Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy.

Area of Science:

• Hematology
• Oncology
• Gene Therapy
• Molecular Biology

Background:

• Elivaldogene autotemcel (eli-cel) gene therapy, utilizing lentiviral vectors with ABCD1 cDNA, has demonstrated efficacy in treating cerebral adrenoleukodystrophy.
• The potential oncogenic risk associated with eli-cel treatment remains an area of clinical concern.

Purpose of the Study:

• To investigate the oncogenic risk of elivaldogene autotemcel (eli-cel) gene therapy.
• To analyze integration sites and genetic alterations in patients who developed hematologic malignancies after eli-cel treatment.

Main Methods:

• Integration-site analysis, genetic studies, flow cytometry, and morphologic assessments were performed on peripheral blood and bone marrow samples.
• Data were collected from patients participating in eli-cel clinical trials (ALD-102, ALD-104) and a follow-up study (LTF-304).

Main Results:

• Seven out of 67 patients developed hematologic cancers, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
• Predominant clones in affected patients showed lentiviral vector insertions at oncogenes like MECOM-EVI1 and PRDM16, along with somatic mutations (e.g., KRAS, NRAS, WT1).
• Allogeneic hematopoietic stem-cell transplantation (HSCT) led to remission in most patients with MDS, while the patient with AML achieved donor chimerism.

Conclusions:

• Hematologic malignancies in a subset of eli-cel treated patients are linked to clonal vector insertions in oncogenes and subsequent acquisition of genetic defects.
• These findings highlight the importance of ongoing monitoring for oncogenesis in gene therapy recipients.