Positive results for Casgevy but with one patient death from myeloablative busulfan conditioning | ASH 2025

Researchers reported positive clinical trial results for the pioneering gene therapy Casgevy (exagamglogene autotemcel) in young children at the annual meeting of the American Society of Hematology (ASH) today, but they also reported that one child died from multiorgan failure from the chemotherapy used to prepare patients’s bone marrow for gene therapy.

The results were from two trials, one that enrolled children with sickle cell disease and another that enrolled children with beta thalassemia that requires treatment with blood infusions. The child who died had beta thalassemia, a genetic disorder that results in low hemoglobin levels.

Treatment with Casgevy is a multistep process that involves removing blood stem cells, genetically modifying them, and then reinfusing them back into the patient. Before the stem cells are reinfused, patients are treated with busulfan, a harsh chemotherapy agent that has been in use since the 1950s, to ablate existing bone marrow cells, which allows the infused, genetically modified stem cells to take hold, or “engraft.” Veno-occlusive liver disease, when the small blood vessels in and leading into the liver become blocked, is a well-characterized side effect of busulfan, and that is what happened in this case.

“Unfortunately, one pediatric participant with TDT [transfusion-dependent beta thalassemia] died of pneumonia in the setting of multiorgan failure, secondary to veno-occlusive disease of the liver [VOD], and we know that fatal VOD is a known complication of busulfan chemotherapy,” Haydar Frangoul, M.D., M.S., a hematologist/oncologist and the medical director of pediatric hematology/oncology for the Sarah Cannon Pediatric Transplant and Cellular Therapy Program at TriStar Centennial Medical Center, both in Nashville, Tennessee, said at a press briefing on Wednesday in advance of the research being presented at the hematology meeting.

Frangoul said two, or 15.3%, of 13 patients with TDT developed veno-occlusive disease of the liver, which he said was “very comparable” to the 12.5% rate in the older patients, ages 12 to 35.

At the 2024 ASH annual meeting, Beam Therapeutics reported that a study participant in a trial of its experimental gene-editing therapy (a possible competitor to Casgevy) died of respiratory failure that the trial investigators traced back to busulfan, not the gene therapy. In the phase 3 trial of Casgevy that led to its approval as a treatment for sickle cell disease in individuals 12 and older, a study participant who had lung disease attributed at least in part to busulfan died from COVID-19 infection.

The FDA approved Casgevy as a one-time treatment for sickle cell disease in patients 12 and older in December 2023 and as a treatment for transfusion-dependent beta thalassemia in the same age group in January 2024.

The results presented at the ASH meeting today are from trials assessing Casgevy as a treatment for transfusion-dependent thalassemia and sickle cell disease in children ages 2 to 11, although the data shared today was confined to a smaller group of children ages 5 to 11. As of April 10, 2025, 13 children in that age group with transfusion-dependent beta thalassemia had been treated with Casgevy and 11 with sickle cell disease. Frangoul said approximately half (5 of 13) of the children with transfusion-dependent beta thalassemia had the most severe genotype of the disease, and all of the patients with sickle cell disease did

Not needing a transfusion (“transfusion independence”) for 12 consecutive months or more was the primary end point in the trial that enrolled children with beta thalassemia. Frangoul said that all six of the patients for whom there was 12 months of follow-up had met that end point, and the mean duration of transfusion independence was 19.8 months, ranging from 14 months to 22 months. He also reported that 12 of the 13 participants stopped red blood cell transfusions at an average of 1.3 months and that the duration of transfusion independence ranged from 2.3 months to 22.5 months.

The written abstract summarizing the research results says that the total hemoglobin and fetal hemoglobin levels increased by approximately the same amount in these young children treated with Casgevy as they did in adolescents and adults treated with the CRISPR-edited gene therapy.

Among the children with sickle cell disease, all four for whom there was 12 months of follow-up reached the end point of 12 months or more without a vaso-occlusive crisis, according to Frangoul. (Vaso-occlusive crises occur when the misshapen red blood cells of sickle cell disease block blood vessels. The blockages cause ischemic pain and possible damage to oxygen-deprived tissue.) Frangoul said that none of the children with sickle cell disease treated with Casgevy had had a vaso-occlusive crisis and that the follow-up period ranged from 3.2 months to 24.1 months.

The written abstract of the trial results also mentions that increases in fetal hemoglobin among the patients with sickle cell disease were similar in this cohort of young children to the increase seen in the age group of 12 and older.