Counseling Patients On Exa-cel Gene Therapy Journey, With Haydar Frangoul, MD, MS

Following the US Food and Drug Administration (FDA)’s expanded approval of exagamglogene autotemcel (exa-cel; Casgevy) for children ≥2 years of age with sickle cell disease (SCD) and recurrent vaso-occlusive crises (VOCs) or transfusion-dependent β-thalassemia (TDT), the next challenge will be helping patients and families understand what undergoing gene therapy actually entails.

“I think we need to be more thoughtful about explaining the gene therapy journey, what I call it, because it's truly a journey,” Haydar Frangoul, MD, MS, director of the pediatric stem cell transplant program at Sarah Cannon Research Institute and TriStar Centennial Children’s Hospital and first author of multiple landmark exa-cel studies told HCPLive.

Explaining the Gene Therapy Process

Unlike an allogeneic bone marrow transplant, where a donor provides stem cells for a recipient, exa-cel uses a patient’s own hematopoietic stem cells that are collected, genetically modified, and returned after treatment.

“The therapy is long, so unlike a bone marrow transplant, when you have a donor and you have a recipient and you can bring them in, and you can do a transplant within few weeks,” explained Frangoul. “Here, you have to collect the cells, you have to manufacture them.”

The manufacturing process adds several steps before infusion, requiring patients and families to understand that treatment involves a longer timeline than traditional transplantation.

In the phase 3 pediatric studies supporting the expanded indication, children underwent collection of their own stem cells followed by ex vivo CRISPR/Cas9 editing and myeloablative conditioning with busulfan before receiving exa-cel.

How to Counsel Patients on Myeloablative Conditioning

Before receiving exa-cel, patients undergo myeloablative conditioning to prepare the bone marrow for the edited cells. For many individuals with SCD or TDT, this may be their first experience with intensive chemotherapy.

“Unlike our patients that we treat, for example, in the setting of cancer therapy, where they get a bone marrow transplant, they have received chemo, they have lost their hair, they have developed complications related to chemotherapy. Here, in this therapy, people with sickle cell disease and thalassemia have never received chemo.”

Frangoul emphasized that counseling should include both the immediate effects of chemotherapy and the temporary immune suppression associated with conditioning.

“The discussion should include the short-term side effect of chemotherapy, which includes the loss of your hair, the development of mouth sores, the immune suppression as far as decreasing the immune system.”

While exa-cel avoids risks associated with donor transplantation, including graft-versus-host disease and graft rejection, conditioning-related toxicities remain an important consideration. In the pediatric phase 3 study, all participants experienced ≥ 1 grade 3 or 4 adverse event. Two children with TDT developed severe veno-occlusive liver disease considered related to busulfan conditioning, including 1 death.

Discussing Fertility Before Treatment

Beyond short-term toxicities, Frangoul highlighted fertility as one of the most important long-term considerations before beginning therapy.

“The big one is infertility. So there is a higher risk of infertility with using busulfan chemotherapy, and individuals, parents, and children and adults considering this therapy need to consider whether they would want to pursue fertility preservation before this therapy.”

Because exa-cel is now being considered for younger patients, including children and adolescents, fertility preservation discussions may become an increasingly important part of treatment planning.

For clinicians, these conversations provide an opportunity to help families weigh the potential benefits of gene therapy alongside the risks and practical considerations involved in undergoing treatment.

Editor’s Note: Frangoul reports relevant disclosures with Vertex Pharmaceuticals, Editas Medicine, Rocket Pharmaceuticals, and others.

References

1. US Food and Drug Administration. FDA approves first gene therapy fsor young children with sickle cell disease. July 1, 2026.

2. Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649-1662. doi:10.1056/NEJMoa2309676.

3. Frangoul H, et al. Exagamglogene autotemcel in children with severe sickle cell disease and transfusion-dependent β-thalassemia. N Engl J Med. 2026.