In Treatment for Leukemia, Glimpses of the Future

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http://www.nytimes.com/2012/07/08/he...he-future.html

In Treatment for Leukemia, Glimpses of the Future

By GINA KOLATA
Published: July 7, 2012

ST. LOUIS — Genetics researchers at Washington University, one of the world’s leading centers for work on the human genome, were devastated. Dr. Lukas Wartman, a young, talented and beloved colleague, had the very cancer he had devoted his career to studying. He was deteriorating fast. No known treatment could save him. And no one, to their knowledge, had ever investigated the complete genetic makeup of a cancer like his.

So one day last July, Dr. Timothy Ley, associate director of the university’s genome institute, summoned his team. Why not throw everything we have at seeing if we can find a rogue gene spurring Dr. Wartman’s cancer, adult acute lymphoblastic leukemia, he asked? “It’s now or never,” he recalled telling them. “We will only get one shot.”

Dr. Ley’s team tried a type of analysis that they had never done before. They fully sequenced the genes of both his cancer cells and healthy cells for comparison, and at the same time analyzed his RNA, a close chemical cousin to DNA, for clues to what his genes were doing.

The researchers on the project put other work aside for weeks, running one of the university’s 26 sequencing machines and supercomputer around the clock. And they found a culprit — a normal gene that was in overdrive, churning out huge amounts of a protein that appeared to be spurring the cancer’s growth.

Even better, there was a promising new drug that might shut down the malfunctioning gene — a drug that had been tested and approved only for advanced kidney cancer. Dr. Wartman became the first person ever to take it for leukemia.

And now, against all odds, his cancer is in remission and has been since last fall.

While no one can say that Dr. Wartman is cured, after facing certain death last fall, he is alive and doing well. Dr. Wartman is a pioneer in a new approach to stopping cancer. What is important, medical researchers say, is the genes that drive a cancer, not the tissue or organ — liver or brain, bone marrow, blood or colon — where the cancer originates.

One woman’s breast cancer may have different genetic drivers from another woman’s and, in fact, may have more in common with prostate cancer in a man or another patient’s lung cancer.

Under this new approach, researchers expect that treatment will be tailored to an individual tumor’s mutations, with drugs, eventually, that hit several key aberrant genes at once. The cocktails of medicines would be analogous to H.I.V. treatment, which uses several different drugs at once to strike the virus in a number of critical areas.

Researchers differ about how soon the method, known as whole genome sequencing, will be generally available and paid for by insurance — estimates range from a few years to a decade or so. But they believe that it has enormous promise, though it has not yet cured anyone.

With a steep drop in the costs of sequencing and an explosion of research on genes, medical experts expect that genetic analyses of cancers will become routine. Just as pathologists do blood cultures to decide which antibiotics will stop a patient’s bacterial infection, so will genome sequencing determine which drugs might stop a cancer.

“Until you know what is driving a patient’s cancer, you really don’t have any chance of getting it right,” Dr. Ley said. “For the past 40 years, we have been sending generals into battle without a map of the battlefield. What we are doing now is building the map.”

Large drug companies and small biotechs are jumping in, starting to test drugs that attack a gene rather than a tumor type.

Leading cancer researchers are starting companies to find genes that might be causing an individual’s cancer to grow, to analyze genetic data and to find and test new drugs directed against these genetic targets. Leading venture capital firms are involved.

For now, whole genome sequencing is in its infancy and dauntingly complex. The gene sequences are only the start — they come in billions of small pieces, like a huge jigsaw puzzle. The arduous job is to figure out which mutations are important, a task that requires skill, experience and instincts.

So far, most who have chosen this path are wealthy and well connected. When Steve Jobs had exhausted other options to combat pancreatic cancer, he consulted doctors who coordinated his genetic sequencing and analysis. It cost him $100,000, according to his biographer. The writer Christopher Hitchens went to the head of the National Institutes of Health, Dr. Francis Collins, who advised him on where to get a genetic analysis of his esophageal cancer.

Harvard Medical School expects eventually to offer whole genome sequencing to help cancer patients identify treatments, said Heidi L. Rehm, who heads the molecular medicine laboratory at Harvard’s Partners Healthcare Center for Personalized Genetic Medicine. But later this year, Partners will take a more modest step, offering whole genome sequencing to patients with a suspected hereditary disorder in hopes of identifying mutations that might be causing the disease.

Whole genome sequencing of the type that Dr. Wartman had, Dr. Rehm added, “is a whole other level of complexity.”

Dr. Wartman was included by his colleagues in a research study, and his genetic analysis was paid for by the university and research grants. Such opportunities are not available to most patients, but Dr. Ley noted that the group had done such an analysis for another patient the year before and that no patients were being neglected because of the urgent work to figure out Dr. Wartman’s cancer.

“The precedent for moving quickly on a sample to make a key decision was already established,” Dr. Ley said.

Ethicists ask whether those with money and connections should have options far out of reach for most patients before such treatments become a normal part of medicine. And will people of more limited means be tempted to bankrupt their families in pursuit of a cure at the far edges?

“If we say we need research because this is a new idea, then why is it that rich people can even access it?” asked Wylie Burke, professor and chairwoman of the department of bioethics at the University of Washington. The saving grace, she said, is that the method will become available to all if it works.

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A Life in Medicine

It was pure happenstance that landed Dr. Wartman in a university at the forefront of cancer research. He grew up in small-town Indiana, aspiring to be a veterinarian like his grandfather. But in college, he worked summers in hospitals and became fascinated by cancer. He enrolled in medical school at Washington University in St. Louis, where he was drawn to research on genetic changes that occur in cancers of the blood. Dr. Wartman knew then what he wanted to do — become a physician researcher.

Those plans fell apart in the winter of 2002, his last year of medical school, when he went to California to be interviewed for a residency program at Stanford. On the morning of his visit, he was nearly paralyzed by an overwhelming fatigue.

“I could not get out of bed for an interview that was the most important of my life,” Dr. Wartman recalled. Somehow, he forced himself to drive to Palo Alto in a drenching rain. He rallied enough to get through the day.

When he returned to St. Louis, he gave up running, too exhausted for the sport he loved. He started having night sweats.

“I thought it might be mono,” he said. “And I thought I would ride it out.”

But then the long bones in his legs began to hurt. He was having fevers.

He was so young then — only 25 — and had always been so healthy that his only doctor was a pediatrician. So he went to an urgent care center in February 2003. The doctor there thought his symptoms might come from depression, but noticed that his red and white blood cell counts were low. And Lukas Wartman, who had been fascinated by the biology of leukemia, began to suspect he had it.

“I was definitely scared,” he said. “It was so unreal.”

The next day, Mr. Wartman, who was about to graduate from Washington University’s medical school, went back there for more tests. A doctor slid a long needle into his hip bone and drew out marrow for analysis.

“We looked at the slide together,” Dr. Wartman said, recalling that terrible time. “It was packed with leukemia cells. I was in a state of shock.”

Dr. Wartman remained at the university for his residency and treatment: nine months of intensive chemotherapy, followed by 15 months of maintenance chemotherapy. Five years passed when the cancer seemed to be gone. But then it came back. Next came the most risky remedy — intensive chemotherapy to put the cancer into remission followed by a bone-marrow transplant from his younger brother.

Seven months after the transplant, feeling much stronger, he went to a major cancer meeting and sat in on a session on his type of leukemia. The speaker, a renowned researcher, reported that only 4 or 5 percent of those who relapsed survived.

“My stomach turned,” Dr. Wartman said. “I will never forget the shock of hearing that number.”

But his personal gauge of recovery — how far he could run — was encouraging.

By last spring, three years after his transplant, Dr. Wartman was running six to seven miles every other day and feeling good. “I thought maybe I would run a half marathon in the fall.”

Then the cancer came back. He remembered that number, 4 or 5 percent, for patients with one relapse. He had relapsed a second time.

This time, he said, “There is no number.”

His doctors put him on a clinical trial to try to beat the cancer with chemotherapy and hormones. It did not work.

They infused him with his brother’s healthy marrow cells, to no avail.

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A Clue in RNA

Dr. Wartman’s doctors realized then that their last best hope for saving him was to use all the genetic know-how and technology at their disposal.

After their month of frantic work to beat cancer’s relentless clock, the group, led by Richard Wilson and Elaine Mardis, directors of the university’s genome institute, had the data. It was Aug. 31.

The cancer’s DNA had, as expected, many mutations, but there was nothing to be done about them. There were no drugs to attack them.

But the other analysis, of the cancer’s RNA, was different. There was something there, something unexpected.

The RNA sequencing showed that a normal gene, FLT3, was wildly active in the leukemia cells. Its normal role is to make cells grow and proliferate. An overactive FLT3 gene might be making Dr. Wartman’s cancer cells multiply so quickly.

Even better, there was a drug, sunitinib or Sutent, approved for treating advanced kidney cancer, that inhibits FLT3.

But it costs $330 a day, and Dr. Wartman’s insurance company would not pay for it. He appealed twice to his insurer and lost both times.

He also pleaded with the drug’s maker, Pfizer, to give him the drug under its compassionate use program, explaining that his entire salary was only enough to pay for 7 ½ months of Sutent. But Pfizer turned him down too.

As September went by, Dr. Wartman was getting panicky.

“Every day is a roller coaster,” he said at the time, “and everything is up in the air.”

Desperate to try the drug, he scraped up the money to buy a week’s worth and began taking it on Sept. 16. Within days, his blood counts were looking more normal.

But over dinner at a trendy St. Louis restaurant, he picked at his chicken and said he was afraid to hope.

“Obviously it’s exciting,” he said. “But Sutent could have unanticipated effects on my bone marrow.” Maybe his rising red blood cell counts were just a side effect of the drug. Or maybe they were just a coincidence.

“It’s hard to say if I feel any different,” Dr. Wartman said.

And the cost of the drug nagged at him. If it worked, how long could he afford to keep taking it?

The next day, a nurse at the hospital pharmacy called with what seemed miraculous news: a month’s supply of Sutent was waiting for Dr. Wartman. He did not know at the time, but the doctors in his division had pitched in to buy the drug.

Two weeks later, his bone marrow, which had been full of leukemia cells, was clean, a biopsy showed.

Still, he was nervous. The test involved taking out just a small amount of marrow. Cancer cells could be lurking unseen.

The next test was flow cytometry, which used antibodies to label cancer cells. Again, there were no cancer cells.

But even flow cytometry could be misleading, Dr. Wartman told himself.

Finally, a yet more sensitive test, called FISH, was done. It labels cancer cells with fluorescent pieces of DNA to identify leukemia cells. Once again, there were none.

“I can’t believe it,” his awe-struck physician, Dr. John DiPersio, told him.

Dr. Wartman, alone in his apartment, waited for his partner, Damon Berardi, to come home from work. That evening, Mr. Berardi, a 31-year-old store manager, opened the door with no idea of Dr. Wartman’s momentous news. To his surprise, Dr. Wartman was home early, waiting in the kitchen with champagne and two flutes he had given Mr. Berardi for Christmas. He told Mr. Berardi he should sit down.

“My leukemia is in remission,” he said. The men embraced exultantly, and Dr. Wartman popped open the champagne.

“I felt an overwhelming sense of relief and a renewed vision of our future together,” Mr. Berardi said. “There were no tears at that moment. We had both had cried plenty. This was a moment of hope.”

Hunches and Decisions

Dr. Wartman and his doctors had fateful decisions to make, with nothing but hunches to guide them. Should he keep taking Sutent or have another bone-marrow transplant now that he was in remission again?

In the end, Dr. DiPersio decided Dr. Wartman should have the transplant because without it the cancer might mutate and escape the Sutent.

Meanwhile, Pfizer had decided to give him the drug. Dr. Wartman has no idea why. Perhaps the company was swayed by an impassioned plea from his nurse practitioner, Stephanie Bauer.

Dr. Wartman’s cancer is still gone, for now, but he has struggled with a common complication of bone-marrow transplants, in which the white blood cells of the transplanted marrow attack his cells as though they were foreign. He has had rashes and felt ill. But these complications are gradually lessening, and he is back at work in Dr. Ley’s lab.

His colleagues want to look for the same mutation in the cancer cells of other patients with his cancer. And they would like to start a clinical trial testing Sutent to discover whether the drug can help others with leukemia, or whether the solution they found was unique to Lukas Wartman.

Dr. Wartman himself is left with nagging uncertainties. He knows how lucky he is, but what does the future hold? Can he plan a life? Is he cured?

“It’s a hard feeling to describe,” he said. “I am in uncharted waters.”

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Pity it could take as long as a decade.

[porchrat]

Problem comes when you need to suppress a gene that does something truly important. These sorts of treatments are not easily targeted.

This sort of genomic analysis in combination with a proteomic analysis and gene therapy will IMO be the treatment of the future for many diseases. Right now this sort of analysis is beyond the resources of most people but the duration of the analysis and the costs are falling very fast.