Successful Gene Therapy for Cerebral Adrenoleukodystrophy Linked to Increased Risk for Blood Cancer

Treatment with the gene therapy elivaldogene autotemcel (eli-cel) significantly extended overall survival and freed patients with cerebral adrenoleukodystrophy of major functional disabilities longer than hematopoietic stem cell transplant. However, 7 of 67 patients involved in two clinical trials developed blood cancers within 4 months of treatment.

The findings come from a study published in the New England Journal of Medicine that examined the drivers behind the development of hematologic cancer following treatment in a subset of patients.

Cerebral adrenoleukodystrophy (cerebral ALD) is caused by a mutation in the ABCD1 gene. The condition primarily affects young boys (typically between 4 and 10 years of age) and results in an inability break down very-long-chain fatty acids (VLCFAs), which accumulate in the body’s tissues. The buildup of saturated VLCFAs that build up in the brain, nervous system and adrenal gland may result in inflammation and damage to the myelin covering nerve fibers. The brain becomes less able to transmit signals to other parts of the body and there is an increased risk for paralysis.

Eli-cel, marketed as Skysona by Bluebird Bio, is a gene therapy that involves the transplant of autologous CD34+ cells that have been transduced with a lentiviral vector containing ABCD1 complementary DNA. The therapy was approved by the U.S. Food and Drug Administration in 2022 for treatment of males, aged 4 to 17 years old, with evidence of early and active cerebral ALD.

Two completed trials (ALD-102 and ALD-104) with ongoing long-term follow-up were integrated into the LTF-304 study. Seven patients developed hematologic cancer — six with myelodysplastic syndrome (MDS) and one with acute myeloid leukemia (AML). Five patients with MDS subsequently underwent allogeneic HSCT, with 4 remaining free of MDS without recurrence of symptoms of cerebral ALD; one patient died from presumed graft-versus-host disease after HSCT. The patient with AML also underwent HSCT and is alive. The most recent patient to develop MDS is alive and awaiting HSCT.

The researchers concluded that the cases were associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects.

In an accompanying editorial, Cynthia E. Dunbar, of the translational Stem Cell Biology Branch of the National Heart, Lung, and Blood Institute, noted that survival following fully matched HSCT was not as great as with eli-cel. In addition, it’s estimated that only 20% of the boys with cerebral ALD have a matched donor for HSCT.

“Autologous gene therapy for cerebral adrenoleukodystrophy has, strikingly, preserved neurologic function and extended life in patients treated early in the disease course, and I hope that vector modifications can make the process less genotoxic in the future,” Dunbar wrote.