Memories of classical ballet performances dance in Wanda Sihanath's head when she thinks about her childhood in Elgin, Illinois. She remembers balancing at the barre to Beethoven and pirouetting to Vivaldi.
Even though it rarely affected her dance lessons, she also remembers being sick -- very sick.
A trial gene therapy helps patients with a genetic blood disorder avoid transfusions
"I have high hopes for the future of thalassemia," one patient says
Sihanath, now 22, was diagnosed as a young child with the genetic blood disorder beta thalassemia. She was treated with occasional blood transfusions, which became monthly when she turned 14.
"I knew for a fact I was sick and I definitely wasn't normal like every other kid, but it never really personally affected me," said Sihanath, now a graduating senior majoring in biomedical engineering at Arizona State University.
The blood transfusions were a normal part of her life, she said -- until she participated in a gene therapy study in 2014.
As part of that study, Sihanath was the first patient to receive a transplantation in her blood of her own genetically modified stem cells to treat the beta thalassemia.
"I've been transfusion-free since my transplant," Sihanath said.
"I have high hopes for the future of thalassemia," she said. "We are getting closer to a cure, and gene therapy is a growing research field."
Among all the patients with severe beta thalassemia who participated in that study, the gene therapy either reduced or eliminated the need for long-term blood transfusions.
Results of the small study, which involved two early clinical trials funded by biotechnology company Bluebird Bio, were published Wednesday in The New England Journal of Medicine. Phase three of the trial is currently underway.
"The standard procedure for a curative option for thalassemia would be a bone marrow transplant from a brother or sister, which is not without significant risk, but more importantly, most people will not have that appropriate sibling donor," said Dr. Alexis Thompson, head of hematology and director of the Comprehensive Thalassemia Program at Ann & Robert H. Lurie Children's Hospital of Chicago, who led the new research.
The study "actually allows us to envision treating thalassemia with curative intent using the patient as their own donor," she said.
"If we can envision treating patients as if the patients were their own donors, they are not exposed to some of the risks that come from transplants when you're using someone else's stem cells," she said. "Relatively speaking, this procedure was well-tolerated by the patients, with no unexpected toxicities related to gene therapy."
The study presents some very early results, and the gene therapy approach requires much more testing and research to answer the questions that remain.
The road to becoming transfusion-free
Beta thalassemia is an inherited blood disorder caused when the body doesn't make enough of a protein called hemoglobin, an important part of your red blood cells. It's found around the world, occurring most frequently in people from Mediterranean countries, North Africa, the Middle East, India, Central Asia and Southeast Asia. The total incidence of symptomatic cases each year is estimated to be about 1 in 100,000 people throughout the world.
In general, thalassemia can be well-managed with blood transfusions and chelation therapy which removes excess iron from the body with drugs, according to the US Centers for Disease Control and Prevention. Most people with severe anemia from thalassemia require red blood cell transfusions every two to three weeks.
The new study suggests a way to cut the need for those transfusions. It involved two trials with 22 patients total, 12 to 35 years old, with transfusion-dependent beta thalassemia. Transfusion dependence was defined in the study as having to receive at least eight transfusions per year, or at least 100 milliliters per kilogram of body weight of red blood cells per year, in the two years prior to enrolling in the study.
The two trials were to evaluate the safety and efficacy of a gene therapy for beta thalassemia using LentiGlobin, an investigational therapy by Bluebird Bio. It works by inserting a functional human beta hemoglobin gene into a patient's own stem cells outside the body and then transplanting those modified cells back into the patient's blood stream.
One of the trials in the study, called HGB-204, included 18 patients and was conducted at six sites around the world: four in the United States, one in Australia and one in Thailand. The other trial, HGB-205, included four patients and was conducted at Necker Children's Hospital in Paris.
In all of the patients, their own stem cells were harvested in a process involving the use of the drugs filgrastim and plerixafor, which move stem cells from the bone marrow to the bloodstream. Once the stem cells were collected, they were sent to a lab where they were transduced with LentiGlobin, which inserted that healthy beta-globin gene.
To prepare their bodies for the gene therapy, patients then underwent four days of the chemotherapy drug busulfan intravenously. Next, their modified stem cells were transplanted back into their bodies. After transplantation, they were monitored and followed up with during a period ranging from 15 to 42 months.
The researchers found that, "of those 22 patients, 15 of those patients became transfusion-independent, which meant that they were not transfused for a minimum of a one-year period," Thompson said. "For some, now it's been even much longer than a one-year period."
The researchers also found no serious adverse side effects related to the gene therapy and no significant unexpected safety issues.
"The side effects that were seen in these two clinical trials are consistent with what we expect from a transplant of any kind that uses chemotherapy," Thompson said.
There were five mild adverse effects in the HGB-204 trial and nine serious adverse events, including two episodes of veno-occlusive liver disease, attributed to the chemotherapy. In the HGB-205 trial, all four patients had adverse events related to the chemotherapy, such as mouth sores.
"There were no novel side effects identified that related either to the LentiGlobin vector or the gene therapy procedure itself," Thompson said. "We clearly want to watch for a much more extended period of time to be sure that there are no additional safety concerns."
In separate studies, some of the same researchers had tested the feasibility of transferring a healthy beta-globin gene into the cells of a beta thalassemia patient. In 2010, they first reported the successful use of the gene therapy for beta thalassemia in a patient.
Now, the findings in the new study appear to expand on that idea.
Another trial is underway
The study had some limitations, including that the trials involved only patients 12 and older and that they were followed for only a few years. More research is needed to determine whether the study results would hold for a longer period of time and would emerge among younger patients.
Thompson said that a follow-up phase three clinical trial is underway and will include younger participants.
"We are continuing to examine the phase three data," she said, adding, "We hope to answer that question: Can this actually achieve transfusion independence for more patients?"
LentiGlobin is also being tested in patients with sickle cell disease, another group of inherited red blood cell disorders, which suggests that the therapy might have potential to be widely used for various diseases.
It remains too early to know how much such a gene therapy will cost if it's approved for use in the public. Stem cell transplants of any kind can be very expensive; some estimates say a stem cell transplant to treat cancer can range from $350,000 to $800,000, according to the American Cancer Society.
"The things that I would note, however, are that one needs to evaluate the overall cost of patients who undergo sibling transplants and see if it is comparable," Thompson said.
"When we look at what the alternative might be -- having a stem cell transplant of any kind -- that is one number that has to be borne in mind. The second is looking at what the costs are for annual care for individuals with thalassemia," she said.
"When you take into consideration the cost of iron chelators as well as the cost of being transfused every three to four weeks, it is also considerable," she said. "Thalassemia care is by no means inexpensive in its current form."
The questions that remain
Dr. Douglas Higgs, professor of hematology and director of the MRC Haematology Unit at the University of Oxford in England, called the new study "important."
"Even though this is the best we can achieve at the moment, not all patients become free of transfusions and we still do not know the long-term effects of manipulating the genome of stem cells in this way," Higgs said in a statement.
"A major question hanging over this approach, which is hugely expensive, is whether this procedure, which involves killing off abnormal stem cells to replace them with modified stem cells, will ever become clinically possible in developing countries where the majority of these disorders of hemoglobin occur," he said.
Dr. Alessandra Biffi, director of the gene therapy program at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and an associate professor of pediatrics at Harvard Medical School, wrote an editorial published alongside the new study in The New England Journal of Medicine.
"Beta-thalassemia is one of the first examples in which gene therapy could be applied to a large population of patients who reside mostly in developing countries," Biffi wrote.
"Thus, the large-scale feasibility and cost management of this potentially curative treatment, as well as of the other gene therapies being developed for beta-thalassemia, present exciting challenges for the gene-therapy community," she wrote.
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