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I – Gene & Cell Therapy Trials in Progress -> Gene & Cell Therapy Trials in Progress

Myelodysplastic Syndromes after Eli-cel Gene Therapy for Cerebral Adrenoleukodystrophy (CALD)

Type: Oral Abstract Session

Presentation Details
Session Title: Late-Breaking Abstracts II
Location: Ballroom C
Start Time: 5/18/2022 8:45
End Time: 5/18/2022 9:00

As of March 2021, 55 patients with CALD had been treated with elivaldogene autotemcel gene therapy (eli-cel; Lenti-D lentiviral vector [LVV]-transduced autologous CD34+ cells) in ALD-102 (NCT01896102) and ALD-104 (NCT03852498) studies, with long-term follow-up in LTF-304 (NCT02698579). Lenti-D LVV was designed to express the ABCD1 cDNA to enable production of adrenoleukodystrophy protein (ALDP) across different cell lineages and contains the MNDU3 promoter. Non-clinical assessments, including the In Vitro Immortalization (IVIM) assay, did not identify insertional mutagenesis as a quantifiable hazard. In ALD-102, 91% of evaluable patients treated with eli-cel were alive and free of major functional disabilities 24 months (M) post-infusion. To date, the safety/tolerability of eli-cel treatment regimen primarily reflects effects of mobilization/apheresis and conditioning regimens, but 3 cases of myelodysplastic syndrome (MDS) were diagnosed in Jul, Aug and Nov 2021, and one finding suggestive of benign clonal predominance has been identified. Here, we present further details on these cases, including hematologic data received up to 31 January 2022. Two patients from ALD-104 were diagnosed with MDS with single lineage dysplasia without excess blasts at 14 and 26 M post-infusion. Notably, both patients achieved platelet engraftment >100 days after infusion. Insertion site analysis (ISA) revealed clonal predominance at first protocol assessment (M6), with 2 and 4 vector insertions in the predominant clones including, in both cases, a single insertion in the MECOM gene. Chromosome analysis, Fluorescence In-Situ Hybridization (FISH) and Rapid Heme Panel (RHP) analysis revealed no typical driver mutation of myeloid neoplasms. MDS cases were considered likely mediated by Lenti-D LVV insertion due to EVI1 dysregulation, specifically mRNA overexpression. Both patients have subsequently undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). One patient from ALD-102 developed MDS with excess blasts 92 M after eli-cel treatment. ISA detected insertions in multiple genes, including PRDM16. There was no evidence of a MECOM insertion. RHP showed somatic KRAS and NRAS mutations; chromosome analysis, hematologic malignancy fusion panel, and FISH did not reveal any abnormal findings. Investigations are ongoing to determine the role of Lenti-D LVV in MDS development. The patient has completed a first cycle of chemotherapy. In the separate patient with benign clonal predominance after treatment in ALD-102, a clone with multiple insertions, including a single MECOM insertion with EVI1 dysregulation, expanded and persisted over multiple years (follow up: 77M). Multiple bone marrow evaluations at 6-12 M intervals have revealed no signs of dysplasia or hematologic malignancy and peripheral blood counts remain normal. 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.

David A. Williams1, Jacob R. Bledsoe2, Christine N. Duncan1, Florian S. Eichler3, Bartosz Grzywacz4, Ashish O. Gupta5, Troy Lund5, Paul J. Orchard5, Sarah Slauson6, Dustin Whitney6, Jakob T. Sieker6, Geoffrey Parsons6

1Dana-Farber & Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA,2Dept of Pathology, Boston Children's Hospital, Boston, MA,3Massachusetts General Hospital & Harvard Medical School, Boston, MA,4Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Minneapolis, MN,5Division of Blood and Marrow Transplantation, Dept. of Pediatrics, University of Minnesota, Minneapolis, MN,6bluebird bio Inc., Cambridge, MA
  D.A. Williams: 1; Commercial Interest i.e. Company X; bluebird bio Inc.. 1; What was received? i.e. Honorarium; Licenced intellectual property for hemoglobinopathies to bluebird bio Inc.. Potential for future royalty/milestone income. Past income via BCH institutional licensing agreement. 1; For what role? i.e. Speaker; Consulting. 2; Commercial Interest i.e. Company X; bluebird bio Inc.. 2; What was received? i.e. Honorarium; GMP vector for SCD clinical trial. 2; For what role? i.e. Speaker; Independent contractor. 3; Commercial Interest i.e. Company X; Orchard Therapeutics. 3; For what role? i.e. Speaker; Co-founder. 4; Commercial Interest i.e. Company X; Orchard Therapeutics. 4; What was received? i.e. Honorarium; Research Funding/Potential for future royalty/milestone income. 4; For what role? i.e. Speaker; Independent contractor. 5; Commercial Interest i.e. Company X; Novartis. 5; What was received? i.e. Honorarium; Advisory fees donated to NAPAAC. 5; For what role? i.e. Speaker; Steering Committee Member. 6; Commercial Interest i.e. Company X; Alerion Biosciences (now licensed to Avro Bio). 6; What was received? i.e. Honorarium; Potential for future royalty/milestone income. 6; For what role? i.e. Speaker; Co-founder. 7; Commercial Interest i.e. Company X; Beam Therapeutics. 7; For what role? i.e. Speaker; Scientific Advisory Board Member. 8; Commercial Interest i.e. Company X; Emerging Therapy Solutions. 8; For what role? i.e. Speaker; Chief Scientific Chair. 9; Commercial Interest i.e. Company X; Geneception/Skyline Therapeutics. 9; For what role? i.e. Speaker; Scientific Advisory Board. 10; Commercial Interest i.e. Company X; Biomarin. 10; For what role? i.e. Speaker; Insertion Site Advisory Board.

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