S1633 UPDATED RESULTS FROM THE HGB-206 STUDY IN PATIENTS WITH SEVERE SICKLE CELL DISEASE TREATED UNDER A REVISED PROTOCOL WITH LENTIGLOBIN GENE THERAPY USING PLERIXAFOR-MOBILISED HAEMATOPOIETIC STEM CELLS
Authors: J. Kanter, A.A. Thompson, M.Y. Mapara, J.L. Kwiatkowski, L. Krishnamurti, M. Schmidt, A.L. Miller, F.J. Pierciey, W. Huang, J.-A. Ribeil, M.C. Walters, J.F. Tisdale
Journal: HemaSphere (2019)

Background: β-globin gene transfer can modulate and may even correct the clinical expression of sickle cell disease (SCD). LentiGlobin gene therapy (GT) contains autologous CD34+ haematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), which encodes β-globin with an anti-sickling substitution (HbAT87Q). In 7 patients with severe SCD treated with LentiGlobin GT in the Phase 1/2, HGB-206 study (NCT02140554) under the original protocol and with drug product (DP) made from bone marrow harvested (BMH) HSCs (Group A, fully enrolled), HbAT87Q production was stable, but suboptimal. The protocol was revised to include pre-harvest red blood cell (RBC) transfusions, higher target busulfan levels, and refined DP manufacturing (Group B, fully enrolled). Patients in Group C were treated under the revised protocol and with DPs made from plerixafor-mobilised HSCs. Aims: To describe the safety and efficacy of LentiGlobin GT in Group C patients in the ongoing HGB-206 study. Methods: Adults with severe SCD (history of recurrent vaso-occlusive crisis, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were enrolled. Before HSC collection, patients in Group C received ≥2 months of RBC transfusions, targeting Hb of 10 – 12 g/dL and HbS <30% of total Hb. CD34+ HSCs were collected by aphaeresis 4 – 6 hours post 240 microg/kg plerixafor and transduced with the BB305 LVV. After myeloablative busulfan, DP was infused and patients were monitored for adverse events (AEs), engraftment, HbAT87Q levels, and haemolysis markers. Summary statistics are median (min – max). Results: Nine Group C patients (25 [19 – 35] years old) were treated with LentiGlobin GT as of 14 Sep 2018, with 5.2 (0.5 – 9.2) months of follow-up. The DP vector copy number was 3.8 (2.8 – 5.6) copies/diploid genome and cell dose was 6.5 (3 – 8) x106 CD34+ cells/kg, with 81 (68 – 90) % CD34+ cells transduced. As of 14 Sep 2018, 8 and 7 patients achieved neutrophil and platelet engraftment, at 20 (18 – 24) and 28 (19 – 136) days, respectively. Febrile neutropenia (n = 6) and stomatitis (n = 6) were the most common non-haematologic Grade ≥3 AEs post DP infusion. No DP-related AEs, AEs of veno-occlusive liver disease, or graft failure were reported. Early data show no clonal dominance or vector-mediated replication competent lentivirus. There were no vaso-occlusive events post DP infusion as of datacut date. In 8 patients with ≥1 month follow-up, median HbAT87Q at last visit was 4.6 (2.5 – 8.2) g/dL. At last visit in 4 patients with ≥6 months follow-up, total Hb was 9.9 – 13.7 g/dL without RBC transfusions, with 47 – 60% comprised of HbAT87Q, which nearly equalled or exceeded HbS levels (38 – 49% of total Hb). Baseline reticulocyte counts, total bilirubin, and lactate dehydrogenase were 380 (349 – 415) x109/L (n = 4), 56 (29 – 86) micromol/L (n = 9), and 354 (226 – 738) U/L (n = 7), and at last visit decreased by a median of 64%, 70%, and 45%, respectively. Preliminary data from an exploratory assay to study HbAT87Q expression in RBCs by an anti-βS antibody suggest pancellular distribution of HbAT87Q. Summary/Conclusion: After instituting protocol changes including the use of plerixafor-mobilised HSCs in Group C, we observe that HbAT87Q production at ≥6 months follow-up nearly equalled or exceeded HbS levels. Safety profile of LentiGlobin GT in SCD is consistent with known side effects of HSC collection and myeloablative conditioning, and with underlying SCD. Data from additional patients enrolled under an amended protocol and inclusion of adolescents will help assess the clinical impact of LentiGlobin GT in SCD.