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E - Disease Models and Clinical Applications -> Hematologic and Immunologic Diseases

217: Lentiviral-Mediated Gene Therapy for Fanconi Anemia [Group A]: Results from Global RP-L102 Clinical Trials

Type: Oral Abstract Session

Presentation Details
Session Title: Hematologic and Immunologic Diseases
Location: Room 501 ABC
Start Time: 5/18/2023 16:30
End Time: 5/18/2023 16:45

Background: Fanconi anemia (FA) is an inherited deoxyribonucleic acid (DNA) repair disorder that results in progressive bone marrow failure (BMF) in 80% of patients within the first decade of life. Allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative for FA-related BMF. Although survival exceeds 80% in experienced transplant centers, adverse effects including 100-day mortality and increased cancer risk present persistent limitations. The current studies utilize autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) and rely upon the proliferative advantage of gene-corrected FA HSPCs, enabling engraftment without conditioning. We report results from global RP-L102 studies. Methods: Patients with FANCA mutations, age ≥1 year with no HLA-matched sibling donor and ≥30 CD34+ cells/µL in bone marrow (BM) are eligible. Peripheral blood (PB) cells are collected via leukapheresis. Following CD34+ enrichment, HSPCs are transduced with a lentiviral vector carrying the FANCA gene, and infused without cryopreservation or conditioning. Patients are followed for 3 years for safety assessments (including insertion site analysis [ISA]) and for evidence of efficacy (increasing vector copy number [VCN], mitomycin-C [MMC] resistance in BM colony forming cells [CFCs]), and stabilization/correction of cytopenias). Results: As of October 2022, 12 patients age 2 to 6 years have received RP-L102. Sustained engraftment has been demonstrated in 7 of 10 evaluable patients with ≥12 months of follow up as indicated by peripheral blood mononuclear cell (PBMC) VCN (median: 0.53; range: 0.19-0.65 at 12-40 months). Six of these 7 patients have increasing BM CFC MMC resistance with concurrent hematologic stabilization (median: 85%; range: 22-94% at 12-40 months). One patient without genetic correction had progressive BMF and underwent successful alloHSCT. A transient serious Grade 2 RP-L102 infusion-related reaction was observed in one patient and resolved without sequelae. No patients have developed RCL. One patient developed T cell lymphoblastic lymphoma determined to be unrelated to gene therapy. There has been no evidence of RP-L102 related bone marrow dysplasia, clonal dominance or insertional mutagenesis. Conclusions: RP-L102 conferred phenotypic correction as demonstrated by sustained increase in BM CFC MMC resistance, genetic correction and hematologic stabilization in at least 6 patients with ≥1 year of follow up. Sustained engraftment, phenotypic correction, and hematologic stability was achieved in the absence of conditioning. RP-L102 represents a potentially curative therapy for FA-related BMF, which can be administered without transplant-conditioning related toxicities. Updated results for patients (n=12) with ≥ 1 year of follow-up will be presented.

Agnieszka Czechowicz1,2,3, Julián Sevilla4, Claire Booth5, Susana Navarro6, Rajni Agarwal1,2,3, Josune Zubicaray4, Paula Río6, Kritika Chetty5, Gráinne O'Toole5, Jinhua Xu-Bayford5, Philip Ancliff5, Elena Sebastián4, Grace Choi7, Miriam Zeini7, Eileen Nicoletti7, Cindy Eide8, John E. Wagner8, Gayatri Rao7, Adrian J. Thrasher5, Jonathan Schwartz7, Maria-Grazia Roncarolo1,2,3, Juan A. Bueren6

1Stanford School of Medicine, Palo Alto, CA,2Lucile Packard Children's Hospital, Palo Alto, CA,3Center for Definitive and Curative Medicine, Palo Alto, CA,4HIUNJ/CIBERER, Madrid, Spain,5UCL Great Ormond Street Institute of Child Health, London, United Kingdom,6CIEMAT/CIBERER/IIS-FJD, Madrid, Spain,7Rocket Pharmaceuticals, Inc., Cranbury, NJ,8University of Minnesota, Minneapolis, MN
  A. Czechowicz: 1; Commercial Interest i.e. Company X; 48 Bio, GV, Lyrik Therapeutics, Prime Medicine, Spotlight Therapeutics, Stemodontics, Teiko Bio. 1; What was received? i.e. Honorarium; Consultant Fee. 1; For what role? i.e. Speaker; Consultant. 2; Commercial Interest i.e. Company X; 48 Bio, Beam Therapeutics, Decibel Therapeutics, Editas Medicine, GV, Lyrik Therapeutics, Magenta Therapeutics, Prime Medicine, Spotlight Therapeutics, Stemodontics, Teiko Bio. 2; What was received? i.e. Honorarium; Equity. 2; For what role? i.e. Speaker; Other. 3; Commercial Interest i.e. Company X; Rocket Pharmaceuticals, Inc., Jasper Pharmaceuticals, STRM.Bio. 3; What was received? i.e. Honorarium; Research Funding. 3; For what role? i.e. Speaker; Other.

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