Durable stroke-free survival after lovotibeglogene-autotemcel in sickle cell disease with prior overt stroke

ABSTRACT Overt ischemic stroke is a severe complication of sickle cell disease (SCD), with a high risk of recurrence without lifelong chronic transfusion therapy. We report outcomes, including from ongoing long-term follow-up of 6 participants with prior overt stroke who were treated with lovotibeglogene autotemcel (lovo-cel) in the phase 1/2 HGB-206 study and followed for up to 9 years (ClinicalTrials.gov identifiers: NCT02140554 and NCT04628585). Participants (median [range] age at consent, 22 [19-34] years) had received chronic transfusions for 10-18 years before treatment; 2 had moyamoya vasculopathy. Following myeloablative conditioning and a single lovo-cel infusion, all participants discontinued chronic transfusion therapy. No recurrent overt strokes were observed through a median (range) follow-up of 87.8 (73.2-115.8) months. Brain magnetic resonance imaging demonstrated no progression of pre-existing ischemic lesions. Sustained hematologic correction was observed in group C participants, with durable HbAT87Q expression. In group C participants, >75% of circulating red blood cells expressed βA-T87Q, consistent with broad erythroid correction. Vaso-occlusive events were absent in group C during the evaluation period and were significantly reduced in group A. Health-related quality-of-life measures showed clinically meaningful improvements in physical function, fatigue, and pain interference. Safety outcomes were consistent with the overall study population. No cases of posterior reversible encephalopathy syndrome, graft failure, or progressive clonal dominance were observed. In this small subgroup, lovo-cel was associated with durable stroke-free survival, transfusion independence, and a safety profile consistent with the overall study population, supporting activity of lovo-cel, an autologous gene therapy, as a one-time strategy for secondary stroke prevention in SCD.