Safety Of Autologous Hematopoietic Stem Cell Transplantation With Gene Addition Therapy For Transfusion-Dependent Beta-Thalassemia, Sickle Cell Disease, And Cerebral Adrenoleukodystrophy

Introduction Allogeneic hematopoietic stem cell (HSC) transplantation (allo-HSCT) is a treatment option for several monogenic diseases; however, its use is limited by the need for a matched donor and risk of HSCT-related complications. Autologous HSC gene addition does not have some of these limitations and may have similar efficacy with an improved safety profile. Ex vivo gene addition therapy using lentiviral vectors (LVV) is being evaluated in patients with transfusion-dependent β-thalassemia (TDT) using betibeglogene autotemcel (beti-cel, LentiGlobin for TDT) in the HGB-204, -205, -207, and -212 studies, sickle cell disease (SCD) using LentiGlobin for SCD in HGB-205 and -206, and cerebral adrenoleukodystrophy (CALD) using Lenti-D in ALD-102. The safety outcomes following autologous gene modified HSCT in these ongoing studies are summarized. Methods HSCs are collected using disease-appropriate procedures, then CD34+ cells are transduced with LVV encoding disease-specific therapeutic transgenes. After myeloablation with busulfan (SCD, TDT) or busulfan/cyclophosphamide (CALD), patients are infused with LVV-transduced CD34+ HSCs. Patients are followed for two years and offered participation in long term follow-up studies (LTF-303 [NCT02633943] or LTF-304 [NCT02698579]). Results Across all 6 studies, 110 patients have been treated as of most recent analyses (Table 1). Patients have been followed for 2 years follow-up. No patient experienced primary or secondary graft failure. One patient with CALD experienced disease progression and died 22 months after drug product (DP) infusion of disease complications. Two additional patients with CALD withdrew from the study after DP infusion and were referred for allo-HSCT. All other patients with CALD, TDT, and SCD remain alive. Most (107/110) patients had ≥ one grade 3 or 4 adverse event (AE) attributed to conditioning; most common AEs were cytopenia, febrile neutropenia, and stomatitis. Myelodysplastic syndrome was reported in one patient with SCD. After investigation for LVV insertion in malignant cells, the AE was assessed as not related to LentiGlobin insertion or transgene expression. AEs reported as related to the DP are shown in Table 1. There was no GVHD and no clinically relevant clonal dominance or LVV-mediated replication competent lentivirus. Summary Data from 110 patients followed for up to 5 years supports that the safety profile of gene-modified autologous HSCT does not carry the risks of GVHD, graft rejection, and long-term immunosuppression attendant to allo-HSCT. While the safety profile beyond 5-years is still being established, these data suggest that HSC gene therapy may be an acceptable therapy for patients with TDT, SCD, and CALD, particularly in patients at increased risk of complications from allo-HSCT, such as those who lack a suitable donor or are more advanced in age.