Children living with rare blood disorders face serious clinical risks and lifestyle disruptions. Fortunately, multiple gene therapies have emerged in recent years, providing new opportunities to reduce the impact these conditions have on children and their families.
Andrew Koh, M.D., Pediatric Hematologist/Oncologist at Children’s HealthSM and Associate Professor at UT Southwestern, discusses four new gene therapies and how they are changing the outlook for children with rare blood disorders. All four therapies are available at Children’s Medical Center in Dallas, part of the Children’s Health system, and the Pediatric Cellular and ImmunoTherapeutics Program (CITP), a joint venture between Children’s Health and UT Southwestern.
Which patients with rare blood disorders now have access to gene therapy?
The latest breakthroughs are in sickle cell disease (SCD). Two gene therapies, Lyfgenia and Casgevy, were approved in December 2023 for children ages 12 and older who have SCD and a history of vaso-occlusive events (VOEs). Casgevy was also just approved for children ages 12 and older with transfusion-dependent beta thalassemia (TDT).
The two therapies have similar efficacy in sickle cell disease (severe VOEs eliminated for more than 90% of clinical trial patients several months post-infusion) but different mechanisms of action. Lyfgenia uses edited versions of a child’s stem cells to produce healthy adult hemoglobin. Casgevy uses edited cells to enable production of fetal hemoglobin, an oxygen-rich form that compensates for the impaired adult hemoglobin otherwise produced by the child.
Two additional gene therapies have been available for other disorders since fall of 2022. Zynteglo is approved for children of all ages with TDT, but it’s important to note that clinical trials included no one younger than 4. Skysona is approved for boys ages 7 to 14 with early, active cerebral adrenoleukodystrophy (CALD). This means they are asymptomatic or mildly symptomatic and meet certain brain MRI criteria.
How do these gene therapies change the treatment landscape?
They give children an effective treatment option that goes far beyond basic symptom management without taking on the challenges of bone marrow transplant (BMT).
Before now, BMT was our only way to help children change the course or severity of their disorder, and we could only offer it to a fraction of patients. It’s very difficult to find a suitable donor, and even when you do, the risk of graft-versus-host disease (GVHD) is significant – up to 15% in SCD.
GVHD and donor compatibility aren’t problems with the four gene therapies, because they use a child’s own cells. As a result, many more children now have access to treatment that can significantly change what it means to live with their disorder.
What is your approach to mitigating risks and side effects?
Most side effects are associated with the chemotherapy regimen that precedes infusion – infection, mucositis, nausea, etc. Prevention and management are no different from how we care for children receiving chemo for bone marrow transplants or cancer.
That said, there are two acute risks to be aware of:
- Long-term risk of blood cancer with the four therapies is unknown as of now, because the trials followed children for just a handful of years. However, studies in conditions like severe combined immunodeficiency have shown that patients taking gene therapy can have a higher risk of developing cancer many years after treatment. So patients receiving these four new gene therapies are asked to join a registry for long-term monitoring and reporting.
- Infertility is another possible outcome of the chemo regimen. We have a team dedicated to fertility preservation who consults with children and parents about future family plans, assesses each child’s risk from low to high, and walks them through their options.
What does the future hold for these therapies?
The manufacturers may refine the chemo doses over time, which should help reduce side effects and improve the child’s overall experience of treatment. The current doses are based on what children receive for bone marrow transplants, because those doses are well established and trusted. Now the manufacturers can study how to tailor the dosage to these therapies and patient groups.
But the greatest benefits will come when these therapies are studied and approved for younger children. As children with CALD grow up, they risk developing very serious problems, from loss of communication to dependency on tube feeding. SCD also has long-term risks, such as delayed puberty, chronic medical comorbidities and decreased life expectancy. If we can provide gene therapy early in a child’s life, we may help them avoid setbacks like these.
How is Children’s Health leading the way in delivering complex care for rare diseases?
Because of our size and connection to UT Southwestern, we see more children with rare diseases than many centers. We’re passionate about giving our patients every available opportunity through:
- Early adoption: We applied for certification to provide each of these new therapies as soon as they became available. We are now a certified treatment center for Lyfgenia and Zynteglo. We were also one of the first pediatric centers certified to provide Kymriah, the CAR T-cell therapy for leukemia.
- Improving treatment protocols: I lead a lab that studies the role of gut microbiota in modulating the health of patients with cancer and blood disorders. For these new gene therapies, we will investigate how the healthy resident bacteria in the gut (the microbiome) can protect children from infections but also speed the time of engraftment and path to recovery.
- Leading our own research: Our CITP is spearheading a multicenter study in solid tumors, looking at why they don’t respond to immune checkpoint inhibitor therapy (ICT) in pediatric patients. We will see whether combining ICT with chemotherapy is more successful, as it is in some adult cancers.
Learn more about our exceptional care for pediatric blood disorders and cancers >>
