, then 400, then 600 milligrams. The drug was working. “It’s going great guns,” he wrote. His white blood cells and platelets were under control, and the percentage of Philadelphia chromosome–positive cells was steadily diminishing.
Rose was taking chemotherapy and interferon for CML when she heard about the trial on television. “Leukemia didn’t make me sick, just the medicines,” she wrote in the Gazette. By July 1999, after four months on STI-571, her blood and bone marrow were clear of the mutant gene. High medical bills and her inability to work had left her destitute. She and her husband lost their house and car and filed for bankruptcy. But, she wrote, “Now I can look forward to playing with my grandchildren.”
Lucille entered blast crisis in July 1999, four years after being diagnosed with CML during a routine checkup. She assumed she’d be dead within six months when she started STI-571. Three months later, she was traveling to her daughter for Thanksgiving to see her and her own grandchildren and great-granddaughter. “I’m feeling well,” she wrote. “I have so much to be thankful for.”
Linda’s husband was on the phase I trial at OHSU, and she wrote about how the drug had changed her life. “Now I can get really pissed off at my kids . . . without being concerned that I should be a bit more lenient because their father has cancer. . . . I can look at photos from a trip we took to London before the diagnosis—and not start crying. . . . I can stop calculating survival statistics.”
Mark’s wife was diagnosed in 1995. Interferon worked wonders for a while, though it left her tired and with flu-like symptoms lasting four years, including a persistent fever of 102 degrees. He’d cut down on work to help care for their children, their home, and his wife, including giving her the painful injections of medicine each day. He had read about STI-571 online, and they’d met with Druker when interferon was still working, keeping her white blood cell counts in check, though she felt miserable. Eventually, she developed heart damage and had to stop the interferon. She enrolled in an STI-571 trial, and within a few months her blood work was completely normal.
Eduardo was the first Brazilian to take STI-571. Five months after starting treatment, he was playing tennis and swimming several times a week and had been featured in a Brazilian magazine as “the local STI case,” helping to spread the word to other CML patients in his country.
Then there was LaDonna, who wrote her story for the June 2000 issue of the STI Gazette: “In February my funeral was arranged. I said goodbye to my children and family. I was very tired of being sick and looked forward to peace in death. I could not tolerate interferon[,] and hydrea did little but give me stomach distress. I couldn’t eat or hold anything down.” On the way to see LaDonna at the hospital, her husband picked up a local paper. His eyes fell upon an item about Druker and the STI-571 study. On February 16, 2000, LaDonna entered the phase II study for accelerated stage CML patients.
“I came in a wheelchair and could barely walk,” LaDonna wrote. “I did not want to do the study. My family and doctor insisted. My Philadelphia chromosome was 97%. My white count was 220,000. My spleen was very painful and large (29 cm). I was on pain patches and couldn’t sit up. Four months later, my white count is normal, no blasts, and the Philadelphia chromosome is 1%! I’m able to function and have fun with my family.” Her spleen shrank to 6 centimeters, and she was no longer in pain.
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Like so many of the profiles, LaDonna’s “Message of Hope” ended with gratitude: “Thank goodness for Dr. Druker and STI-571. Every day is a gift from God.”
Expressions of thanks to Druker were woven throughout every issue of the STI Gazette. “Kiss Druker. Hug Druker. We love you, Dr. Druker,” two patients wrote. They swapped ideas for T-shirts bearing his name to wear when they were interviewed, “just to keep this modest humanitarian in everyone’s mind as the man who made all this possible,” someone wrote. In June 2000, one patient reported that she had planted a tree in his name in the Millennium Forest outside Jerusalem. Again and again, patients thanked him, Carolyn Blasdel, and the rest of the staff. Online, on the message boards, the sentiments were the same. As far as they were concerned, Druker had saved their lives.
With all of these miracle stories, the public began to take an interest. The media attention surrounding the ASH conference of 1999 had brought the drug into the public consciousness. In Oregon, local papers continued covering Druker’s work, though national coverage died down as the phase II trial got under way. Then, at the end of 2000, almost a year after the phase II studies had been fully launched, People magazine decided to do a profile of the doctor behind the cancer wonder drug. The story was assigned to Alexandra Hardy, the same writer who’d interviewed Druker five years earlier for the Associated Press.
Druker remembered her. He remembered that she had asked him when the clinical trials would start for this compound that had proved so interesting in the laboratory. He also remembered her boots and hair. After the interview for People, Hardy and Druker developed a friendship. It turned out that they belonged to the same gym. Hardy’s story was published February 19, 2001. A few weeks after that, said Druker, “I got the nerve to ask her out.”
Hardy had found Druker to be a tough profile subject. Everyone she interviewed kept praising him, and as a journalist that made her nervous. One of his patients told Hardy that Druker was “right up there, right under God.” The stories and accolades were too fawning for a journalistic profile. She searched for one person who could offer some balance and make this doctor seem a bit more real. She never found such a source during her interviews. Afterward, however, she did. “I became that person,” she said. As they fell for each other, this doctor who was so idolized by his patients became human to her. Finally he had someone who could know him outside of the hospital, who could see him not just as a doctor but as a regular, imperfect person—a man who often lacks diplomacy when expressing his opinions, and who gets cranky when he’s hungry—and as she came to see that imperfect person, she found she liked him all the more.
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A TRUCKLOAD OF DATA
The results seen in phase I continued strongly in phase II. In the study of accelerated stage CML (more than 15 percent blast cells),
149 out of 181 patients had a positive hematologic response. In 96 of those patients, red and white blood cell counts returned to normal. Cells with the Philadelphia chromosome began disappearing. One year after starting treatment, 43 of 181 patients had a major cytogenetic response, with 30 patients showing no sign of the mutant chromosome.
The story for the phase II trial of blast crisis patients (30 percent or more blast cells) was the same. Here, the responses were somewhat less dramatic; these were, after all, the sickest patients, and the investigators knew from the start that even those who responded vigorously to the drug at first could relapse just as fast. Of the 229 patients, 119 had some kind of positive hematologic response. Sixty-four patients returned to chronic-stage CML, and in thirty-five, blood counts normalized completely. The responses lasted an average of ten months, with some lasting more than a year. These were patients who, like LaDonna, had either decided what kind of burial they wanted or were too sick to think about it. About fifteen of the blast crisis patients had no mutant genes when the study concluded.
The phase II trials of blast crisis and accelerated stage patients tested two dose levels, 400 milligrams per day and 600 milligrams per day. Both worked, but when the investigators analyzed the data, they noticed that patients who took the higher dose tended to respond better and live longer. Higher doses, they could see, might be the best approach for patients with more advanced disease.
In the phase II trial of chronic CML patients, 532 patients had taken 400 milligrams of STI-571 for an average of 254 days when the data were analyzed. About 250 patients had a dramatic drop in the number of cells containing the mutant gene. In all but seventeen patients enrolled in the trial, the disease was halted.
The Philadelphia Chromosome Page 24