How stem cell transplant researchers are helping kids with rare non-malignant diseases

How stem cell transplant researchers are helping kids with rare non-malignant diseases
Four-year-old Idan Zablocki was born with a rare genetic immune disorder known as Hyper IgM. He's being treated as part of a clinical trial at Fred Hutchinson Cancer Research Center. Photo courtesy of the Zablocki family

When Idan Zablocki was a baby, he was rare and miraculous the way every baby is to their parents. He was also strappingly healthy and happy.

But one day when he was 8 months old, his parents, Amanda and Akiva Zablocki, noticed that Idan was breathing very quickly. Two weeks of back-and-forth trips to his pediatrician brought no clear answers other than a vague diagnosis of a viral infection and the hope that it would clear on its own. Then Idan’s oxygen levels suddenly plummeted and the family rushed him to the hospital.

Idan spent several weeks in the pediatric ICU and his doctors discovered that he had a unique type of pneumonia, known as pneumocystis pneumonia, or PCP.

Healthy children don’t get PCP, the Zablockis were told.

Those terrifying weeks and that discovery eventually led to the diagnosis of a one-in-a-million condition: Hyper IgM Syndrome, a very rare genetic immune disorder. Idan’s immune system can’t produce normal antibodies, the specialized proteins that both fight off infectious viruses and bacteria and trigger our immune systems to build lasting defenses against those pathogens.

For the first several months of his life, his body was protected with Amanda’s antibodies, left over in his blood from in the womb. Maternal antibodies typically only last about six months after birth.

Idan, who is now 4 years old, is vulnerable to many types of infectious viruses and bacteria in the world around him, infections that people with functioning antibodies can easily combat. This means that his native New York City is baited with invisible threats to his health at every step.

He is part of a relatively small group of patients and survivors with Hyper IgM, but he’s a member of a much larger group of children with what are termed non-malignant blood disorders.

Individually, their diseases are rare, but combined, this group is a major driving force in pediatric medicine. Children with non-malignant blood disorders make up roughly a third of the pediatric patients undergoing transplants in the U.S., said Fred Hutchinson Cancer Research Center transplantation researcher Dr. Lauri Burroughs, who is also one of Idan’s physicians at Seattle Children’s Hospital.

Burroughs sees children with many different rare diseases that can often be treated or cured with similar approaches as those used for blood cancers, such as stem cell transplants. In addition to Hyper IgM, she treats patients with sickle cell disease; bone marrow failure disorders; severe combined immunodeficiency, or SCID; hemophagocytic lymphohistiocytosis, or HLH; and other inherited immune disorders.

Transplantation researcher Dr. Lauri Burroughs wants to make transplants safer and more effective for children with non-malignant blood disorders. Fred Hutch file photo

Burroughs started out in her medical career as a specialist in pediatric oncology, but later found herself drawn to diseases like Idan’s, blood disorders that aren’t cancers — but where lessons learned from oncology may apply.

“There’s a lot of voices for oncology,” Burroughs said. “Children [with non-malignant blood disorders] have life-threatening diseases as well … and there are just not as many voices for them. There is a significant need for more research in this area.”

A piece that’s missing

Stem cell transplantation is the only cure for Hyper IgM and for many of the other non-malignant blood disorders Burroughs treats. However, the transplant procedure is often very toxic for patients with severe immune deficiencies and other non-malignant diseases.

It’s kind of a catch-22 in her work, Burroughs said.

“Patients with non-malignant diseases are born with an important piece that’s missing or not working properly that is often critical for their long-term survival. A transplant can fix that missing piece. But unfortunately, due to their underlying disease, patients are often very sick when they come to transplant and as a result, they often would not survive the transplant,” she said. “If they could just get through the transplant, they would be cured.”

When she first came to Seattle for a fellowship in pediatric hematology and oncology at Fred Hutch in 2001, transplantation for patients with non-malignant diseases was not as far along as the treatment approaches used for patients with cancer, Burroughs said.

In order for a transplant to work, patients undergo a procedure known as conditioning which helps prepare their body for the transplant. Typically, the conditioning regimens use high doses of chemotherapy, with or without radiation, to remove most of the abnormal bone marrow cells and make room for healthy donor cells. In cancer patients, the chemotherapy and radiation are also used to wipe out as many cancerous cells as possible — an effect that patients with non-malignant blood disorders don’t need.

But patients with non-malignant blood disorders are often too sick to tolerate these harsh treatments. Looking for alternatives for her patients and others like them, Burroughs and her colleagues turned to a drug known as treosulfan. The drug has similar effects preparing the body for transplant, but with fewer toxic side effects than traditional conditioning regimens.

Burroughs and her colleagues are leading the country’s only trial testing this drug in patients with non-malignant blood disorders undergoing transplants with well-matched donor cells. The Phase 2 trial is open to children and adults under 50 years old with a variety of non-malignant blood disorders.

And they’re seeing promising results, Burroughs said. They’ve treated more than 60 patients with a variety of nonmalignant disorders through the trial, and 95 percent of these patients have survived two years past the procedure. The trial doesn’t directly compare this treatment to other conditioning regimens, but historically, two-year survival for this population of patients is around 75 to 80 percent, Burroughs said.

Idan is one of those participants — actually, he’s been through the experimental procedure twice.

Not just another transplant

When the Zablockis first received Idan’s diagnosis, they immediately went into research mode. Even before the exact disorder was determined, Idan’s doctors knew that he had some type of serious immune deficiency — and that he would likely need a transplant.

There wasn’t a ton of information readily available about Hyper IgM, but Akiva Zablocki, Idan’s father, has experience acting as his own medical advocate. Zablocki is an 11-year brain tumor survivor who was originally told his tumor was inoperable. He started researching options and eventually found a neurosurgeon thousands of miles away from his home in New York who was willing to operate — and successfully removed the entire tumor from his brainstem. Zablocki has since worked to build online communities for brain tumor survivors and other patients currently navigating the U.S. medical system.

So he had some muscle memory to draw on when it came to his son’s treatment.

Not all Hyper IgM families choose transplants for their children, who are typically diagnosed in their first year after a serious infection, like Idan was. The procedure can be deadly for their weakened immune systems, and rejection of the donor immune cells is also more likely in these patients than in other disorders. But without a transplant, Hyper IgM patients live to an average of just 24 years old due to deadly infections or organ damage.

“Because it’s such a rare disease, we wanted to find a center that both understood Hyper IgM, that understood that it wasn’t just another transplant, but that it is a unique, rare disease,” Akiva Zablocki said. “But we also wanted to find a center that would do a transplant that would not harm our son more than needed.”

The Zablockis started talking to transplant experts in New York City, then broadened their reach to other East Coast and Midwest cities. In the middle of their research, they found out about Burroughs’ trial and the gentler approaches to transplants she and her Seattle colleagues were pursuing.

“Akiva’s and my jaw dropped,” Amanda Zablocki said. “It was just so different and the approach was much more in line with what we were hoping to hear.”

After a visit with the Seattle physicians, the Zablockis decided to move their family across the country for six months to pursue a transplant for Idan. He received a stem cell transplant as part of Burroughs’ trial in 2013, when he was 14 months old.

‘Why am I so lucky?’

The work of going through a transplant is hard, Burroughs said — for her patients and their families. But the rewards are great.

“Historically, the conditioning regimens used for transplant were really hard on patients, particularly patients with non-malignant disorders such as Hyper IgM,” she said. Because her patients have such weakened immune systems and often have life-threatening infections they “were already starting up a big giant hill,” she said. “You know the transplant will cure them and fix the life-threatening piece of their disease if you can get them through the transplant.”

When asked which of her patients particularly stick in her memory, besides Idan, Burroughs replied quickly: All of them.

“Every patient has an impact on me. It’s impossible for them not to,” she said. “I don’t know how you can not be impacted by another person’s suffering.”

The Zablockis saw that side of Burroughs too, they said.

“She took Idan’s case on as part of her protocol and instead of treating it like another statistic in a study, she really became invested in the outcome,” said Amanda Zablocki, who is a healthcare attorney. “She’s been fighting right there beside us the entire time. You really feel that.”

After Idan’s (first) transplant, in 2013, the family knew the news was likely bad by about a month later. The doctors saw that the number of donor cells that had engrafted, or taken hold, in Idan’s body was lower than they would have liked to see.

“That was heartbreaking,” Akiva said. But the family still had over a year of medical limbo after returning to New York, during which Burroughs and Idan’s other doctors tried to stop the graft from slipping away.

Ultimately, it didn’t work.

Those moments are among the hardest and most difficult of her job, Burroughs said.

“I struggle internally when I know I’ve just given a family devastating news and then I’m driving home deciding dinner,” she said, blinking back tears. “Why am I so lucky? To be able to take my child to soccer, or figure out what he’s going to eat for dinner, make him eat his vegetables, struggle with the normal things of life.”

The Zablockis regrouped in New York, preparing for another trip to Seattle and another transplant. Idan received his second transplant this summer, a day before his fourth birthday.

He’s a little more than four months post-transplant now, “still early in the process,” Akiva said. His donor cell numbers looked much more promising than the first go-around, his parents said, but as of late November, they are gradually slipping. So, more treatments and more limbo.  

In the midst of all their travels, the many medical appointments, and their jobs, Idan’s parents also founded the Hyper IgM Foundation. The website and the group primarily serve to connect families like theirs affected by this rare disease, families looking for answers and community. But they’re also partnering with researchers and have raised money to give out their first two grants to support promising research into Hyper IgM cures, Akiva Zablocki said.

No matter what happens with this second transplant, their work with the community they’ve helped build will continue, he said.

As for Idan, “our story is still continuing,” Akiva said.

Pediatric disease research is the focus of this year's Hutch Holiday Gala, a fundraising event benefiting Fred Hutch research held Dec. 3.

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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