Unique set of tissue samples ‘ready to teach’ lessons about pediatric leukemia

Hutch-based repository leads to lifesaving treatments for young cancer patient
Hornish family
Austin, Havianna, Suzanne and Tom Hornish on their annual family July 4th sailing celebration, 2017. Photo courtesy of the Hornish family

Seattle shines in the summer. Sightseers come for good food, pleasant weather and the great outdoors. When the Hornish family arrived in Seattle eight years ago, they were prepared for a short vacation. Then their 6-year-old daughter, Havianna, was diagnosed with acute myeloid leukemia.

“We left in July 2009, with the intent of being gone for a week,” recalled Suzanne Hornish, Havianna’s mom. “We didn’t go home for a whole year.”

Havianna had been feeling unwell as the family drove up from their home in San Diego. When her pallor and fatigue only lingered, Suzanne and her husband, Tom, and their 9-year-old son, Austin, took Havianna to Seattle Children’s Hospital to be evaluated. Once the doctors recognized that the rising first-grader had leukemia, they admitted her straightaway.

The news sent Tom and Suzanne’s heads spinning. It took three days for them to “start thinking again,” said Tom. They faced a wrenching choice: stay in a strange city or return home. When they reached out to family and friends with medical connections, the response was overwhelming.

“We had probably 20 to 30 people who said, ‘Stay where you’re at, the Hutch is the right place,’” he said.

What they didn’t realize at the beginning of their odyssey was that Seattle is an epicenter of pediatric AML research. Havianna would benefit not only from a bone marrow transplant — a Nobel Prize–winning advance pioneered by Fred Hutch’s Dr. E. Donnall Thomas — but also from a then-new treatment made possible by a unique collection of frozen tissue samples housed at Fred Hutchinson Cancer Research Center.

This collection is the largest repository of pediatric AML tissue samples in the world. Dr. Soheil Meshinchi, a Fred Hutch and Seattle Children’s pediatric oncologist, manages the bank for the Children’s Oncology Group (COG), a National Cancer Institute–supported clinical trial group that is the world’s largest organization devoted exclusively to studying childhood cancer. Its pediatric AML tissue bank stores 40,000 living specimens from roughly 6,000 patients treated in COG trials in the U.S., Canada, Australia and New Zealand.

Already 40 years in the making, this resource is available to scientists worldwide who are aiming to delve ever deeper into the intricacies of childhood AML. It represents scientists’ hope for improved treatment. And it represents parents’ hope for a better future for their children and for all families facing AML.

“As one of our patient families said, ‘[The children] are alive in there,’” said Meshinchi. “And they’re ready to teach us about their leukemia.”

Dr. Soheil Meshinchi
Dr. Soheil Meshinchi Bo Jungmayer / Fred Hutch News Service

A rare but complex disease

AML is a tricky disease to get a handle on, especially in children. Making up just over 1 percent of cancer cases, AML is already rare: A little more than 21,000 new cases are expected in 2017. Fewer than 10 percent of patients with AML are children.

The average age for AML patients is 67, and scientists focus on these older individuals when developing and testing new therapies. But Meshinchi doesn’t believe that a trickle-down approach benefits kids with this disease. AML cells from different patients may look the same under the microscope, but this similarity is misleading, said Meshinchi. By comparing the molecular characteristics of AML in children and adults, his team found that they don’t have the same disease: The AML seen in a 2-month-old is not the same AML that they see in a 90-year-old.

And maddeningly for investigators, the genetic changes that trigger and sustain the disease are not uniform among patients. Among pediatric AML patients alone, scientists have delineated more than 50 different subtypes.

“Even in this big of a center, we probably have five to 10 AML cases a year. Which would be OK [for research] if the disease was very homogeneous,” said Meshinchi. “If all 100 patients that you diagnose in 10 years all look exactly the same, you can get away with [looking at fewer tumor cell samples]. The problem is it’s an incredibly heterogeneous disease.”

Pediatric AML tissue bank
A lab technician pulls boxes of living samples of AML from children who have participated in Children's Oncology Group trials. The 40,000 samples are stored in a bank at Fred Hutch. Photo by Robert Hood / Fred Hutch News Service

Samples reveal patterns to tailor treatment

Because of this, it is critical that researchers collect and preserve as many samples from children as possible. The Hutch’s vast collection of pediatric AML samples enables scientists to pick out important molecular patterns and gain a clear understanding of the genetic makeup of different AML subtypes, said Meshinchi. More samples lead to clearer patterns and confirm which molecular characteristics could have potential as treatment targets. With this knowledge, precision medicine becomes possible for children with AML.

Once parents give permission, oncologists take several million to a few billion AML cells for research every time they check a child’s blood or bone marrow for cancer, from diagnosis through treatment. Each sample is carefully processed to remove red blood cells and slowly lower its temperature so that the AML cells can be frozen in liquid nitrogen — still living — long term. In this condition, samples can be shipped internationally and stored, ready for study, at Fred Hutch. The COG AML committee reviews research proposals from scientists around the globe who want to use the samples for their studies, approving only those of highest scientific merit.

The process began in the 1970s, when Hutch researchers and COG members Drs. Irwin Bernstein and Bill Woods began putting together a repository of samples collected across the U.S from children treated in COG trials. Since then the repository has supported more than 20 clinical trials, and it continues to grow thanks to the parents who give permission for a portion of their children’s tissue samples to be preserved.

Bernstein and Woods “had the foresight to say, ‘Let’s start collecting diagnostic samples and study them,’” said Meshinchi — even though the scientific tools of the 1970s lagged behind the questions researchers hoped to answer. As technology has advanced, however, the samples have begun to give up their secrets and lead to lifesaving discoveries.

When Havianna’s doctors looked closely at the molecular characteristics of her AML, they spotted a mutation with big implications for her treatment. In her tumor cells, a section of a gene known as FLT3 had duplicated. This AML subtype is known as FLT3-ITD for FLT3-internal tandem duplication. In the 1990s researchers recognized this subtype by profiling the molecular characteristics of samples from the Hutch pediatric AML tissue bank. Havianna was one of about 15 percent of children with AML who have this mutation in their tumor cells.

“This is actually our first target [found using the tissue bank] to change people’s treatment, which significantly impacted people’s survival,” said Meshinchi. The discovery of FLT3-ITD “enabled us to ID these patients very early on, at the time of diagnosis.”

Treated with a standard chemotherapy-only regimen, these children had a survival rate of about 10 to 15 percent; but when oncologists also treated their AML with bone marrow transplantation, the kids’ overall survival jumped to more than 60 percent. “Their outcome really improved dramatically,” said Meshinchi.

Preparing for transplant

One course of chemotherapy didn’t subdue Havianna’s AML, so based on her FLT3-ITD mutation, her doctors recommended a second course — followed by a bone marrow transplant. After the second course of chemo put her AML into remission, Havianna underwent preparatory radiation therapy. The procedure requires that patients remain motionless. Usually, children are sedated to keep them from fidgeting, but Suzanne helped prepare Havianna by turning stillness into a game.

“In Laguna Beach there’s something called the Pageant of the Masters, where they recreate an actual painting and people have to stand very still. We had taken Havianna several years in a row,” said Suzanne. “I told Havianna, ‘You have to pretend that you’re in the Pageant of the Masters.’ So we practiced beforehand how she would have to stand still. She thought it was fun.”

With Suzanne’s training, Havianna, sometimes dressed in a fluffy pink skirt, was able to stay fully awake as she underwent full-body radiation treatments deep below the University of Washington Medical Center. Though Suzanne and Tom were unable to accompany her into the radiation room, Havianna brought along her Thumbelina doll, who still sits by the now-teenager’s bed.

After several rounds of radiation, she received her new bone marrow cells a few days before Christmas, around 1 o’clock in the morning.

“Right on the cusp of a brand new day,” Tom said.

Matching patient to treatment

The ability to pinpoint which children would benefit most from a bone marrow transplant was an incredible advance, but it wasn’t the only lifesaving treatment change to come from the discovery of FLT3-ITD among the banked tissue samples. Hutch investigators found that AML cells with this mutation were susceptible to a drug called sorafenib.

“We were able to show that sorafenib, a drug approved for kidney cancer, actually hits [FTL3-ITD], so we added this drug to the treatment for children with FLT3-ITD and the response has been incredible,” said Meshinchi. Havianna was the first child to receive sorafenib.

After her transplant, doctors had removed a sample of her bone marrow to check for lingering AML cells and found that her disease had not been completely eradicated. One of her doctors warned Tom and Suzanne that Havianna’s chances of survival were probably less than 50 percent.

Tom recalled Meshinchi calling a few days later. Meshinchi told the Hornishes about a new, off-label use of sorafenib, the kidney cancer drug.

“He gave me an example where he’d seen [post-transplant AML cells] with another patient and started the sorafenib. He said, ‘We’ve never seen it again [after the sorafenib]. Would you want to do that?’” said Tom. He and Suzanne considered their options, then agreed to give sorafenib a try. “And we’ve never seen it again either.”

At the time, the use of sorafenib for AML was so new that only nine other AML patients in the U.S. — all adults — were on it. Eight years after Havianna and her family helped pioneer its new use, sorafenib or a similar drug is now standard-of-care for kids with the FLT3-ITD mutation.

Sorafenib is just one of the success stories coming out of the COG pediatric AML tissue bank here at the Hutch. Another recent Hutch discovery made possible by the repository is the fact that in certain children, AML cells make a protein called mesothelin that’s rare in healthy tissue. Similar to the case of FLT3-ITD and sorafenib, mesothelin is also the target of an already available drug. Once again, the tissue bank pointed oncologists toward a new possibility for a tailored and potentially more effective treatment for these kids. Hutch researchers are currently putting together a clinical trial to test the drug’s effectiveness when a patient’s AML is high in mesothelin.

Uncovering mesothelin’s association with AML also opens up the possibility of discovering new drugs. Meshinchi and his colleagues are among those currently working to create cutting-edge new therapies for children with this marker.

The gift of hope

It’s just a box on a form — where parents can elect to reserve a portion of their child’s tumor cells for research — but it opens a door. Every donation is a gift of hope, a step forward for patients to come.

“These are live cells from thousands of patients with AML who were treated in the past, many of whom are no longer here,” said Meshinchi. “But their samples hold the key to better treating our AML patients in the future.”

The Hornishes also hope they can support research that makes lifesaving advances possible for other children and other parents.

“We believe the science and we were open to learning,” said Tom. “We figure even if things didn’t work out for Havianna, it’s good for people to learn and have that scientific knowledge.”

Thanks in no small part to the collected gifts of the many families who had already faced AML, things did work out for Havianna.

Once the Hornishes returned to San Diego, she was able to attend second grade on schedule. Havianna continued on sorafenib for two years. Her cancer has not returned.

“She’s just a normal 14-year-old,” said Tom.

Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.

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