A total of 44 children born with rare genetic disorders were successfully treated with umbilical cord blood (UCB), a readily available source of stem cells, in a new study led by UPMC Children’s Hospital of Pittsburgh.
“The 44 kids came from 20 states and all have returned home,” says the study’s senior author Paul Szabolcs, division director of bone marrow transplantation and cellular therapies at UPMC Children’s Hospital. “There were 20 diseases amongst the 44.”
The plan was to create a universal treatment, rather than finding individual therapies for a host of diseases, which included sickle cell, thalassemia, Hunter syndrome, Krabbe disease, metachromatic leukodystrophy (MLD) and a number of immune deficiencies. It’s the biggest trial of its kind to date.
The results of the study were just published in the journal Blood Advances.
It’s a treatment that has a lot of potential upsides, including cost.
“There has been a lot of emphasis placed on cool new technologies that might address these diseases, but — even if they prove effective — those aren’t available to most centers,” says Szabolcs. “The regimen we developed is more robust, readily applicable and will remain significantly less expensive.”
The children who participated received intravenous cord blood, donated from the umbilical cords and placentas of healthy babies, which was frozen until needed.
“Although UCB transplants have been done for 25 years, survival has not been stellar, and procedure-related mortality has been high,” says Szabolcs. “Some centers have considered 20% mortality ‘acceptable,’ while we think the ultimate goal is getting near zero percent mortality due to procedure-related complications.”
The treatment was designed to deal with patients’ immune system reactions.
“We approached the topic with the mindset to design a regimen that carefully balances low-intensity chemo (bringing safety) with sufficiently effective immunotherapy to blast away the patients’ immune system, therefore preventing rejection,” says Szabolcs. “Rejection has been a common failure when other centers explored the reduced-intensity conditioning (RIC) approach with cord blood. We are the first to prove the RIC is able to give reliable results in long-term engraftment.”
The regimen isn’t toxic to the heart, lungs, liver and kidney. Post-infusion complications have been mild. None of the children experienced chronic graft-versus-host disease.
“A novel ‘plug-in’ immune boost is offered by us for the first time ever, using a tiny fraction of the cord blood (donor lymphocyte infusion) that we refreeze on transplant day and infuse one to two months after to jumpstart immune recovery from this tiny fraction,” explains Szabolcs.
The donor and recipient don’t have to have matching immune profiles. “That’s huge for ethnic minorities,” says Szabolcs.
“Cord blood grafts permit some mismatch, although outcomes tend to get incrementally worse with each mismatch. We have found a suitable cord blood unit for all 50 patients we have searched, even for complex ethnic cases such as Caribbean-African heritage. With our combination of sequential chemo and immune therapy, we were able to overcome the risks of mismatches and minimize the impact of rejection.”
Thirty children in the trial had metabolic disorders, reflecting improper enzyme function. All but one exhibited symptoms of neurodevelopmental delays before the trial started. Within a year of receiving cord blood, all stopped neurological decline — and some began to acquire new skills.
“There has been a stagnation of outcomes in this field, just changing one chemotherapy agent for another, not a true evolution,” says Szabolcs. “We designed an approach now proven to be efficacious for at least 20 diseases. And we believe it might be effective for many, many more.”
Since the paper was submitted, the researchers have used this approach to treat other diseases, including some in adults.
There’s been a lot of interest in adopting this regimen around the world.
“There have been already some aspects that have been copied as we reported preliminary data at scientific meetings, but with the full recipe published now more centers will be able to adopt,” says Szabolcs. “There has already been interest in Europe, and I predict it will be tried in the Americas and Asia as well.”
Funding for the study was provided by the National Heart, Lung and Blood Institute.