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THE ONE THING THEY DIDN’T HAVE
The investigators’ insistence on moving forward with the study was quickly legitimized. The ailing patient’s liver problems resolved and disappeared, and the patient continued as a participant. The dose increases resumed. No other patients came down with liver problems. Druker decided the time had come to enroll patients who were considered slightly more difficult to treat. The study was still restricted to chronic-stage patients, but now he wanted to see how the compound would work on those who had trickier white blood cell counts or other complications. Judy Orem fit the bill.
Orem, who grew up in Portland but had settled down with her husband Frank and raised two children in California, was 35 when her grandmother, May Belle Roscoe, died of leukemia in late 1979. Roscoe had been in and out of the hospital as her chemotherapy grew less effective. The previous April, she began hallucinating and demanded that Orem remove the flowers she’d brought her, believing them poisonous. She thought the nurses on the floor were conspiring against her. In a moment of lucidity, she decided to stop all medication. Her doctor warned her that she’d have about three days to live, that her blood counts would double, then triple, then quadruple, and she would die from an aneurism, which was exactly what happened. Her death certificate reported the cause as CML.
In 1990, Orem’s mother, May Belle’s daughter, was diagnosed with lymphoma, which upon a bone marrow biopsy turned out to be chronic lymphocytic leukemia, or CLL. Like CML, CLL begins in the bone marrow, but the cancer grows in the lymph cells, a different type of white blood cell than is affected in CML. Leukemia isn’t inherited. There are no genes passed down from one generation to the next that carry a leukemia trait. The Philadelphia chromosome is spontaneous, a so-called somatic mutation impossible to predict. Having a mother or grandmother with leukemia, or even both, has no bearing on the health of the daughter or granddaughter. Radiation exposure can increase risk, and the disease occurs more often in men than women and more often in people 65 and older. But a family history of CML has absolutely no bearing on whether or not an individual will develop the disease.
Still, a few years after her mother’s diagnosis Orem started worrying about her own health. The coincidence of having her mother and grandmother get blood cancers left her with the lurking fear that she would be next. In December 1995, during a routine physical, she asked her doctor to do a blood test. The next day, Orem’s doctor called to tell her she needed to see a specialist right away. Her white blood cell count was 66,000, more than 50,000 cells above the upper limit of the normal range. The news was devastating. The fact that she had been almost expecting this to happen to her did nothing to mollify the shock. Her arms and legs grew numb as she hung up the phone. She had leukemia. She was going to die from cancer.
“No, this is wrong,” her husband said when Orem told him. “You’re supposed to bury me, not me you.” They had met during intermission at a local theater’s Gilbert and Sullivan production when she was in high school and he was in college. Forty years later, he could not accept the thought of her dying first.
A bone marrow biopsy immediately confirmed her diagnosis. Orem had CML. The disease was still in chronic stage, with only 5 percent blast cells, the immature, malfunctioning white blood cells that increase as the disease progresses to the blast crisis stage. After Christmas passed, she started on interferon, giving herself shots at home each day, each syringe filled with the standard 3 million units of drug, an amount that could be increased if the drug’s benefit began to wane. She continued at her job managing the office at a program for vision-impaired students while she got the hang of managing her medicine, increasing from 3 million units to 6 million and eventually to 9 million. She joined a support group that her minister had recommended, finding a fellow CML patient who, then five years after her diagnosis, was able to reassure Orem that she would be fine. “That was the most important thing I ever heard,” Orem said.
Orem decided fairly early on that she did not want a bone marrow transplant, knowing the procedure could so easily go wrong. “I would rather be good for two or three years and face death than go through that,” she told her husband.
Over the next three years, Orem continued the interferon. The drug, which works by stimulating the immune system, had proved incredibly effective at lowering white blood cell counts in people with CML for a certain amount of time. But almost always, patients with CML would develop resistance, and the white counts would start rising. Or the side effects of the drug would prove too debilitating. Interferon, a synthetic drug derived from an immune system product, triggers an immune response in much the way that its naturally occurring counterpart activates our immune systems to fight a viral infection. The similarity shows in the side effects: When people take interferon, they often develop a fever, chills, and a paralyzing fatigue, like having a flu that lasts for months or even years at a time. The drug can also cause severe depression.
Orem lost weight and was often tired while she was taking interferon. She had such a strong aversion to smells that walking through a grocery store became torturous. Her short-term memory became uncharacteristically faulty; if she paused mid-sentence, she’d have a hard time picking up where she left off. As it was for so many CML patients, interferon became the defining hallmark of the disease. Many times, family members wouldn’t remember details about the cancer, but they would remember the decimation wrought by the drug: the tiredness, the persistent flu-like symptoms, the depression. But for Orem, as for so many CML patients, the drug was working well enough to continue, keeping her white blood cell counts at a safe level.
In 1997, Orem’s friend, who worked as a medical technologist in Portland, had heard a radio item about a doctor up the hill at OHSU who was studying a new drug for CML. Druker had received funding from the Leukemia and Lymphoma Society, a fact that bolstered the friend’s interest and confidence in his work. She had taken on the role of surrogate nurse for Orem and promptly called Druker’s office to give them Orem’s phone number. Orem and Druker talked, and he put her on his list of possible trial candidates. But, he explained to her, she wouldn’t be eligible for the study unless the interferon stopped working.
In June 1998, just as Bud Romine was taking the first human dose of STI-571, Orem’s medication stopped working. Her white blood cell counts were rising. Her doctor added a chemotherapy drug called ara-C to boost the power of interferon, but it didn’t work. Druker, who’d been keeping tabs on Orem’s condition, asked her to make the trip to Portland for a preliminary examination. She was eligible now, but her white blood cell counts had to reach 20,000 before she could enroll.
Until now, Druker had restricted the trial to those patients with slowly rising counts. He knew that if the drug didn’t work on someone whose blood counts were rising rapidly, then the patient would die very soon, and their enrollment would have been in vain. Plus, people with slowly rising blood counts are easier to manage when side effects arise. But with early indications that STI-571 was working, Druker felt bold. For him, that didn’t mean disclosing the news or letting himself believe what was happening; it meant enrolling more challenging cases.
That September, Druker told Orem she could enroll in January. He had no idea whether the drug would work for her. Orem’s doctor wasn’t crazy about the idea. “Let somebody else try it first,” she’d counseled. But Orem knew she didn’t have that long to wait. Frank encouraged her to go for it. He knew that going back on interferon was not an option, and he felt confident that the kind doctor up in Portland would stop the treatment if it was harming his wife. Believing she had about six months to live, she and Frank took their children and grandchildren on a trip to New Zealand. “It was a family memory trip,” said Orem. It was the kind of thing they had talked about doing when they retired.
After a close call with a dangerously high platelet count, Orem returned from New Zealand with blood cell counts that made her eligible to start the trial in
January 1999. Now allowed to enroll two patients each month, Druker also began treating a woman whose white blood cells counts had escalated from 20,000 to 125,000 in a single week. These two patients raised the stakes. Treating asymptomatic, easily managed patients with STI-571 was interesting enough. Could the drug work in a less stable situation?
Within three weeks, both patients’ blood counts had returned to normal. Orem was astonished. After all, it was only by chance that her friend had heard about the trial, and she had come very close to staring death in the face. By February 1999, just weeks after entering the trial, she was flush with energy. “At that point, I knew we had something that nobody had ever seen before,” said Druker. “It was just absolutely amazing.”
Still, it wasn’t enough to leave Druker feeling confident about the drug’s efficacy. Day after day, he looked after his patients. For months, they were all he thought about. He spent hours explaining the drug to them, listening to their concerns, responding as best he could, and opening his office to them for visits. But kept hidden behind his reassuring bedside manner was the persistent, gnawing question: Will this last? The question weighed on his mind nonstop, and he would not allow himself for a second to think the answer might be yes.
The hematologic responses continued. The cytogenetic responses—decreases in the number of cells expressing the Philadelphia chromosome—were also happening, though less rapidly. The effects were being sustained. The side effects followed the same consistent pattern, with nothing that was really intolerable. There was the initial stomach cramping that subsided, the pain as swollen bones settled back to normal, and the water retention that showed up in puffy eyes. The first few days on the drug were often difficult, but there were no persistent side effects requiring medical attention. It was the polar opposite of chemotherapy. “The problem that I was having was it was too good to be true,” said Druker. “If I told you I could give you a pill that was going to put your cancer in remission with no side effects, would you believe it?”
In April 1999, the protocol was amended again. The earliest trial patients, those who had enrolled at dose levels too low to help, were allowed back into the study at the effective dose of 300 milligrams. Bud Romine, patient number one, returned to OHSU. The minister from Bakersfield returned to Sawyers’s clinic. The drug worked in both of them.
A few weeks after Romine’s return, Druker was holding his usual clinic hours. From the start, he’d set aside time to meet with each phase I patient one-on-one. He wanted to make sure they had a chance to ask questions about the drug and to have their questions answered. One day in April, Druker opened his office door still carrying the knot in his stomach that the drug’s benefit might come to an end. He was dreading that moment, waiting to wake up from what had to be a dream. “I was trying to protect myself from getting too excited,” he said.
Bud Romine sat in a chair across from Druker. He was responding well to the higher dose of the drug. His blood counts were normalizing, and there were signs of a cytogenetic response, too. When Druker asked Romine how he was doing, the words tumbled out. The sword that had been hanging over his neck, waiting to fall, was now gone, Romine told him. He’d been waiting to die, and now he knew he was going to live. The next patient was Judy Orem. She talked to Druker about how she had resumed making plans for the future, her hope now restored. Another patient talked about how the black cloud over his head had been lifted. The drug had given him his life back.
A resistance inside Druker suddenly melted. For the first time, he allowed himself to believe in what was happening. As he watched the tears roll down their cheeks, Druker shed his own as he finally allowed himself to believe what was happening. “I realized they were so far ahead of me,” said Druker. “They already accepted that this drug had worked and had changed their lives.”
Before starting the trial, these patients had been told that there was nothing more that could be done, and that they should say their good-byes and tie up the loose ends of their lives because their time was limited. For Druker, that day in his clinic was a first glimpse at what this drug had really done: “It was to give these patients the one thing they didn’t have, and that was hope.”
For some of the phase I patients, their restored future came with a strange twist. Having been told they were going to die, some had sold everything, packed their lives up so as to leave nothing behind for anyone to deal with. They’d quit their jobs and spent their savings. Now, with life returning to normal, they were finding themselves at an unexpected loss. Still, no one complained. It was enough to be alive.
EARLIER IN 1999, Druker and the other investigators had flown to New Jersey to meet with Novartis executives at the company’s US headquarters. They wanted to expand the study to include blast crisis patients, the ones who had only weeks or months to live. In a typical phase I study design, these would have been the only patients enrolled. Novartis’s decision to focus on early-stage patients, though motivated by the company’s wish to get the fastest possible reading on the drug, had turned out to be ideal. But Druker and the others felt that if STI-571 could save lives, they needed to get it to the sickest patients. “None of us thought the drug would work in blast crisis,” said Sawyers, “but if it did, we needed to know.” Novartis agreed.
These late-stage patients began enrolling in the study in the spring of 1999. At OHSU, UCLA, and MD Anderson, patients confined to wheelchairs and attached to oxygen tanks were brought in by family members, all of them hoping for something that would help. No one was expecting a miracle, maybe just an extra month or two.
The responses began within a week after starting STI-571. Among several dying patients, white blood cell counts dropped, making room for restorative red blood cells to proliferate and heal the body. The color returned to their faces. They gained strength. They got up out of their wheelchairs and walked out of the hospital.
The results were mind-boggling, but they also set off alarm bells: This drug had to reach as many CML patients as possible as quickly as possible. The only way to do that was through a phase II clinical trial. The next step in development, the phase II study would enroll more patients at more sites, giving more people access to the drug. Phase I had room for dozens of patients at most; at phase II, hundreds of patients could enroll. The company could have a phase II study for chronic-stage patients and a phase II study for those with more advanced disease. And it was the next necessary step toward submitting the drug for FDA approval, which would allow for the widest release of the drug. The company would need at least a year of phase II data for the regulatory review, so there was no time to lose. In a normal clinical trial, phase II doesn’t begin until phase I ends. There is time to reflect on the data collected from those first patients, to decide on the best dose and best approach for phase II. But here, that approach made no sense. “Every dose was working after we got to 350 to 400 milligrams,” said Sawyers. “Why do we have to keep going? We’ve got to stop and do the phase II.”
In June 1999, as Sawyers, Talpaz, and Druker were on their way to Basel to begin planning the phase II study with Novartis executives, Sawyers received the results from one of his chronic-stage patient’s latest genetic tests. He stared at the numbers on the page: 0 out of 20 cells containing the Philadelphia chromosome. It was the first complete cytogenetic remission, a landmark moment for the trial. All of the cells with the cancer-driving genetic mutation had been eradicated. It was what everyone—the doctors, the patients, the company—had been hoping for. A lowering of blood counts was fantastic and a sign of improving health. A disappearance of the mutant gene was the promised land. Unable to reach Druker, who’d already boarded his flight, and unable to contain his excitement, Sawyers called the patient. “We knew we had a home-run drug at that point,” he said.
There were some disappointments. One or two early-stage patients did not respond to the drug, their blood counts failing to be reined in. The most dramatic failures were among the blast crisis patients who had been brought back f
rom the brink of death. After the sudden recoveries, many of them relapsed just as quickly. “The patient who was in the wheelchair, on oxygen, [and then] walking and dancing . . . two weeks later, [was] back in the wheelchair and on oxygen,” said Sawyers. The swiftness and severity of the relapse shocked Sawyers, especially in the wake of the elation over how well the drug was working.
Sawyers wanted to understand what was going wrong with the late-stage patients. Why would they respond so well at first and then relapse? What was different between those patients and the chronic-stage patients? “It was absolutely essential to understand the molecular basis for that,” he said. So, as he continued to run the phase I and then phase II studies, he also returned to the lab. Sawyers wondered if understanding the late-stage patients might also shed light on a rare few chronic-stage patients who had the Philadelphia chromosome but didn’t respond to STI-571 at all.
THE LOSSES, MAINLY concentrated in the blast crisis patients, were uncommon. For the most part, the positive responses were sustained. If the drug kept working, then people with CML could live normal, healthy lives simply by swallowing a tiny pill once a day.
Nobody used the word “cure,” though. The measurements charted in the phase I study were not proof that the drug would extend lives. The true clinical benefit of the drug could be gauged only by whether, and by how much, it prolonged life or reduced symptoms. Hematologic and cytogenetic responses were surrogate end points, stand-ins showing that the drug was doing things that should, in theory, extend survival and reduce suffering. Considering that it was the profusion of white blood cells that ultimately led to a CML patient’s demise, measuring those numbers along with the number of cells harboring the genetic mutation known to cause the disease seemed fairly reliable indicators of the drug’s benefit. But that wasn’t a cure. If a patient stopped taking the drug, the disease returned. More to the point, not enough time had elapsed to see if STI-571 helped CML patients live longer, healthier lives than they would have without the drug.
The Philadelphia Chromosome Page 21
