S1632 SAFETY AND EFFICACY OF LENTIGLOBIN GENE THERAPY IN PATIENTS WITH TRANSFUSION‐DEPENDENT B‐THALASSAEMIA AND NON‐B0/B0 GENOTYPES IN THE PHASE 3 NORTHSTAR‐2 STUDY
Authors: Locatelli F. , Thompson A.A. , Hongeng S. , Porter J.B. , Sauer M.G. , Kwiatkowski J.L. , Thrasher A.J. , Thuret I. , Elliot H. , Tao G. , Colvin R.A. , Walters M.C. 
Published: June 2019

Background:Transfusion‐dependent β‐thalassaemia (TDT) is a severe genetic disease typically treated by regular, lifelong red blood cell (RBC) transfusions that may result in serious complications and organ damage. Most patients with TDT are not candidates for allogeneic haematopoietic stem cell (HSC) transplantation. LentiGlobin gene therapy is being investigated in patients with TDT and contains autologous CD34+ HSCs transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β‐globin with a T87Q amino acid substitution.Aims:To evaluate LentiGlobin gene therapy in paediatric, adolescent, and adult patients with TDT (≥100 mL/kg/yr of red blood cells [RBCs] or ≥8 RBC transfusions/yr) and non‐β0/β0 genotypes in the ongoing, international, single‐arm, phase 3 Northstar‐2 study (HGB‐207; NCT02906202).Methods:HSCs are mobilised with G‐CSF and plerixafor, collected by aphaeresis, and CD34+ cells are transduced with the BB305 LVV. Patients receive single‐agent, pharmacokinetic‐adjusted, myeloablative busulfan before the transduced cells are infused. The primary endpoint is transfusion independence (TI, weighted average haemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). Patients are followed for 2 yrs and offered participation in a long‐term follow‐up study.Results:Sixteen patients have been treated in Northstar‐2 as of 14 September 2018. The median age was 19 (min‐max: 8–34) yrs; 2 patients <12 yrs of age have been treated. Median time to neutrophil and platelet engraftment was 19 (min‐max: 13–32) days and 44.5 (min‐max: 20–84) days, respectively. As of the most recent data analysis, 1 patient (1‐month follow‐up) and 4 patients (≤2 months follow‐up) had not achieved neutrophil and platelet engraftment, respectively.Non‐haematologic grade ≥3 adverse events in ≥3 patients included stomatitis, febrile neutropenia, epistaxis, pyrexia, and liver veno‐occlusive disease (VOD). One event of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. There have been no graft failures, deaths, detection of vector‐mediated replication competent lentivirus, or insertional mutagenesis.Of the 3 patients evaluable for TI, 2 have satisfied the primary endpoint of TI. Ten of 11 patients with ≥3 months follow‐up have stopped RBC transfusions. At last study visit, these 10 patients had total Hb levels of 11.1–13.3 g/dL comprised of 7.7–10.6 g/dL gene therapy‐derived Hb, HbAT87Q. Hb levels remained stable with median Hb of 11.9 g/dL (n = 9), 12.2 g/dL (n = 7), and 12.3 g/dL (n = 5) at 6, 9, and 12 months after LentiGlobin infusion, respectively.To assess correction of dyserythropoiesis, bone marrow samples from 6 patients with ≥12 months follow‐up were assessed for cellularity and myeloid:erythroid (M:E) ratios. All 5 patients who stopped RBC transfusions showed improved M:E ratios at month 12 (min‐max: 0.77–1.1) compared to baseline (min‐max: 0.18–0.45). Four of these 5 patients had soluble transferrin receptor levels available at month 12 and showed a decrease at month 12 (median 45.3; min‐max: 37.7–69.4 nmol/L) compared to baseline (median 173.5; min‐max: 90.6–235.3 nmol/L; reference range: 22.4–51.8 nmol/L).Summary/Conclusion:The safety profile of LentiGlobin gene therapy in Northstar‐2 is generally consistent with previous experience with busulfan conditioning. Delayed platelet engraftment was observed in some patients. Ten of 11 of patients with ≥3 months follow‐up stopped chronic RBC transfusions following treatment with LentiGlobin. Total Hb is stable at near‐normal levels and bone marrow morphology indicates improvements in erythropoiesis.