SCD LentiGlobin gene therapy: new data on VOC and ACS

Sickle cell disease (SCD) patients in the HGB-206 Group C study experienced high-level, sustained expression of gene-therapy-derived haemoglobin, as well as a near-complete reduction of serious vaso-occlusive crises (VOCs) and acute chest syndrome (ACS).

Dr Julie Kanter (University of Alabama, USA) provided new results on the largest cohort of the study, Group C, in which stem cells were extracted from the peripheral blood of patients by plerixafor mobilisation and apheresis, instead of bone marrow, with an altered protocol for gene therapy transduction with LentiGlobin gene therapy [1]. LentiGlobin therapy transduces autologous CD34+ cells with the BB305 lentiviral vector, encoding a human β-globin gene with the anti-sickling T87Q mutation (β^A-T87Q). Patients underwent myeloablation with busulfan before infusion with the transduced cells and were then monitored for engraftment, safety, and efficacy.

In Group C of HGB-206, 25 SCD patients were treated with LentiGlobin, with follow-up up to 24.8 months (median 12.1 months); 18 patients had been followed for at least 6 months.

Median levels of gene-therapy-derived β^A-T87Q contributed to >40% of total haemoglobin. At last visit, total haemoglobin ranged from 9.6-16.2 g/dL, and β^A-T87Q levels ranged from 2.7-9.4 g/dL. At month 6, the production of β^A-T87Q was associated with a reduction in the proportion of sickle cell haemoglobin (HbS) in total haemoglobin.

All patients in Group C were able to stop regular blood transfusions and remain off transfusions at 3 months post-treatment. There was a 99.5% mean reduction in annualised rate of VOCs and ACS among the 14 patients who had at least 6 months of follow-up and a history of VOCs or ACS, defined as 4 or more VOCs or ACS events in the 2 years prior to treatment (median was 8 events). There were no reports of serious VOCs or ACS up to 24 months post-treatment in patients.

Patients treated with LentiGlobin for SCD demonstrated improvement in key markers of haemolysis, as well. By month 6 post-treatment, reticulocyte counts, lactate dehydrogenase, and total bilirubin normalised compared with pre-treatment. In 9 patients who had at least 6 months of follow-up, the average proportion of red blood cells positive for β^A-T87Q was greater than 70%, and on average more than 85% of red blood cells contained β^A-T87Q at 18 months post-treatment, suggesting near-complete pancellularity of β^A-T87Q distribution.

At data cut-off in March 2020, the safety data from all patients in HGB-206 are generally reflective of SCD and the known side effects of haematopoietic stem cell collection, including myeloablative conditioning. There were no serious adverse events related to LentiGlobin for SCD, and the non-serious related adverse events were mild-to-moderate and self-limited. One patient with a history of frequent pre-treatment VOCs, pulmonary and systemic hypertension, venous thrombosis, obesity, sleep apnoea, and asthma had complete resolution of VOCs following treatment, but suffered sudden death 20 months after treatment with LentiGlobin for SCD. The patient's autopsy revealed cardiac enlargement and fibrosis, and concluded the cause of death was cardiovascular, with contributions from SCD and asthma. An independent monitoring committee agreed this death was unlikely related to LentiGlobin for SCD gene therapy.

In conclusion, LentiGlobin gene therapy not only appears to be safe, with stable transduction levels which result in stable supplementation of HbS with β^A-T87Q, biological markers of SCD normalise, resulting in transfusion-independence and resolution of VOCs and ASC events.

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   1. Kanter J, et al. Outcomes in patients treated with lentiglobin for sickle cell disease (SCD) gene therapy: updated results from the phase 1/2 HGB-206 GROUP C study. EHA25 Virtual, 11-21 June 2020, Abstract S282.

Posted on 28 August, 202016 February, 2024