Cerebral adrenoleukodystrophy (CALD) is an uncommon genetic brain condition that mainly affects young boys, leading to a gradual deterioration in neurological function and, ultimately, premature death. A study led by researchers from Massachusetts General Hospital, along with Boston Children’s Hospital and their partners, revealed that six years after the first approved gene therapy for CALD, an impressive 94 percent of participants showed no decline in neurological abilities, with over 80 percent avoiding severe disabilities. These findings, shared in two articles in the New England Journal of Medicine, outline the long-term results for those who underwent the eli-cel gene therapy, while also addressing safety issues related to the potential development of blood cancers following the treatment.
“Cerebral adrenoleukodystrophy is a heartbreaking condition that affects children during their critical childhood development,” stated Florian Eichler, MD, who leads the Leukodystrophy Clinic in the Neurology Department at Massachusetts General Hospital and is the primary author of the long-term outcomes paper. “When I started treating CALD patients, 80 percent of them were in a critical state upon arrival at our clinic, but that situation has reversed. We cautiously celebrate the stabilization of this neurological disease and the opportunity to restore a fulfilling life to these children, but our joy is tempered by the occurrence of malignancies in some patients. We are actively working to understand and address this issue.”
In 2022, the U.S. Food and Drug Administration authorized the first gene therapy for CALD, known as elivaldogene autotemcel (eli-cel), which was evaluated clinically by researchers from Mass General and Boston Children’s Hospital. In the latest study, 32 boys aged 3 to 13 with early-stage CALD participated in the ALD-102 trial, which was backed by bluebird bio, Inc., the entity behind the therapy.
The therapy employs a Lenti-D lentiviral vector to introduce a properly functioning copy of the ABCD1 gene—which is defective in those affected by CALD—into blood stem cells extracted from the patient. These stem cells are then reinfused into the patient through an autologous hematopoietic stem cell transplantation (HSCT). This approach minimizes the risk of graft-versus-host disease compared to other treatment options.
During the ALD-102 trial, one patient developed myelodysplastic syndrome (MDS) with excess blasts, a type of blood malignancy that appeared to have been initiated by the Lenti-D lentiviral vector used for the gene therapy. In a subsequent trial (ALD-104), six out of 35 patients also experienced hematologic malignancies (MDS in five cases and acute myeloid leukemia in one), which seem to be linked to the vector as well. These findings were detailed in a second article published in the same journal edition. The ALD-104 trial differed from the first regarding the chemotherapy drug used during HSCT (fludarabine instead of cytoxan), among other modifications that could have influenced the heightened risk of leukemia seen in this trial.
“Our report discussing leukemias in this condition is an essential step in assessing the risks tied to the eli-cell therapy and lentiviral vector technology,” remarked Christine Duncan, MD, the medical director for Clinical Research and Clinical Development in the Gene Therapy Program at Boston Children’s Hospital and the lead author of the second report. “While the overall results of the trials are encouraging, we aspire to broaden our studies to provide families facing such a devastating illness with more insight and choices.”
The research team will persist in investigating the potential factors leading to hematologic malignancies, which are complex and not yet fully understood. Enhancing lentiviral vectors and optimizing HSCT protocols for CALD is of high priority. With the advancement of newborn screening for adrenoleukodystrophy, there is a greater chance for early detection of CALD, which could expand opportunities for identifying patients who may benefit from gene therapy, particularly those without suitable donors for allogeneic HSCT.
“As both a clinician and senior investigator, it is profoundly moving to see the significant progress we’ve made over the last decade in the battle against CALD,” stated David A. Williams, MD, who heads the Division of Hematology/Oncology at Boston Children’s Hospital. “Although the risks associated with gene therapy and vector technology are genuine, our advancements provide hope for families facing limited treatment options. Each step forward brings us closer to providing the answers these families urgently seek. Our commitment to enhancing the safety of the vector through ongoing research is steadfast, as we tirelessly endeavor to ensure the long-term safety and effectiveness of gene therapy solutions for this challenging disease. These efforts include contributions from multiple researchers globally and are currently in progress.”
