Contributions
Abstract: S836
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 12:30 - 12:45
Location: Room A8
Background
The purpose of β-globin gene transfer into hematopoietic stem progenitor cells (HSPCs) is to express a functional adult β-globin that reduces or eliminates sickle cell disease (SCD) symptoms. The investigational gene therapy LentiGlobin Drug Product (DP) contains autologous CD34+ HSPCs transduced with the BB305 lentiviral vector, which encodes β-globin with an anti-sickling mutation (HbAT87Q). Initial results from a Phase 1 HGB-206 study (NCT02140554) of LentiGlobin in patients with severe SCD treated with CD34+ HSPCs from bone marrow harvesting (BMH) showed acceptable safety, but suboptimal HbAT87Q production. The revised protocol instituted pre-harvest RBC transfusions, increased target busulfan levels, increased the DP VCN after manufacturing, and investigated plerixafor-mediated mobilization/apheresis for DP manufacturing.
Aims
To investigate the safety and efficacy of a revised LentiGlobin gene therapy protocol with plerixafor-mobilized HSPCs in severe SCD.
Methods
Adult patients 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. In lieu of BMH-derived HSPCs for back-up and DP manufacturing (Group [Grp] A), the revised protocol instituted ≥2 months of RBC transfusions before plerixafor mobilization/apheresis for back-up HSPC collection but retained BMH for DP manufacturing (GrpB). A GrpC evaluated DP and back-up prepared with plerixafor-mobilized HSPCs. Following HSPC collection, patients received myeloablative conditioning, followed by DP infusion. Adverse events (AEs), engraftment, vector copy number (VCN) and HbAT87Q production were monitored.
Results
As of Nov 30, 2017, 10 patients (18-42 yrs) received LentiGlobin DP. In 7 GrpA patients, the median DP VCN and cell dose were 0.6 (0.3-1.3) copies/diploid genome and 2.1 (1.6-5.1) x 106 CD34+ cells/kg, with 8% - 42% CD34+ cells transduced. Median follow-up was 21.6 (17.8-26.7) months, as of Oct 26, 2017. At last visit, the median peripheral blood (PB) VCN, total Hb and HbAT87Q levels were: 0.1 (0.1-0.2), 9.7 (7.5-10.9) g/dL and 0.7 (0.5-2.0) g/dL. In 2 GrpB patients, DP VCN and cell dose improved: DP VCNs were 1.4/3.3 and 2.9/5.0 (2 DP lots per patient) and total cell doses were 2.2 and 3.2 x 106 CD34+ cells/kg, with 46% - 95% cells transduced. At 9 (pt 1313; GrpB) and 6 months (pt 1312; GrpB) follow-up, PB VCNs were 0.5 and 2.5, total Hb levels were 10.4 and 12.6 g/dL, and HbAT87Q levels were 3.0 and 6.4 g/dL. Of 11 patients enrolled in GrpC, 6 completed plerixafor mobilization/apheresis. DPs in 4 GrpC patients had median VCN and cell dose of 3.3 (2.8-4.6) and 6.9 (3-8) x 106 CD34+ cells/kg, with 78% - 88% cells transduced. One GrpC patient received DP and at 1-month follow-up (as of Dec 6, 2017) had a PB VCN of 2.5. Additional follow-up results will be presented. There were 17 Grade 3-4 AEs reported in 5 patients after BMH (N=9). There were 5 Grade 3-4 AEs reported in 3 patients after plerixafor mobilization/apheresis (N=7). The AEs that were Grade 3-4 after DP infusion were consistent with myeloablative busulfan. To date, there was no graft failure and no Grade 3-4 DP-related infusional toxicity/AEs.
Conclusion
Patients enrolled and treated in a revised protocol had improvements in DP VCN and HbAT87Q levels with no new significant safety events to date. Plerixafor mobilization in patients with severe SCD appears safe and can result in DPs with VCNs comparable to, and cell doses higher than, BMH. Longer follow-up and additional experience will clarify the effect of protocol changes.
Session topic: 26. Gene therapy, cellular immunotherapy and vaccination - Clinical
Keyword(s): Autologous hematopoietic stem cell transplantation, Gene therapy, sickle cell disease
Abstract: S836
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 12:30 - 12:45
Location: Room A8
Background
The purpose of β-globin gene transfer into hematopoietic stem progenitor cells (HSPCs) is to express a functional adult β-globin that reduces or eliminates sickle cell disease (SCD) symptoms. The investigational gene therapy LentiGlobin Drug Product (DP) contains autologous CD34+ HSPCs transduced with the BB305 lentiviral vector, which encodes β-globin with an anti-sickling mutation (HbAT87Q). Initial results from a Phase 1 HGB-206 study (NCT02140554) of LentiGlobin in patients with severe SCD treated with CD34+ HSPCs from bone marrow harvesting (BMH) showed acceptable safety, but suboptimal HbAT87Q production. The revised protocol instituted pre-harvest RBC transfusions, increased target busulfan levels, increased the DP VCN after manufacturing, and investigated plerixafor-mediated mobilization/apheresis for DP manufacturing.
Aims
To investigate the safety and efficacy of a revised LentiGlobin gene therapy protocol with plerixafor-mobilized HSPCs in severe SCD.
Methods
Adult patients 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. In lieu of BMH-derived HSPCs for back-up and DP manufacturing (Group [Grp] A), the revised protocol instituted ≥2 months of RBC transfusions before plerixafor mobilization/apheresis for back-up HSPC collection but retained BMH for DP manufacturing (GrpB). A GrpC evaluated DP and back-up prepared with plerixafor-mobilized HSPCs. Following HSPC collection, patients received myeloablative conditioning, followed by DP infusion. Adverse events (AEs), engraftment, vector copy number (VCN) and HbAT87Q production were monitored.
Results
As of Nov 30, 2017, 10 patients (18-42 yrs) received LentiGlobin DP. In 7 GrpA patients, the median DP VCN and cell dose were 0.6 (0.3-1.3) copies/diploid genome and 2.1 (1.6-5.1) x 106 CD34+ cells/kg, with 8% - 42% CD34+ cells transduced. Median follow-up was 21.6 (17.8-26.7) months, as of Oct 26, 2017. At last visit, the median peripheral blood (PB) VCN, total Hb and HbAT87Q levels were: 0.1 (0.1-0.2), 9.7 (7.5-10.9) g/dL and 0.7 (0.5-2.0) g/dL. In 2 GrpB patients, DP VCN and cell dose improved: DP VCNs were 1.4/3.3 and 2.9/5.0 (2 DP lots per patient) and total cell doses were 2.2 and 3.2 x 106 CD34+ cells/kg, with 46% - 95% cells transduced. At 9 (pt 1313; GrpB) and 6 months (pt 1312; GrpB) follow-up, PB VCNs were 0.5 and 2.5, total Hb levels were 10.4 and 12.6 g/dL, and HbAT87Q levels were 3.0 and 6.4 g/dL. Of 11 patients enrolled in GrpC, 6 completed plerixafor mobilization/apheresis. DPs in 4 GrpC patients had median VCN and cell dose of 3.3 (2.8-4.6) and 6.9 (3-8) x 106 CD34+ cells/kg, with 78% - 88% cells transduced. One GrpC patient received DP and at 1-month follow-up (as of Dec 6, 2017) had a PB VCN of 2.5. Additional follow-up results will be presented. There were 17 Grade 3-4 AEs reported in 5 patients after BMH (N=9). There were 5 Grade 3-4 AEs reported in 3 patients after plerixafor mobilization/apheresis (N=7). The AEs that were Grade 3-4 after DP infusion were consistent with myeloablative busulfan. To date, there was no graft failure and no Grade 3-4 DP-related infusional toxicity/AEs.
Conclusion
Patients enrolled and treated in a revised protocol had improvements in DP VCN and HbAT87Q levels with no new significant safety events to date. Plerixafor mobilization in patients with severe SCD appears safe and can result in DPs with VCNs comparable to, and cell doses higher than, BMH. Longer follow-up and additional experience will clarify the effect of protocol changes.
Session topic: 26. Gene therapy, cellular immunotherapy and vaccination - Clinical
Keyword(s): Autologous hematopoietic stem cell transplantation, Gene therapy, sickle cell disease