Introduction: β-globin gene transfer into hematopoietic stem cells (HSCs) has the potential to reduce or eliminate the symptoms of severe sickle cell disease (SCD) and reduce or eliminate transfusion requirements in transfusion-dependent β-thalassemia (TDT). LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the BB305 lentiviral vector, which encodes a human β-globin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to those observed with γ-globin. We previously reported proof of concept for LentiGlobin DP treatment in severe SCD and early data from 4 treated patients with TDT. We now report 18 months of follow-up for the patient with SCD and between 9 and 30 months of follow-up for the 4 patients with TDT.
Patients (5-35 years of age) with severe SCD (e.g. ≥2 acute chest syndrome episodes or ≥2 vaso-occlusive crises [VOC] in preceding year/in year prior to regular transfusions) or TDT (≥100mL/kg of packed red blood cells [RBCs] per year) were enrolled. Following mobilization and apheresis (for TDT) or bone marrow harvest (for SCD), autologous CD34+ cells were transduced with the BB305 lentiviral vector. Patients underwent myeloablative conditioning with busulfan prior to infusion of the transduced cells. After infusion, patients were monitored for hematologic engraftment, vector copy number (VCN), and HbAT87Q expression. Disease-specific assessments included transfusion requirements for TDT, or VOCs and hospitalizations for SCD. Safety assessments included adverse events (AEs) and integration site analysis.
Results: As of July 2016, 1 patient with severe SCD (male; 13 years old) and 4 patients with TDT (2 male, 2 female; 16-19 years old) have received LentiGlobin DP in Study HGB-205. The median LentiGlobin DP cell dose was 8.9 (range 5.6-13.6) x 106 CD34+ cells/kg with a DP VCN of 1.2 (range: 0.8-2.0) vector copies/diploid genome. Median post-infusion follow-up as of July 6, 2016 is 20.8 months (range 9.5-31.3). All subjects successfully engrafted after receiving LentiGlobin DP, with a median time to neutrophil engraftment of 17 days (range 14-38 days). VCN in peripheral blood has remained generally consistent from Month 3 in all patients with a range of 0.2 to 3.4 at last measurement. The toxicity profile observed from start of conditioning to latest follow-up remains consistent with myeloablative conditioning with single-agent busulfan, with no DP-related ≥Grade 3 AEs or serious AEs and no evidence of clonal dominance reported to date.
Three patients with TDT have β0/βE genotypes and 1 is homozygous for the severe β+ mutation IVS1 nt 110 G>A. The 2 patients who have completed the 2-year primary follow-up period (both β0/βE) have not required RBC transfusions for 31 and 28 months, with total Hb of 10.9 and 13.5 g/dL, and HbAT87Q expression of 7.7 and 10.1 g/dL, respectively, at most recent study visit. Iron chelation has been discontinued and phlebotomy initiated for 1 of the patients. The remaining patient with β0/βE genotype has 9 months of follow-up and has not required transfusions since 4 days post-LentiGlobin DP infusion, achieving a total Hb of 11.3 g/dL at last study visit. The patient with the severe IVS1 genotype has 12 months of follow-up and has been free of transfusions for 9 months, with a total Hb of 8.3 g/dL at last study visit.
The patient with severe SCD, who prior to study enrollment received regular RBC transfusions, has experienced no clinical symptoms or complications of SCD in the 18 months since treatment, despite discontinuing transfusions 3 months after LentiGlobin DP infusion. Total Hb in this patient was 12.5 g/dL, with 6.6 g/dL HbAT87Q (53%) and 5.7 g/dL HbS (45%) at last study visit. Compared with values at screening, unconjugated bilirubin had dropped 78% (50 to 11 μmol/L), lactate dehydrogenase had dropped 54% (626 to 287 U/L), and reticulocyte count had dropped 45% (238x109/L to 132x109/L) by Month 18.
Conclusions: Data from this ongoing Phase 1/2 clinical study suggest that treatment with LentiGlobin DP can result in sustained production of therapeutic HbAT87Q, which ameliorates the clinical and biochemical effects of severe SCD and TDT, with an acceptable safety profile. Gene therapy presents a potentially promising therapy for patients with severe hemoglobinopathies. Further follow-up and additional data from patients are needed to confirm the encouraging results seen to date in this study.
Ribeil:Bluebirdbio: Consultancy; Addmedica: Research Funding. Payen:bluebird bio: Patents & Royalties. Hermine:Alexion: Research Funding; Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Asmal:bluebird bio: Employment, Equity Ownership. Joseney-Antoine:bluebird bio: Employment, Equity Ownership. De Montalembert:Addmedica: Research Funding; Novartis: Research Funding, Speakers Bureau. Leboulch:bluebird bio, Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
Asterisk with author names denotes non-ASH members.