Gene Therapy for Fanconi Anemia [Group A]: Interim Results of RP-L102 Clinical Trials

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.3968-3968
• Main Authors: Czechowicz, Agnieszka, Sevilla, Julián, Agarwal, Rajni, Booth, Claire, Zubicaray, Josune, Río, Paula, Navarro, Susana, Ancliff, Philip, Sebastian, Elena, Beard, Brian C, Law, Kenneth M, Choi, Grace, Zeini, Miriam, Duran-Persson, Camilla, Nicoletti, Eileen, Wagner, John E, Rao, Gayatri R, Thrasher, Adrian J., Schwartz, Jonathan D, Bueren, Juan A, Roncarolo, Maria Grazia
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-147071

▪ Background: Fanconi anemia (FA) is a disorder of defective deoxyribonucleic acid (DNA) repair, progressive bone marrow failure (BMF), and a predisposition to hematologic malignancies and solid tumors. Approximately 60 to 70% of all cases result from a mutation in the Fanconi Anemia Complementation Group A (FANCA) gene (FA-A). 80% of FA patients experience BMF within the first decade of life. Allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative for BMF; however, its efficacy is limited by human leukocyte antigen (HLA)-matched sibling donor availability and transplant-related toxicities. Lentiviral mediated gene therapy utilizing autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) confers a proliferative advantage to gene-corrected HSPCs as demonstrated in preclinical studies and the FANCOLEN-I clinical trial conducted in Madrid, Spain. We report results from ongoing RP-L102 studies using “Process B” manufacturing optimizations including transduction enhancers, commercial grade vector, and modified cell processing. Methods: Patients (pts) with a FANCA gene mutation, age ≥1 year with no HLA-matched sibling donor and at least 30 CD34+ cells/µL in bone marrow (BM) are eligible. Peripheral blood (PB) mononuclear cells are collected via leukapheresis on 2 consecutive days after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. CD34+ HSPCs are enriched, transduced with a lentiviral vector encoding for the FANCA gene (PGK-FANCA-WPRE) and infused without cryopreservation or conditioning. Patients are followed for 3 years post-infusion for safety assessments (replication competent lentivirus [RCL], insertion site analysis [ISA]) and to ascertain evidence of efficacy (increasing PB and BM vector copy number [VCN] and mitomycin-C [MMC] resistance in BM colony forming units [CFUs]), along with stabilization/correction of cytopenias. Results: As of March 2021, 9 pts (aged 2 to 6 years) have received RP-L102. Evidence of engraftment has been identified in 6 pts with ≥6 months of follow up as indicated by PB VCN. 2 of 3 pts with follow up of ≥12 months have shown increased MMC resistance in BM CFUs. 1 pt developed BMF requiring alloHSCT after influenza B infection. 1 pt had a serious Grade 2 transient RP-L102 infusion-related reaction. Updated safety and efficacy data for pts with ≥12 months of follow-up will be presented. Conclusions: RP-L102's safety profile remains favorable. Increasi