Background: The ongoing Phase 1/2 HGB-206 study (NCT02140554) of LentiGlobin for SCD (bb1111) GT uses a modified human β-globin gene that expresses an anti-sickling hemoglobin (HbA T87Q). The relationships between biological outcomes, clinical outcomes, and clonality in the initial cohort (Group A) and the cohort treated after substantial changes were made to the study protocol and manufacturing process to improve clinical benefit (Group C) are presented here. Methods: Patients (pts; ≥18 in Group A and ≥12-≤50 yrs in Group C) with SCD and recurrent severe vaso-occlusive events (VOEs), overt stroke, or tricuspid regurgitant jet velocity of >2.5 m/s, were enrolled. The initial protocol (cell collection and target busulfan dose) and manufacturing process in Group A was modified to improve cell dose, transduction efficiency, HbA T87Q expression, and clinical benefit. CD34+ cells (collected by bone marrow [BM] harvesting in Group A and plerixafor mobilization/apheresis in Group C) were transduced with BB305 lentiviral vector (LVV). LentiGlobin was infused after myeloablative busulfan conditioning. Transduction, SCD-related outcomes, clonality, and safety were assessed; data are median (min-max) unless otherwise stated. Results: As of 17 February 2021, there were 61.5 (55.5-66.1) months of follow-up post-LentiGlobin infusion in Group A (n=7) and 17.3 (3.7-37.6) months in Group C (n=35). After protocol and manufacturing modifications, median drug product vector copy number (DP VCN) and transduction efficiency were increased in Group C (3.7 c/dg with 80.3% transduced cells) compared with Group A (0.6 c/dg with 27.7% transduced cells). Peripheral blood (PB) VCN stabilized by Month 6 post-infusion and was sustained throughout follow up in both groups; however, the median PB VCN was correspondingly higher in Group C than in Group A (1.45 c/dg vs 0.09 c/dg). A higher DP VCN, %LVV+, and PB VCN in Group C generated increased HbA T87Q of 5.2 (2.6-8.8) g/dL (n=30) compared with HbA T87Q of 0.5 (0.1-1.8) g/dL (n=7) in Group A at Month 6. This was associated with near pancellular expression of HbA T87Q at ≥6 months post-infusion in Group C with a mean of 87% of red blood cells containing β A-T87Q by 18 months (n=14). Group C featured significantly higher median unique insertion sites (UIS) than Group A (p = 1.43 x 10 -12;Fig 1), consistent with increased polyclonality. Critically, median UIS also correlated strongly with PB VCN (Spearman rho = 0.97; Fig 1) and HbA T87Q at Month 6 post-infusion and was associated with improved clinical efficacy in Group C, with complete resolution of severe VOEs and near normal levels of key hemolysis markers. In Group C, the only treatment (tx) emergent serious adverse events (TESAEs) reported in >1 pt were abdominal pain, nausea, opioid withdrawal syndrome, and vomiting (n=2, 5.7% each). No events of malignancy were reported in Group C. One event of sudden death, considered unlikely related to LentiGlobin, occurred >18 months post-tx in a patient with significant baseline SCD-related cardiopulmonary disease. In Group A, the most common TESAE was sickle cell anemia with crisis (n=4, 57%). Two events of acute myeloid leukemia (AML) were reported in Group A pts at 3 and 5 years post-tx, both of which were considered unlikely related to the LVV. Both pts had classic AML driver mutations identified post-diagnosis. One pt died of AML and the second pt is receiving therapy for AML. The modifications made in Group C are anticipated to reduce risk of AML. To monitor safety, BM and PB will be screened for the presence of AML driver mutations prior to treatment, and patients already treated will have regular cytogenetic screening in addition to BB305 LVV integration site analysis. Summary: Alterations to the protocol and manufacturing process in HGB-206 resulted in improved cell dose, transduction efficiency, HbA T87Q expression, and clinical outcomes in Group C compared with Group A. Polyclonality was strongly correlated to PB VCN and HbA T87Q production, indicating that superior engraftment of LVV-transduced cells leads to favorable clinical outcomes. The safety profile post-LentiGlobin for all treated patients with SCD remains generally consistent with the risks of autologous stem cell transplant, myeloablative busulfan conditioning, and underlying SCD. Figure 1 Figure 1. Disclosures Thompson: Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. Kwiatkowski: Bluebird Bio: Other: Consultancy Fees; Imara: Other: Consultancy Fees; Celgene: Honoraria; Silence Therapeutics: Honoraria; Agios: Honoraria; ApoPharma: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Sangamo: Research Funding; Terumo BCT: Research Funding. Aygun: National Heart, Lung, Blood Institute: Research Funding; Global Blood Therapeutics: Consultancy; National Institute of Nursing Research: Research Funding; Patient Centered Outcomes Research Institute: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmidt: GeneWerk GmbH, Heidelberg, Germany: Current equity holder in publicly-traded company; German Cancer Research Center, Heidelberg, Germany: Current Employment. Pierciey: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Whitney: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Rogers: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Nnamani: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Foos: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Miller: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Lynch: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Walters: Vertex pharmaceuticals: Consultancy; Ensoma, Inc.: Consultancy; BioLabs, Inc: Consultancy; AllCells, Inc: Consultancy. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Bonner: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company.
Introduction We investigated the impact of β-thalassemia genotypes and disease genetic modifiers including HBA and KLF1 genotype and sentinel single-nucleotide polymorphism (SNP) genotypes at 3 major HbF quantitative trait loci (QTL) on clinical outcomes of TDT patients treated with beti-cel gene therapy in two phase 3 studies, HGB-207 (NCT02906202) and HGB-212 (NCT03207009). Methods HBA deletions and triplications were determined by gap-polymerase chain reactions. HBG2 (including rs7482144, Xmn1 site) and HBG1 promoters, HBA2, HBA1, and KLF1 underwent individual nucleotide sequencing. Multiplex amplification refractory mutation system (ARMS) tests were used to identify HbF QTL SNPs (rs10128556 in HBBP1; rs766432, rs1427407, rs10189857 in BCL11A; rs9399137, rs66650371 in HMIP). Thalassemia severity score (TSS) was calculated as defined by Danjou et al, Haematologica, 2015, considering gender, HBB and HBA genotypes, and 4 SNPs in HbF QTL (HBG2, BCL11A, HMIP). Correlative analyses were performed to assess relationships between genotype, presence/absence of non-HBB mutations (HBA2, HBA1, KLF1), presence/absence of HbF QTL SNPs (HBG2, BCL11A, HMIP), and TSS with the achievement of transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without red blood cell [RBC] transfusions for ≥12 months). Correlation coefficients used percentage bend correlation. Statistical significance threshold was p ≤ 0.05. Results As of 3 March 2020, 38 patients were treated in HGB-207 and HGB-212 (β0/β0 genotype n=9; non-β0/β0 genotype n=29 [β+/β+ n=8; β0/β+ n=15; βE/β0 n=6]). All patients were heterozygous or homozygous for mutations or SNPs that may modulate disease severity; 20 patients were homozygous for ≥1 mutation or SNP. Patients had the following alleles associated with higher HbF synthesis: HBG2 rs7482144 C>T (Xmn1 site), C/T n=9, T/T n=1; BCL11A rs1427407 G>T, G/T n=8; BCL11A rs10189857 A>G, A/G n=16, G/G n=18; HMIP rs9399137 T>C, T/C n=9, C/C n=2. Three patients were heterozygous for single α-globin gene deletion (-α/αα) and 2 were heterozygous for α-globin gene triplication (αα/ααα). Median TSS was 3.65 (min - max 0.4 - 8.1). TI was achieved by 23/27 (85%) evaluable patients; 4 patients with ≥ 12 months follow-up have been transfusion free for > 10 months but were not yet evaluable for TI (Figure). β-thalassemia genotype did not strongly correlate with TI (two-sided Fisher's Exact Test, p-value = 0.78). Month 12 median (min - max) peripheral blood vector copy number (PB VCN) was 1.5 (0.2 - 5.0) c/dg in TI or transfusion-free patients (n=27) and 0.2 (0.2 - 0.4) c/dg in patients who did not achieve TI (n=4). The transfusion-free patient (β0/β0) with the lowest month 12 PB VCN was homozygous for T/T at rs7482144 (HBG2Xmn1 site) and G/G at rs10189857 (BCL11A), and heterozygous for single α-globin gene deletion. Endogenous Hb (5.9 g/dL HbF + 0.2 g/dL HbA2) and gene therapy-derived HbAT87Q (4.4 g/dL) at month 12 enabled this patient to stop transfusions. Tests of association of SNPs and mutations with TI were not significant; no p-value < 0.31 (chi-squared test). As only 4 patients did not achieve TI, the power to detect an association was limited. Larger sample sizes are needed to determine if individual SNPs and mutations may have an impact on TI. In TI or transfusion-free patients (n=27), TSS correlated strongly with month 12 endogenous unsupported Hb (HbA + HbA2 + HbF + HbE without RBC transfusions for 60 days) (correlation coeff. = -0.76, p < 0.0001), but not with HbAT87Q (correlation coeff. = 0.26, p = 0.19) or unsupported total Hb (correlation coeff. = 0.32, p = 0.10). Beti-cel-related adverse events (AE) in >1 patient were abdominal pain (n=2 non-β0/β0; n=1 β0/β0), thrombocytopenia (n=3 non-b0/b0). Serious AEs in ≥3 patients post-infusion were thrombocytopenia (n=2 non-β0/β0; n=1 β0/β0), pyrexia (n=1 non-b0/b0; n=2 β0/β0), veno-occlusive disease (n=3 non-β0/β0). Summary Genetic characterization of TDT patients treated with beti-cel revealed diverse HBB and non-HBB mutations and polymorphisms that may influence disease severity. Higher PB VCN and HbAT87Q levels were associated with increased likelihood of TI. In instances of lower HbAT87Q, higher endogenous HbF might be a determinant in whether TI is achieved. Despite genetic heterogeneity, beti-cel enabled patients to achieve TI regardless of β-thalassemia genotype, TSS, disease genetic modifiers including HBA, and HbF QTL SNP genotypes. Disclosures Walters: Veevo Biomedicine: Consultancy; AllCells, Inc: Consultancy; Editas: Consultancy. Chui:bluebird bio, Inc.: Other: Payment for lab use for the sequencing analyses done for the studies. Lal:bluebird bio, Inc.: Research Funding; Agios Pharmaceuticals: Consultancy; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding; Novartis: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Terumo Corporation: Research Funding; Chiesi USA: Consultancy; Insight Magnetics: Research Funding. Locatelli:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Apopharma: Research Funding; Bristol Myers Squibb: Consultancy; Imara: Consultancy; Celgene: Consultancy; Sangamo: Research Funding; Terumo Corp: Research Funding; Novartis: Research Funding. Porter:bluebird bio, Inc.: Consultancy, Honoraria; Vifor Pharmaceuticals: Honoraria; La Jolla Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Silence Therapeutics: Honoraria. Thuret:Apopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis pharma: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials. Kulozik:Novartis: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Thrasher:4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership. Yannaki:bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; SANDOZ: Speakers Bureau; Gilead: Speakers Bureau. Yang:bluebird bio,Inc.: Current Employment, Current equity holder in publicly-traded company. Whitney:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Petrusich:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Colvin:bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Thompson:BMS: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; CRISPR/Vertex: Research Funding; Biomarin: Research Funding; Baxalta: Research Funding.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.