PHILADELPHIA — The meds Shelby Campbell needed for her rare blood disorder stopped working just after her sixth birthday. She lost her appetite and was often doubled over in pain. She continued getting blood transfusions but her doctors struggled to manage side effects that threatened her organs. By the time she turned 7, the doctors told her parents they had to do something — soon.
Several months later, Shelby laid in her mother’s arms on a hospital bed, napping. Her medical team — who deemed the late June 2023 day Shelby’s “re-birthday” — gathered around, preparing to administer a life-changing treatment. Her doctor, Tim Olson, connected the first of two syringes to a small tube that led to a port in Shelby’s chest. Both syringes were filled with a translucent, slightly beige liquid. Everyone in the room, holding their breaths, knew it was worth more than if it were liquid gold: $2.8 million, to be exact.
In a stroke of luck, or divine providence as Shelby’s parents see it, this gene therapy for her disease, beta thalassemia, had been approved just the year before. If all went well, it would replace Shelby’s deficient stem cells with ones that produce red blood cells correctly, and Shelby would hopefully never need transfusions again, like nearly 90% of patients in the pivotal clinical trial for the therapy.
“We have hope that this is a miracle cure,” her mom, Michelle Campbell, had told STAT a few months earlier, “but I’m not exactly looking forward to it.”
Olson slowly pushed in the suspended stem cells, which had been collected from Shelby’s bloodstream four months earlier and modified to contain the right genetic instructions for making red blood cells. It took less than eight minutes for him to empty the syringes.
When Olson finished, the room clapped.
“Happy birthday,” her mom whispered.
And they waited for the miracle to begin.
The treatment, Bluebird Bio’s Zynteglo, is a one-time, essentially curative therapy, but that “one time” takes place over the course of months. For Shelby, it will be more than a year. By the time it’s done, she’ll have spent seven weeks in the hospital, received toxic chemotherapy to wipe out the defective cells, lost her hair, suffered high fevers and mouth sores, and been isolated from friends and unable to attend school for more than seven months while her immune system recovers.
Fewer than 15 other people with beta thal have started the Zynteglo process, but gene therapies for the far more common sickle cell disease, from Bluebird and from Vertex and CRISPR Therapeutics, were approved in the U.S. last week. Treatments for immune diseases and cystine buildup are on the way as well. All of these gene therapies will require stem cell transplants like Shelby’s, meaning thousands more patients will go through the same arduous process in the near future.
In chronicling Shelby’s journey, STAT visited her in the hospital and spent more than a year talking to the Campbell family, other people with beta thalassemia, and those who treat it to understand how this kind of slow-moving miracle affects patients and caregivers during and after the therapy.
Michelle and Adam Campbell’s journey to Shelby didn’t involve nightly hormone shots or feeling little baby kicks. Instead, they had endless fundraisers and adoption paperwork.
With their friends and family, they hosted bake sales, burger nights, car washes, and a $2.50-per-piece jigsaw puzzle fundraiser that created a picture of their adoption announcement, all to pay for thousands of dollars in home study and adoption fees. They notarized and overnighted so much paperwork before they left for China that even the employees at the UPS in their small Pennsylvania town were impatient to meet Shelby.
When applying for adoption, the Campbells checked off every box of medical conditions they were prepared to care for, including hearing impairment, because Michelle taught deaf children in a special education program. They were told to expect a wait of up to six months, so when the phone rang after only seven days, they assumed it was because they had matched with a deaf child.
Instead, Shelby had beta thalassemia.
The genetic disorder causes the body to make red blood cells that can’t carry iron. The day after they got home from China, Shelby went to the Children’s Hospital of Philadelphia for a blood transfusion. Like many other people with beta thalassemia, Shelby would need transfusions once every three weeks, seemingly for the rest of her life.
The Campbells adopted Shelby two days before her second birthday. For the next three years, the blood transfusions and thalassemia medications were the easiest part of Shelby’s medical care. But when she turned 6, her chelation meds, which rid the body of excess iron from blood transfusions, stopped working. The only alternative to prevent organ damage was an older treatment that would have to be pumped through a needle under her skin for 12 hours a day. That worked, for a while, though it was frustrating to miss dance recitals and field hockey games because she had to be home by 6:30 every night.
The Campbells had watched friends in thalassemia patient groups go through clinical trials for various gene therapies. They always thought they might try one when Shelby was older, to send her off to college without needing transfusions or meds. They wanted to give their daughter the chance to harvest her eggs before having the infertility-causing chemo required for gene therapy, even though Shelby insisted she would want to adopt when she grew up.
But when Shelby’s doctors looked at her MRI scans in the fall of 2022, that all fell apart. A year earlier, the Campbells’ options would have been limited: Finding a matching bone-marrow donor for a transplant was nearly impossible, as the Campbells didn’t know anything about her biological family. And clinical trial openings were rare. But the Campbells were in the right place at the right time. A gene therapy called Zynteglo had received FDA authorization in August 2022.
Even though Zynteglo is billed as a one-time therapy, getting any gene therapy that requires a stem cell transplant is an excruciating, months-long process.
These therapies allow patients to become their own stem cell donors, with a little help from science. The process began in February, when Shelby’s blood stem cells were collected. The team circulated her blood through a machine, separated out the desired cells, and couriered them to Houston, Texas. There, Bluebird’s manufacturing partner Lonza modified them to add a working hemoglobin-producing gene — a process that takes only a few days. The subsequent FDA-required quality testing takes much longer — typically 70 to 90 days.
Meanwhile, Shelby went home. For the next couple weeks, she was uncomfortable and tired as her body regenerated platelets and blood cells and stem cells. She wanted to participate in her gymnastics class but was too exhausted to do more than 10 minutes. She complained that her bones, which had just squeezed out the stem cells from her marrow, were achy.
In June, Shelby returned to Children’s Hospital of Philadelphia and had surgery to place a central line — a semi-permanent IV port in her chest. Doctors also harvested her ovarian tissue as part of a clinical trial of an experimental procedure to try to preserve fertility. Finally, she underwent four days of chemo to kill off her native stem cells and make room in her bone marrow for the corrected cells.
While the hospital stay was long and frequently unpleasant, it did give Shelby an excuse to convince her mom to start a YouTube channel so she could try out her dream job: a YouTube scientist, like her hero Emily Calandrelli, social media star and host of “Emily’s Wonder Lab” on Netflix.
The influencer jargon rolls off her tongue perhaps a little too easily. “Hey guys, welcome back to my channel. Before I get started, hit that subscribe button, turn on the notifications, and give us a huge thumbs up,” Shelby says in one video, tugging on the bathroom sink with a huge smile. “So we’re going to be doing my nighttime routine; I already got in my pajamas. …”
Shelby needed a new toothbrush every time she brushed, in case bacteria were growing in her old one. Her mom played a song to distract her from the flavor of the mouthwash — “because it’s mint and I HATE MINT” — which is a special formulation meant to prevent chemo mouth sores (which she got anyway).
Shelby does, however, love sour flavors, which turns out to be useful for a cell therapy recipient. The liquid in which the stem cells are frozen — once in the bloodstream, circulated through the lungs, and breathed out — creates a nasty taste. During her transplant, it woke Shelby up. Her mom offered her a Sour Patch Kid, which previous patients had figured out is perfect for covering up the yucky taste.
They don’t always talk about the less-fun parts of the Zynteglo process on the YouTube channel. Shelby got a feeding tube the day after the infusion, while she was still feeling OK. The nurses let her count to three when she was ready. Several times, she counted, “One, two…” before saying she wasn’t brave enough. It took 20 minutes for her to finally get to “three,” and she threw up the tube two days later while gagging on her mouthwash. Before the end of her hospital stay, she would have to have it placed five more times.
Zynteglo patients are in the hospital for a longer time after the infusion than they are before and during it. They also feel way, way worse during this phase.
Though patients will sometimes have a bit of nausea and fatigue while on chemo, said Olson, they then go through a “honeymoon period” before their cell numbers go down.
Shelby’s hair started falling out on Day 7 post-transplant. Her scalp was so itchy, she asked her mom and grandparents to help pull the hair out. Her mom tried to trim the rest of it as short as she could with craft scissors. Shelby was happy when someone finally came with clippers to shave her head, though at first she didn’t want to see herself without any hair on FaceTime or in pictures.
Several days after the infusion, Shelby started getting thick mucosal secretions, sores throughout the gastrointestinal tract, and fevers. On Day 9, she had to get down on her hands and knees to force the mucus out of her stomach, the output laced with blood.
“That yuckiness, for lack of a better medical term, sort of persists for the next couple of weeks until the new cells start to grow,” Olson said.
Shelby’s blood cell and platelet counts bottomed out on Day 11. She slept nearly all day, had a fever so bad they called in a doctor at 1 a.m., and had bruises from her low platelet counts and was constantly throwing up blood and phlegm. Over the next few weeks, she got platelets — sometimes every day — and a couple transfusions, and ended up needing injections to jump-start her blood cell production.
By Day 12 post-transplant, both Shelby and her mom were tired of being in the hospital and struggling to lift their moods. Michelle looked at a pack of slap bracelets they’d been gifted and decided they were going to get Shelby out of bed by walking around the floor to hand them out. “We’re going to have Unicorn Day,” she declared.
They did all of the unicorn-themed activities they had brought to the hospital in a barrage of clear totes, and Shelby loved it so much that they kept doing it. There was Bug Day, Hello Kitty Day (her Hello Kitty figurines ended up in mounds of pink slime), Purple Day (the same day she got her central line out and screamed for 35 minutes as she came out from under the anesthesia), Science Day (the day she had a four-hour nosebleed but managed to hand out stickers), and Beach Day (she handed out sunglasses and had another four hours of being sick and having a nosebleed).
Because the chemo knocked out her immune system temporarily, Shelby’s hospital visitor list was small to keep her from getting infected. Michelle’s parents — Gram and Papa — stayed with them on Tuesdays and Wednesdays, sleeping in a room in the Ronald McDonald House. Adam came after work on Fridays and stayed the whole weekend. After Shelby lost a tooth, the tooth fairy slipped in one night, too.
Every night, Michelle went through their infection-prevention routine: replacing the bed linens; swapping out one of the six different versions of Shelby’s stuffed puppy named Puppy, which also needed to be washed every day; giving Shelby a special bath to keep her port from getting infected; and supervising her mouth-care routine. After Shelby took her nightly meds and went to sleep, her mom would wipe down any toys and surfaces Shelby had touched with special wipes, and throw away anything that couldn’t be cleaned, like slime and cardboard boxes that had been turned into imaginary cars.
Then she would lie down on the converted hospital room couch-table-bed, blocking out the beeping of alarms and nurses’ footsteps, and try to sleep.
Staying in the hospital for seven weeks seems like it would be the hardest part of the journey, but Michelle worried about going home. In the quiet of their ranch house in southern Pennsylvania, just across the Susquehanna River from Harrisburg, there would be no nurses deciding what medicines to give, or remembering how many times Shelby is supposed to be fed through her tube each day. There would just be Adam and Michelle.
When they arrived home in August, Michelle felt the helplessness of having to be both “nurse” and “mom” most acutely when she had to put Shelby’s feeding tube back in — twice. Shelby begged to be held, but her mom couldn’t both hold her and reinsert the tube up her nose at the same time.
There’s the isolation, too. While they were technically isolated at the hospital, nurses and a steady stream of therapists and doctors came in and out of their room every day. But for Shelby, home is like social-distancing spring 2020 all over again — no school, no sleepovers, no indoor visitors besides her grandparents and her masked second-grade teacher — for at least six months. Between the social isolation, lingering chemo brain fog, and some anti-nausea medications that made Shelby feel like her brain was “glitchy,” she went through a bit of a mental health roller coaster after arriving home.
“I think that’s part of [a] transplant that maybe isn’t talked about as much,” said Michelle. “You talk about what’s going to happen at transplant, you talk about rules at home, but not necessarily that fallout or [the] side effects that the kids might experience.”
The need to stay at home, isolated, creates a barrier for many people interested in getting Zynteglo or the sickle cell gene therapies. The patients need caregivers, and both need to be able to take extended periods of time away from home, school, and work, said Alexis Thompson, chief of the hematology division at CHOP. Finding a time to do the therapy and someone to take care of the patient is one of the biggest hurdles, especially for adults.
For the Campbells, many factors had to come together to make it possible for Shelby to get the therapy. As a teacher, Michelle was able to take the summer off to stay with Shelby in the hospital. They lived only two and a half hours away from one of the country’s premier pediatric cell and gene therapy centers, which meant they could go home and come back for the months of weekly and biweekly follow-up visits instead of having to find an apartment in Philadelphia.
Adam’s and Michelle’s employers have allowed them to take a day off every week to drive Shelby to appointments; her grandparents have been able to watch her at home while her parents are at work; and the family could afford the financial hit from lost income, lodging, and travel — including $60 in tolls every time they drove to the hospital.
“You hear ‘six to eight weeks at the hospital’ and that’s one thing. But six to nine months at home is also, I think, something to make sure you can commit to and have the support for,” said Michelle. “It’s something that families should think about before they’re like, ‘Yeah, sign me up for eight weeks and my kid’s cured.’ It’s definitely not a quick fix or an easy fix.”
Almost six months out from the transplant, things are looking up. Shelby won’t get declared transfusion-free until a year after her transplant, but her blood, platelet, and hemoglobin numbers are slowly increasing. Her body is making its own hemoglobin for the first time in her life. Shelby hasn’t needed a transfusion since she was in the hospital — now over four months ago. She got to remove her own feeding tube, has been feeling more like herself, and her medical team is comfortable with seeing her for follow-ups less frequently.
Shelby turned 8 and the Campbells partied like it was 2020 with a “Bluey”-themed drive-thru party. In November, her local movie theater closed down so Shelby could see a private showing of the Taylor Swift Eras Tour film. Her hair is growing back.
As the Campbells have begun to watch friends with thalassemia go through the process, they’re finally looking back and realizing how much they’ve persevered through. Once, Michelle asked Shelby if she wanted to send a video message to a friend who was getting his feeding tube that day.
“You might need to get it in a few times but once you get used to it, it’s not that scary and you know what to expect,” Shelby said, like an experienced professional. She told him that he should drink water because it usually makes the tube go down easier, and giggled when she said removing the tube feels like a “really big booger coming out.”
Her mom was surprised at the wise advice — all she could remember was Shelby screaming every time they inserted her tube.
Shelby continued. “After a day or two, you get used to it and it feels like it’s not there,” she said, beaming.
Eventually, the Campbells will only have to go to CHOP once a year, instead of the 10,000-plus miles they’ve driven to doctors’ appointments and the hospital this year. Shelby’s gotten her blood drawn through a port for years and was confused when her parents and her medical team brought up removing it because she soon won’t need it anymore.
Shelby will be able to go see the Christmas lights this year because she won’t need to be home every night for her 12-hour meds. She won’t miss as much school for transfusions and medical appointments. She won’t have to choose a college near a transfusion center; she can have any job she wants because she won’t have to miss work every 21 days.
It might take a year, or two, or three, but if all goes well, Shelby should eventually get so used to the normality Zynteglo brings to her life that — as with her feeding tube — she won’t even feel like it’s there anymore.