‘Can’t sit and wait’: Gene therapy trial aims to cure rare Fanconi anemia

Hutch News

'Can't sit and wait': Gene therapy trial aims to cure rare Fanconi anemia

At annual hematology meeting, Fred Hutch researchers updated their treatment of 11-year-old Behzad

Dec. 4, 2016
 Mahazareen Dastur and son Behzad

At Fred Hutch, Mahazareen Dastur discusses the decision to enroll her son Behzad, 11, in a clinical trial to correct Fanconi anemia. Behzad focuses on his handheld game.

Photo by Robert Hood / Fred Hutch News Service

[Editor's note: This is an update of a 2015 story about this clinical trial]. 

The boy has asked pointedly about cancer. He's asked if his health problems would vanish if he ate more fruit, drank more milk. He's asked if he’s to blame. And he's become reluctant to have his blood periodically tested. 

“The hardest part for my son has been understanding and trying to accept what the disease probably has in store for him,” says his mother, Mahazareen Dastur, whose son, Behzad, 11, was diagnosed six years ago with Fanconi anemia, or FA.

The rare, inherited blood disorder often leads to bone marrow failure, leukemia and other cancers in adulthood. A while back, Dastur forged something of a mantra: "We can't just sit and wait." And she continues to speak with a mother's toughness — a determination rooted in love and hope. 

"It is a waste of effort and energy thinking about FA and how overwhelming it can be. I just think it is better to be informed and deal with an issue when it comes up. I also think there are people and families who are worse off than we are," Dastur said last week.  

The illness prompted Dastur and her son to agree to travel from their home in Mumbai, India to Seattle to enroll him in a study at Fred Hutchinson Cancer Research Center. In May 2015, scientists at Fred Hutch removed bone marrow from Behzad. Using a safety-modified version of HIV, they delivered and inserted a functional gene into those harvested cells. The team then returned Behzad’s bone marrow to his body — hopefully, correcting his anemia and preventing the development of leukemia.

Behzad's blood cell counts — which were declining significantly before the therapy — have stabilized. The latest blood tests show the corrected cells have the ability to engraft and amplify, Fred Hutch researchers reported Sunday at the annual meeting of the American Society of Hematology in San Diego. 

"These [re-engineered] cells are expected to have a growth advantage and, we hope, would ultimately replace the affected Fanconi anemia blood and marrow cells since the non-corrected cells would die off over time," said Dr. Hans-Peter Kiem, Endowed Chair for Cell and Gene Therapy at Fred Hutch and the trial’s co-principal investigator and Food and Drug Administration Investigational New Drug sponsor.

Behzad has the most common genetic form of the disorder, Fanconi A — one of 19 FA genes discovered to date. As part of the Phase 1 clinical trial at Fred Hutch, he is the only child in the United States to undergo this type of gene therapy for FA.

Dr. Hans-Peter Kiem

Dr. Hans-Peter Kiem

Photo by Matt Hagen

'A true team effort'

Kiem collaborated with fellow Fred Hutch researcher Dr. Jennifer Adair, lead author of the paper presented Sunday at ASH. They also worked with Dr. Pamela Becker, a hematologist at the University of Washington School of Medicine and co-principal investigator of the trial.

“This was a true team effort and could not have been accomplished without the help of a large team,” Kiem said. That group involved Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner, and included Dr. Lauri Burroughs, who specializes in bone marrow transplantation for children, as well as Dr. Ann Woolfrey, a pediatric oncologist. 

Behzad was the first child enrolled in this trial but the second patient to join. 

Earlier, the U.S. Food and Drug Administration instructed the team to first try the procedure on an adult with FA. The first patient was a 20-year-old American man. After he received the gene therapy, a test showed that his hematocrit level — the proportion of red blood cells — had stabilized near the normal range, the researchers said. 

“Obviously, we do not yet know if this is going to work [for Behzad]. But if this works,” Kiem said, “this will be wonderful for both the family and for our team.”

Dr. Jennifer Adair

Dr. Jennifer Adair

Fred Hutch file photo

"A Phase 1 trial is designed to test safety and feasibility of new treatments. In both patients, the gene therapy treatment was safe," Adair said. 

She and the team hope to be ready to launch a Phase 2 study in the next three to five years, Adair said. In a Phase 2 trial, scientists use the treatment in a larger group of patients to test how effective it is and to further evaluate its safety. 

"These results are very promising. ... [And] we have learned a great deal about how to improve the feasibility, which will in turn, we believe, improve the efficacy," Adair said.

The standard treatment for FA is a bone marrow transplant from a matched donor. Behzad's mother checked family members and marrow registries and could not find a match for Behzad. For patients with the disease, BMT success is limited if the marrow donor is not a matched sibling and about 70 percent of FA patients lack such donors, Adair noted in the new paper. "Gene therapy could be an alternative, correcting the genetic defect ... [and] negating the need for a BMT donor," she wrote. 

What's more, successful bone transplantation carries another significant risk for people with FA.

Up to 70 percent of all bone marrow recipients develop a side effect called graft-vs.-host disease (GVHD), an often-debilitating illness in which the donor cells attack the patient’s own healthy body. It can be miserable, causing rashes, vomiting, severe diarrhea or liver problems.

Among FA patients, however, GVHD can be devastating: It appears to be linked to the later development of oral cancer, said Dr. Laura Hays, executive director of the Fanconi Anemia Research Fund, an Oregon-based nonprofit that supports affected families.

“It’s a pretty sad story because we have so many of these FA patients who have gone through bone marrow transplants and their anemia is fixed and they’re still getting head and neck cancer,” Hays said.

Even worse, when those cancers emerge in people with FA, their bodies can’t tolerate chemotherapy, Hays said.

Despite the potentially lethal side effects associated with bone marrow transplants, many people with FA and their families remain “a little scared” about gene therapy, Hays acknowledged. 

“People are excited to find out how it worked but nobody is ready to jump onboard yet,” Hays said. “There’s just a little trepidation because it’s still new to them.”

Behzad’s mother said she has felt that same hesitation in other families — including people she got to know in the summer of 2014 while attending an annual FA camp in Maine. At that gathering, she heard about the Hutch trial.

A mother's hope 

“It is a calculated risk,” Dastur said.

Behzad showed signs of the disorder after turning 4. He had two bouts of pneumonia. He also was small for his age, and so-called “café-au-lait” spots discolored his skin — two typical traits. The most common diagnostic tool for FA is a chromosome test.

Blood can be telling, too. In patients with failing bone marrow, (which often starts between ages 3 and 12 in FA patients), the marrow doesn’t produce enough white blood cells, red blood cells and platelets. Behzad’s counts were low.

In India, Behzad now undergoes periodic blood tests. Doctors at Fred Hutch and SCCA have monitored the results to watch for signs of successful engraftment.

He continues to attend school. And he loves collecting coins, reading, gaming on his tablet and rankling his teenage sister.

“Overall, I'd say he is still doing pretty good for an FA patient,” his mother says. “I do not know where the trial or FA will take us. But then, no one knows much about what will happen tomorrow.”

To read more about Fred Hutch at ASH 2016, go to our page here.

Bill Briggs is a former Fred Hutch News Service staff writer. Follow him at @writerdude. Previously, he was a contributing writer for NBCNews.com and TODAY.com, covering breaking news, health and the military. Prior, he was a staff writer for The Denver Post, part of the newspaper's team that earned the Pulitzer Prize for coverage of the Columbine High School massacre. He has authored two books, including "The Third Miracle: an Ordinary Man, a medical Mystery, and a Trial of Faith." 

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