A UK Intention to Treat Analysis of Brexucabtagene Autoleucel for Relapsed or Refractory Adult Acute Lymphoblastic Leukaemia Following 1 Year of Therapy Access

Background The UK National Adult ALL CAR-T panel, established in 05/2023, ensures robust assessment of eligibility and equitable access to Brexu-cel as the first EMA licensed, nationally approved CAR-T therapy for R/R adult B-ALL (≥26 yrs) in the NHS. The panel is uniquely positioned to facilitate real world data (RWD) collection from point of eligibility determination. Here we evaluate use, toxicity and outcomes for patients (pts) approved within the first 12 months. Methods All pts approved for Brexu-cel between 05/2023 and 05/2024 with sufficient data were included in the analysis. Retrospective data recorded by JACIE-FACT IEC centres were anonymised, collected on a standardised datasheet and collated to support RWD analysis. Results Of 75 pts screened against nationally approved criteria, 54 (72%) were deemed eligible, with sufficient data available for analysis in 51 (ITT cohort). Indication was post-allo-HSCT relapse in 62.7% (32/51) of approved cases. Six were not apheresed (1 progressive disease, 2 deaths from disease, 3 clinical decision), for an apheresis rate of 88% in the ITT cohort. Successful apheresis and manufacture was achieved in 44 (97.7%) and infusion proceeded in 36 (70.6% approved; 81.8% with available product). Reasons for non-infusion included death fromdisease (n=4),progression (n=2) and consent withdrawal (n=2). Thirty-three (64.7%) were male. Median age of approved and infused pts was 52.0 (IQR 43.0-59.0) and 51.5 (IQR 43.5-59.5) years, respectively; 12/51 (23.5%) ITT and 9/36 (25.0%) infused were ≥60 years of age. By UKALL14 revised genetic risk status, 20/51 (39.2%) were standard risk, 5/51 (9.8%) high, 12/51 (23.5%) very high, and 13/51 (25.5%) had tyrosine kinase activating fusions (1/51 unknown). Median prior lines of therapy were 2 (1-4) with 33/51 (64.7%) having prior allo-HSCT, 9/51 (17.6%) prior blinatumomab and 15/51 (29.4%) prior inotuzumab. Seventeen (33.3%) had comorbidity index (HCT-CI) 3+ at point of eligibility. Bridging therapy was delivered in 34/36 (94.4%) of infused pts. At infusion, 22/36 (61.1%) were in CR with 24/36 (66.7%) having ≤5% BM blasts and 8/36 (22.2%) MRD negative. Extramedullary disease featured in 5/36 (13.9%), with no cases of active CNS disease. Median approval-to-infusion time was 60 days (IQR 45.0-77.5). Within 30 days of infusion there was one death due to G5 ICANS. A further 3 pts had insufficient follow up (FU) for D30 response assessment. Of the remainder, 32/32 (100%) were in CR/CRi post-infusion, with 78.1% (25/32) MRD negative (3.1% (1/32) MRD positive; 18.8% (6/32) MRD unknown). Two further deaths occurred before D90 (n=1 soft tissue infection; n=1 unspecified). Six had insufficient FU for D90 response assessment. Of those remaining alive with sufficient FU at D90, 23/24 (95.8%) remained in CR/CRi, with ongoing MRD negativity confirmed in 18/23 (78.3%; 5/23 (21.7%) MRD unknown). With median FU from approval of 7.3 months (95% CI 6.2-10.1) and 8.2 months (95% CI 6.2-10.1) for infused and ITT cohorts respectively, 86.1% (31/36) of infused and 76.5% (39/51) ITT pts remained alive. Estimated OS from approval date was 88.4% (95% CI 71.9-95.5) and 81.0% (95% CI 56.6-92.5) at 6 and 12 months respectively for infused, and 77.2% (95% CI 62.5-86.7) and 72.0% (95% CI 54.1-83.9) for ITT cohorts. At 6 months, RFS for those infused was 82.1% (95% CI 60.8-92.5) (median RFS 11.5 months (95% CI 7.3-NR)), with only one progressing to allo-HSCT. Blasts >5% (vs ≤5%) at infusion was associated with worse RFS (x2 11.56; p=0.003). Of 36 infused pts, 94.4% (34/36) experienced CRS, but only 5.6% (2/36) G3+ events. Median CRS duration was 5 days (IQR 4-6). Neurotoxicity occurred in 61.1% (22/36) with G3+ ICANS in 30.6% (11/36) and 7/36 (19.4%) requiring ITU stay for neurotoxicity. Median ICANS duration was 3 days (IQR 2-4). Conclusions The UK adult ALL CAR-T access scheme uniquely supports consistent patient assessment, collaborative discussion and cross-centre analysis of Brexu-cel use and outcomes from the point of eligibility. In a cohort with median age exceeding that of ZUMA 3, Brexu-cel delivers high rates of MRD negative CR at D30 and D90, with acceptable procedural mortality (8.3% at D90) and ITT survival outcomes comparable to those for infused pts in ZUMA 3. Despite lack of CNS disease and low disease burden in most at infusion, rates of G3+ neurotoxicity mandate consideration during patient selection, consent and therapy delivery.