The Emperor of All Maladies: A Biography of Cancer (82 page)

But Druker was persistent.
In 1993, he left Boston
to start his own laboratory at the Oregon Health and Science University (OHSU) in Portland. Unyoked, at last, from the institution that had forestalled his collaboration, he immediately called Lydon to reestablish a connection. Lydon informed him that the Ciba-Geigy team had synthesized an even larger collection of inhibitors and had found a molecule that might bind
Bcr-abl
with high specificity and selectivity. The molecule was called CGP57148. Summoning all the nonchalance that he could muster—having learned his lessons in Boston—Druker walked over to the legal department at OHSU and, revealing little about the potential of the chemicals, watched as the lawyers absentmindedly signed on the dotted line. “
Everyone just humored me
,” he recalled. “No one thought even faintly that this drug might work.” In two weeks, he received a package from Basel with a small collection of kinase inhibitors to test in his lab.

The clinical world of CML was, meanwhile, reeling from disappointment to disappointment.
In October 1992, just a few months
before CGP57148 crossed the Atlantic from Lydon’s Basel lab into Druker’s hands in Oregon, a fleet of leukemia experts descended on the historic town of Bologna in Italy for an international conference on CML. The location was resplendent and evocative—Vesalius had once lectured and taught in these quadrangles and amphitheaters, dismantling Galen’s theory of cancer piece by piece. But the news at the meeting was uninspiring. The principal treatment for CML in 1993 was allogeneic bone marrow transplantation, the protocol pioneered in Seattle by Donnall Thomas in the sixties. Allo-transplantation, in which a foreign bone marrow was transplanted into a patient’s body, could increase the survival of CML patients, but the gains
were often so modest that massive trials were needed to detect them. At Bologna, even transplanters glumly acknowledged the meager benefits: “
Although freedom from leukemia
could be obtained only with BMT,” one study concluded, “a beneficial effect of BMT on overall survival could be detected only in a patients’ subset, and . . . many hundreds of cases and a decade could be necessary to evaluate the effect on survival.”

Like most leukemia experts, Druker was all too familiar with this dismal literature. “
Cancer is complicated
, everyone kept telling me patronizingly—as if I had suggested that it was not complicated.” The growing dogma, he knew, was that CML was perhaps intrinsically a chemotherapy-resistant disease. Even if the leukemia was initiated by that single translocation of the
Bcr-abl
gene, by the time the disease was identified in full bloom in real patients, it had accumulated a host of additional mutations, creating a genetic tornado so chaotic that even transplantation, the chemotherapist’s bluntest weapon, was of no consequence. The inciting
Bcr-abl
kinase had likely long been overwhelmed by more powerful driver mutations. Using a kinase inhibitor to try to control the disease, Druker feared, would be like blowing hard on a matchstick long after it had ignited a forest fire.

In the summer of 1993, when Lydon’s drug
arrived in Druker’s hands, he added it to CML cells in a petri dish, hoping, at best, for a small effect. But the cell lines responded briskly. Overnight, the drug-treated CML cells died, and the tissue-culture flasks filled up with floating husks of involuted leukemia cells. Druker was amazed. He implanted CML cells into mice to form real, living tumors and treated the mice with the drug. As with the first experiment, the tumors regressed in days. The response suggested specificity as well: normal mouse blood cells were left untouched. Druker performed a third experiment. He drew out samples of bone marrow from a few human patients with CML and applied CGP57148 to the cells in a petri dish. The leukemia cells in the marrow died immediately. The only cells remaining in the dish were normal blood cells. He had cured leukemia in the dish.

Druker described the findings in the journal
Nature Medicine.
It was a punchy, compact study—just five clean, well-built experiments—driving relentlessly toward a simple conclusion: “This compound may be useful in the treatment of
Bcr-abl
positive leukemias.” Druker was the first author and Lydon the senior author, with Buchdunger and Zimmermann as key contributors.

Druker expected Ciba-Geigy to be ecstatic about these results. This, after all, was the ultimate dream child of oncology—a drug with exquisite specificity for an oncogene in a cancer cell. But in Basel, Ciba-Geigy was in internal disarray. The company had fused with its archrival across the river, the pharma giant Sandoz, into a pharmaceutical behemoth called Novartis. For Novartis, it was the exquisite specificity of CGP57148 that was precisely its fatal undoing. Developing CGP57148 into a clinical drug for human use would involve further testing—animal studies and clinical trials that would cost $100 to $200 million. CML afflicts a few thousand patients every year in America. The prospect of spending millions on a molecule to benefit thousands gave Novartis cold feet.

Druker now found himself inhabiting an inverted world in which an academic researcher had to beg a pharmaceutical company to push its own products into clinical trials. Novartis had a plethora of predictable excuses: “
The drug . . . would never work
, would be too toxic, would never make any money.” Between 1995 and 1997 Druker flew back and forth between Basel and Portland trying to convince Novartis to continue the clinical development of its drug. “Either get [the drug] into clinical trials or license it to me. Make a decision,” Druker insisted. If Novartis would not make the drug, Druker thought he could have another chemist take it on. “In the worst case,” he recalled, “I thought I would make it in my own basement.”

Planning ahead, he assembled a team of other physicians to run a potential clinical trial of the drug on CML patients: Charles Sawyers from UCLA, Moshe Talpaz, a hematologist from Houston, and John Goldman from the Hammersmith Hospital in London, all highly regarded authorities on CML. Druker said, “I had patients in my clinic with CML with no effective treatment options remaining. Every day, I would come home from the clinic and promise to push Novartis a little.”

In early 1998, Novartis finally relented
. It would synthesize and release a few grams of CGP57148, just about enough to run a trial on about a hundred patients. Druker would have a shot—but only one shot. To Novartis, CGP57148, the product of its most ambitious drug-discovery program to date, was already a failure.

I first heard of Druker’s drug in the fall of 2002. I was a medical resident triaging patients in the emergency room at Mass General when an intern called me about a middle-aged man with a history of CML who had come in with a rash. I heard the story almost instinctively, drawing quick conclusions. The patient, I surmised, had been transplanted with foreign bone marrow, and the rash was the first blush of a cataclysm to come. The immune cells in the foreign marrow were attacking his own body—graft-versus-host disease. His prognosis was grim. He would need steroids, immunosuppressives, and immediate admission to the transplant floor.

But I was wrong. Glancing at the chart in the red folder, I saw no mention of a transplant. Under the stark neon light of the examining room when he held out his hand to be examined, the rash was just a few scattered, harmless-looking papules—nothing like the dusky, mottled haze that is often the harbinger of a graft reaction. Searching for an alternative explanation, I quickly ran my eye through his list of medicines. Only one drug was listed: Gleevec, the new name for Druker’s drug, CGP57148.
^*

The rash was a minor side effect of the drug. The major effect of the drug, though, was less visible but far more dramatic. Smeared under the microscope in the pathology lab on the second floor, his blood cells looked extraordinarily ordinary—“normal red cells, normal platelets, normal white blood cells,” I whispered under my breath as I ran my eyes slowly over the three lineages. It was hard to reconcile this field of blood cells in front of my eyes with the diagnosis; not a single leukemic blast was to be seen. If this man had CML, he was in a remission so deep that the disease had virtually vanished from sight.

By the winter of 1998, Druker, Sawyers, and Talpaz had witnessed dozens of such remissions. Druker’s first patient to be treated with Gleevec was a sixty-year-old retired train conductor from the Oregon coast. The patient had read about the drug in an article about Druker in a local newspaper. He had called Druker immediately and offered to be a “guinea pig.” Druker gave him a small dose of the drug, then stood by his bedside for the rest of the afternoon, nervously awaiting any signs of toxicity. By the end of the day there were no adverse effects; the man was still alive. “It was the first time that the molecule had entered a human body, and it could easily have created havoc, but it didn’t,” Druker recalled. “The sense of
relief was incredible.”

Druker edged into higher and higher
doses—25, 50, 85, and 140 mg. His cohort of patients grew as well. As the dose was escalated in patients, Gleevec’s effect became even more evident. One patient, a Portland woman, had come to his clinic with a blood count that had risen to nearly thirtyfold the normal number; her blood vessels were engorged with leukemia, her spleen virtually heaving with leukemic cells. After a few doses of the drug, Druker found her counts dropping precipitously, then normalizing within one week. Other patients, treated by Sawyers at UCLA and Talpaz in Houston, responded similarly, with blood counts normalizing within a few weeks.

News of the drug spread quickly. The development of Gleevec paralleled the birth of the patient chat room on the Internet; by 1999, patients were exchanging information about trials online. In many cases, it was patients who informed their doctors about Druker’s drug and then, finding their own doctors poorly informed and incredulous, flew to Oregon or Los Angeles to enroll themselves in the Gleevec trial.

Of the fifty-four patients
who received high doses of the drug in the initial phase I study, fifty-three showed a complete response within days of starting Gleevec. Patients continued the medicine for weeks, then months, and the malignant cells did not visibly return in the bone marrow. Left untreated, chronic myeloid leukemia is only “chronic” by the standards of leukemia: as the disease accelerates, the symptoms run on a tighter, faster arc and most patients live only three to five years. Patients on Gleevec experienced a palpable deceleration of their disease. The balance between normal and malignant cells was restored. It was an
unsuppuration
of blood.

By June 1999, with many of the original patients still in deep remissions, Gleevec was evidently a success. This success continues; Gleevec has become the standard of care for patients with CML. Oncologists now use the phrases “pre-Gleevec era” and “post-Gleevec era” when discussing this once-fatal disease. Hagop Kantarjian, the leukemia physician at the MD Anderson Cancer Center in Texas, recently summarized the impact of the drug on CML: “
Before the year 2000
, when we saw patients with chronic myeloid leukemia, we told them that they had a very bad disease, that their course was fatal, their prognosis was poor with a median survival of maybe three to six years, frontline therapy was allogeneic transplant . . . and there was no second-line treatment. . . . Today when I see a
patient with CML, I tell them that the disease is an indolent leukemia with an excellent prognosis, that they will usually live their functional life span provided they take an oral medicine, Gleevec, for the rest of their lives.”