Multiple insertions were observed in affected participants, including insertions in the MECOM and PRDM16 genes.
Ongoing investigations into cases of myelodysplastic syndrome (MDS) after treatment with elivaldogeneautotemcel (eli-cel; Lenti-D lentiviral vector [LVV]-transduced autologous CD34+ cells) have concluded that more study is necessary of the LVV-mediated oncogenesis but that the gene therapy offers significant clinical benefit to patients with cerebral adrenoleukodystrophy (CALD).
Further analysis of the MDS and clonal dominance cases were presented by David A. Williams, MD, associate chairman, department of pediatric oncology, Dana-Farber Cancer Institute, and chief, hematology/oncology, Boston Children's Hospital, at the 2022 American Society of Gene and Cell Therapy Annual Meeting, taking place May 16-19, 2022 in Washington, DC.
“These cases highlight the need for long-term follow-up and further investigation into the significance of multiple insertions, disease-specific factors, and specific design features of the Lenti-D LVV that could contribute to the development of MDS,” Williams and colleagues wrote.
Eli-cel expresses ABCD1 cDNA with a MNDU3 promoter to restore production of adrenoleukodystrophy protein. Insertional mutagenesiswas not identified as a quantifiable hazard with non-clinical assessments including the In Vitro Immortalization assay, but the cases of MDS are likely mediated by lentiviral vector insertion due to mRNA overexpression.
Eli-cel has been administered to 55 patients with CALD as of March 2021 in the ALD-102 (NCT01896102), ALD-104 (NCT03852498), and LTF-304 (NCT02698579) long-term follow-up studies. The therapy has been shown to be efficacious in this population, with 91% of evaluable patients in the ALD-102 study remaining alive and free of major functional disabilities 24 months post-infusion.
The gene therapy has been well-tolerated in safety endpoints that assessed the effects of mobilization/apheresis and conditioning regimens but 3 participants were diagnosed with MDS in July, August, and November 2021, 2 from ALD-104 with single lineage dysplasia without excess blasts at 14 and 26 months post-infusion, and 1 from ALD-102 with excess blasts 92 months after treatment. An additional participant had benign clonal predominance.
Both patients from ALD-104 achieved platelet engraftment greater than 100 days after infusion and subsequently underwent allogeneic hematopoietic stem cell transplantation. Investigators performed insertion site analysis (ISA) and found clonal predominance at 6 months post-infusion that included a single insertion in the MECOM gene. Further analysis revealed no typical driver mutation of myeloid neoplasms.
ISA revealed that the patient from ALD-102 had insertions in multiple genes, including PRDM16, but not MECOM. This patient has completed the first cycle of chemotherapy. The patient with benign clonal predominance did have insertion in MECOM. The clonal predominance has expanded and persisted up to 77 months after treatment but there have been no signs of dysplasia or hematologic malignancy and peripheral blood counts remain normal.
“The methodology of ISA has evolved over time... we're continuing with further investigations into the significance of the multiple insertions and disease-specific factors that may be contributing... The design of the lentivirus is probably contributing to the MDS... Most of the patients in our cohort have clinically benefited from this treatment. So, the clonal expansions that can evolve to MDS, we need to continue to consider in the context of the alternative which is an allogeneic transplant,” Williams said during his presentation.
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