Photo by Matt Hagen
“We’re working toward a future where we’ll be able to get most AML patients into complete remission and keep them there with therapies that are much less toxic than a total transplant”
- Dr. Fred Appelbaum
When Alan Schulkin was diagnosed with acute myeloid leukemia, or AML, his doctors gave him one shot at a cure: a bone marrow transplant at Fred Hutchinson Cancer Research Center.
The treatment eradicated Schulkin’s cancer but took a brutal toll. He endured side effects including liver and gastrointestinal problems, and also suffered graft-versus-host disease, or GVHD, a life-threatening condition that strikes when donated immune cells attack a patient’s body. Making matters worse, the drug Schulkin took to fend off GVHD left him so weak he couldn’t stand up without help and had to use hiking poles to walk.
Dr. Fred Appelbaum, who oversaw Schulkin’s care, has spent the past 35 years developing therapies that could help AML patients escape these side effects and potentially avoid transplants altogether.
“We’re working toward a future where we’ll be able to get most AML patients into complete remission and keep them there with therapies that are much less toxic than a total transplant,” Appelbaum said.
Precision therapies for AML
In 1970, Appelbaum was in medical school when he ran across Dr. E. Donnall Thomas’ first article describing bone marrow transplantation. Thomas pioneered the revolutionary technique, which transformed leukemia from an incurable condition into a disease with survival rates as high as 90 percent.
“I read that article and the treatment seemed like a miracle,” Appelbaum said. “I decided that’s what I wanted to do with my career.”
Seven years later, Appelbaum was researching marrow transplantation at the National Institutes of Health when Thomas called to offer him a job at Fred Hutch. Appelbaum’s initial assignment was to lead the first-ever study showing transplants were more effective than standard chemotherapy in AML patients. Fully 60 percent of transplant patients were cured versus 25 percent for those who received chemotherapy alone. Still, too many patients were dying.
“I started asking how we could improve transplantation’s results and if there might be alternatives that had fewer side effects,” Appelbaum said.
In the early ’80s, Appelbaum and his colleagues spearheaded new, more precise therapies that can disable leukemia cells without damaging the tissues around them. The therapies rely on antibodies that are genetically engineered to zero in on and attach to leukemia cells. Appelbaum and his colleagues bind radioactive or poisonous molecules to these antibodies, which then deliver the cell-killing payload directly to leukemia cells. One poisonous molecule induced complete remission in 30 percent of patients who were not candidates for conventional chemotherapy.
Now Appelbaum is investigating another potential game-changer: a drug that could cripple AML cells by blocking how they absorb cholesterol, which the cells use to repair themselves. In a phase 2 study, the drug showed a 65 percent response rate when given to patients along with chemotherapy. It is now headed for phase 3 trials that examine whether it’s effective in more people.
Photo by Robert Hood
Improving the transplant process
Transplants may always be necessary for some patients, in part because some leukemia cells are hard targets even for the most precise therapies.
One arm of Appelbaum’s research aims to improve the transplant process. Members of his team are using genetic tests to identify the best matches between patients and bone marrow donors who aren’t related to them. This could help more patients find donors and could reduce a patient’s odds of contracting GVHD.
Appelbaum is also trying to change the AML treatment protocol so patients undergo a full spectrum of genetic tests as soon as they’re diagnosed. These tests help match patients with potential bone marrow donors. Right now, patients only get the tests if chemotherapy doesn’t eliminate their cancer, but that’s often too late.
“Fewer than 10 percent of patients who need transplants early in their course get them in time,” Appelbaum said.
Schulkin, now 58, has been cancer-free for almost four years and biked 50 miles in support of the Hutch’s Obliteride fundraiser in August. He keeps a keen interest in Appelbaum’s research.
“It’s really great to know he’s at the Hutch working on this disease so future patients will have an easier time,” he said.
A new challenge
Appelbaum, 67, was recently elected to the Institute of Medicine – one of his field’s highest honors – and named executive vice president and deputy director of the Hutch. He’ll continue leading innovative research and is now even more involved in shaping Fred Hutch’s strategic direction – and in helping the Hutch find creative new ways to fund its work.
“Most of our funding is federal and that’s proving risky for growth,” he said.
Appelbaum is grateful for the opportunity to advance an institution that has been so pivotal to his career.
“The Hutch is exactly – and I mean exactly – the right environment for me,” he said. “I couldn’t have accomplished anything like I have without the help of my amazing colleagues here. This is my dream job.”
Write to Andy Koopmans at firstname.lastname@example.org