Type: Oral
Session: 801. Gene Therapies: The Long and the Short of Clinical Trials in Blood Disorders
Hematology Disease Topics & Pathways:
Research, clinical trials, Sickle Cell Disease, Biological therapies, adult, Clinical Research, Hemoglobinopathies, pediatric, patient-reported outcomes, Diseases, Gene Therapy, Therapies, Adverse Events, young adult , Study Population, Human
Methods: This analysis includes patients from HGB-206 Group C and HGB-210 who received lovo-cel using the current HSPC mobilization and manufacturing process. Patients with SCD and recurrent severe vaso-occlusive events (VOEs) or history of overt stroke underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and lovo-cel infusion. After 24 months of follow-up post lovo-cel infusion, patients enrolled in the long-term study LTF-307 (NCT04628585). Lab evaluations, SCD-related outcomes (eg, resolution of VOEs), globin response (a composite endpoint evaluating HbAT87Q percentage and total Hb), and safety are reported up to 60 months. An independent Event Adjudication Committee confirmed VOEs met protocol criteria. HRQOL data from Patient-Reported Outcomes Measurement Information System (PROMIS)-57 domains of pain interference, fatigue, and pain intensity are reported up to 48 months.
Results: This analysis includes 47 patients (HGB-206 Group C, n=36; HGB-210, n=11; male, 59.6%; median [range] age, 23 y [12-38]) who received a lovo-cel infusion as of Feb 13, 2023. Median (range) follow-up was 35.5 months (0.3-61.0). Median (range) time to neutrophil and platelet engraftment was 20 days (12-35) and 35 days (19-136). Peripheral blood vector copy number remained stable (median >1 c/dg through follow-up). Median HbAT87Q levels were ≥4.5 g/dL from 6 months post infusion to last study visit. Median (range) total Hb level increased from 8.7 g/dL (6.1-12.5) at relative baseline to 11.8 g/dL (8.4-15.0) at last visit; median percent HbAT87Q of nontransfused total Hb was ≈40% or more (Figure).
Of 33 evaluable patients (ie, ≥18 months follow-up and ≥4 VOEs in the 2 years before enrollment), 30 (90.9%) and 32 (97.0%) had complete resolution of VOEs and severe VOEs during the 6-18 months post infusion, vs a median (range) of 3.5 (1.5-16.5) and 3.0 (0.5-13.0) events/year in the 2 years before enrollment. Additional efficacy analyses in subgroups (eg, stroke history, α-globin genotype) will be presented.
Among patients who had globin response or who had ≥18 months follow-up (n=38), 33 (86.8%) achieved globin response. Hemolysis markers (eg, reticulocytes, total bilirubin, lactate dehydrogenase) approached normal levels.
Among all 47 patients, 44 (93.6%) had ≥1 AE of grade ≥3 after lovo-cel infusion; the most common of which were stomatitis (33 [70.2%] patients) and thrombocytopenia (28 [59.6%]). Serious AEs were reported for 26 (55.3%) patients, the most common of which was chronic pain/acute exacerbation of chronic pain (3 [6.4%]; 2 chronic neuropathic pain and 1 chronic pain associated with anxiety). One patient with -α3.7/-α3.7 genotype was diagnosed with myelodysplastic syndrome with stable complete blood counts 30 months post infusion; updated data to be presented. No veno-occlusive liver disease, graft failure, replication-competent lentivirus, or vector-mediated insertional oncogenesis was observed. Lovo-cel treatment regimen largely reflected known side effects of HSPC collection and busulfan conditioning regimen.
A total of 25 patients (all from HGB-206 Group C; age ≥18 y) had evaluable HRQOL data. Mean scores for PROMIS-57 domains of pain intensity, pain interference, and fatigue improved (ie, decreased) over time up to 48 months (Table).
Conclusion: One-time treatment with lovo-cel resulted in sustained HbAT87Q production and near-complete resolution of VOEs and severe VOEs up to 18 months post treatment; the safety profile was consistent with underlying SCD and myeloablative conditioning. Patients reported sustained improvements in pain intensity, pain interference, and fatigue. Ongoing long-term follow-up will continue to provide important information on efficacy, safety, and patient experience post lovo-cel treatment.
Disclosures: Kanter: Bausch: Consultancy; Watkins, Lourie, Roll & Chance: Consultancy; NHLBI: Research Funding; Austin Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Fulcurm: Consultancy; Takeda: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; ECOR-1: Consultancy; BEAM: Consultancy, Research Funding; Chiesi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Guidepoint Global: Honoraria; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; HRSA: Research Funding; CDC: Research Funding; National Alliance of Sickle Cell Centers: Other: President. Thompson: Beam: Consultancy, Research Funding; global blood therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; CRISPR/Vertex: Consultancy, Research Funding; Novartis: Research Funding; Editas: Consultancy, Research Funding; bluebird bio, Inc.:: Consultancy, Research Funding. Kwiatkowski: Forma Therapeutics: Consultancy, Research Funding; Bluebird Bio: Research Funding; Bristol Myers Squibb: Consultancy; Chiesi Farmaceutici: Consultancy; Agios Pharmaceuticals: Consultancy, Research Funding; BioMarin Pharmaceutical: Consultancy; Vertex Pharmaceuticals: Consultancy; Regeneron Pharmaceuticals: Consultancy; Editas Medicine: Research Funding; Pfizer: Research Funding. Mapara: Crispr/vertex: Consultancy; Incyte: Consultancy; Bluebird bio: Consultancy. Rifkin-Zenenberg: Vertex: Membership on an entity's Board of Directors or advisory committees. Aygun: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees. Kasow: Aruvant: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gupta: Vertex Pharmaceuticals: Consultancy; Bluerock Therapeutics: Membership on an entity's Board of Directors or advisory committees. Zhang: bluebird bio, Inc: Current Employment, Current holder of stock options in a privately-held company. Sheldon-Waniga: bluebird bio, Inc: Current Employment, Current holder of stock options in a privately-held company. Gallagher: bluebird bio, Inc: Current Employment, Current equity holder in publicly-traded company. Gruppioni: bluebird bio, Inc: Current Employment, Current equity holder in private company. Chawla: bluebird bio, Inc: Current Employment, Current equity holder in private company. Elliot: bluebird bio, Inc: Current Employment, Current equity holder in private company. Pierciey: bluebird bio, Inc: Current Employment, Current equity holder in private company. Walters: Vertex Pharmaceuticals: Consultancy; BioChip Labs: Consultancy, Other: Medical Director; AllCells, Inc: Consultancy, Other: Medical Director; Ensoma, Inc: Consultancy.
OffLabel Disclosure: This presentation will include discussion of treatments not yet approved by the FDA.
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