Lentiviral-Mediated Gene Therapy for Patients with Fanconi Anemia [Group a]: Updated Results from Global RP-L102 Clinical Trials
Authors: Czechowicz Agnieszka D. , Sevilla Julián , Booth Claire , Zubicaray Josune , Rio Paula , Navarro Susana , Cherry Kritika , O'Toole Gráinne , Xu-Bayford Jinhua , Ancliff Philip , Sebastián Elena , Rothe Michael , Bastone Antonella L , John-Neek Philipp , Schambach Axel , Wang Wei , Choi Grace , Zeini Miriam , Nicoletti Eileen , Eide Cindy , Wagner John E , Rao Gayatri R , Thrasher Adrian J. , Roncarolo Maria-Grazia , Schwartz Jonathan D , Bueren Juan A , Agarwal Rajni 
Published: December 2024

Background: Fanconi Anemia (FA) is a rare inherited deoxyribonucleic acid (DNA) repair disorder that results in progressive and severe bone marrow failure (BMF) within the first decade of life in 80% of patients. Allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative of BMF, with survival exceeding 80% in experienced centers. AlloHSCT is limited by donor availability and patients may experience short- and long-term toxicities, including 100-day transplant associated mortality, graft-vs-host disease (GvHD), and 3- to 4-fold increased cancer risk. Mozafancogene autotemcel (fanca-cel; RP-L102) is a gene therapy product comprised of autologous hematopoietic stem and progenitor cells (HSPCs) transduced with a lentiviral vector (LV) encoding a functional copy of the FANCA gene. In contrast to alloHSCT, fanca-cel is administered without antecedent conditioning, relying on the proliferative advantage of the gene-corrected cells to enable engraftment. Here, we present data from patients with FA complementation group A (FA-A) treated with fanca-cel in global Phase 1/2 studies with ≥1 year of follow-up.
Methods: Patients with FANCA mutations, age ≥1 year, no HLA-matched sibling donor and ≥30 CD34+ cells/µL in bone marrow (BM) were eligible. Peripheral blood (PB) mononuclear cells were collected via leukapheresis after mobilization with granulocyte colony-stimulating factor (G-CSF) and plerixafor. Following CD34+ enrichment, HSPCs were transduced with an LV carrying the FANCA gene and infused without cryopreservation or conditioning. Patients are being followed for safety and efficacy (increasing vector copy number [VCN], mitomycin-C [MMC] resistance in BM colony forming cells [CFCs]), and stabilization of cytopenias for 3 years in both the parent study and subsequently in a long-term follow-up (LTFU) study.
Results: As of September 2023, 14 patients aged 1 to 6 years at enrollment have undergone successful apheresis and treatment with fanca-cel without significant complications. Mean (SD) age at infusion was 4.05 (1.65) years (range: 1.8-7.0 years); 57.1% were female and majority of the patients were White (not Hispanic or Latino). Twelve patients have ≥12 months of follow-up; mean (SD) follow-up was 2.95 (0.97) years (range: 1.5-4.5 years). Progressive and sustained genetic correction was observed in 8 of the 12 patients with ≥12 months of follow-up, indicative of the corrected cells' proliferative advantage. Improvement in BM MMC-resistance, demonstrative of phenotypic correction, was identified in 7 patients at 12 months post-gene therapy; one additional patient developed BM MMC-resistance and preliminary evidence of hematologic stabilization after 36 months, during the LTFU observation. Genetic and phenotypic correction have been associated with sustained hematologic stability. Additional data will be presented at the time of the meeting.
The most common treatment-emergent adverse events (TEAEs) were pyrexia, anemia, thrombocytopenia, upper respiratory tract infection, and neutropenia. The majority of TEAEs were mild/moderate in severity, non-serious, and unrelated to fanca-cel. One patient experienced a Grade 2 transient infusion-related reaction that resolved without additional clinical sequelae. Overall clonality and diversity indices (Gini, Shannon, and UC50) indicated predominantly polyclonal integration patterns. There were no signs of bone marrow dysplasia, clonal dominance or insertional oncogenesis related to fanca-cel. No patients developed myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Two patients were withdrawn from the study and underwent successful alloHSCT for BMF (n=1) and an unrelated thoracic non-Hodgkin lymphoma (n=1).
Conclusions: Fanca-cel is a potentially curative therapy to prevent FA-related BMF, does not require a suitable allogeneic donor, and does not confer alloHSCT-related toxicities. Progressive engraftment of gene-corrected cells was identified in 8 patients with ≥1 year of follow-up in the absence of conditioning and attendant risks. Genetic correction and concomitant phenotypic correction are associated with sustained hematologic stabilization. Fanca-cel has been well-tolerated with no significant safety signals. The risk-benefit profile of fanca-cel appears favorable.