Brexucabtagene Autoleucel for Relapsed/Refractory Mantle Cell Lymphoma: Real-World Outcomes in the United Kingdom

Abstract

Background: Brexucabtagene autoleucel (brexu-cel, Tecartus) was granted EMA approval in December 2020 for relapsed/refractory (r/r) mantle cell lymphoma (MCL) after failure of 2 lines of therapy, including a BTKi, based on the results of ZUMA-2. In the UK, patients are prospectively approved for treatment by a centralised National CAR-T Clinical Panel (NCCP) using uniform eligibility criteria. We report the safety and efficacy outcomes in UK practice with a focus on intention-to-treat (ITT). Methods: Consecutive patients with r/r MCL from 11 UK centres referred to the NCCP (or Scottish equivalent) between February 2021 and June 2022 and deemed eligible for CAR T were analysed. Eligibility required ECOG PS of 0/1, absence of active CNS disease and ≥2 lines of therapy including prior BTKi (O'Reilly et al, doi: 10.1111/bjh.18378). Organ function requirements were at the discretion of the treating centre. CRS and ICANS were graded using ASTCT criteria. Cumulative steroid dose, administered for CAR-T toxicity, was reported as dexamethasone equivalent. Results: 82 patients (M=59, F=23) of median age 67 years (range 46-80) were approved. At submission, 24.4% (n=20) had blastoid/pleomorphic morphology, 39% (n=32) had high-risk sMIPI score, 17% (n=14) had TP53 mutation/overexpression and 35.4% (n=29) had Ki-67≥30%. Median number of prior lines was 2 (range 2-7) and 26.8% (n=22) were primary refractory to ibrutinib. 86.6% (n=71) and 59.8% (n=49) were harvested and infused respectively (Figure 1). Disease features associated with failure to reach harvest or infusion include blastoid morphology (OR 6.25, 95% CI 1.00-39.09, p=0.05) and a trend towards ECOG PS>0 (OR 4.42, 95% CI 0.88-22.32, p=0.07). Manufacturing failure (MF) occurred in 24.6% (n=17) with subsequent infusion in 47% (n=8). There was no association between MF and lines of therapy, bendamustine exposure, subtype, bulky disease >5cm, peripheral blood CD3+ count or total CD3+ cells harvested. In univariate analysis (UVA), MF was associated with LDH>ULN (OR 3.62, 95% CI, 1.02-12.93, p=0.05). 41.2% of MF (n=7) had circulating disease at T-cell harvest. 61.1% of all patients with circulating disease (n=11/18) had a successful 1st manufacture with a median ALC of 4.2 x 109/L (range 0.8-32.4) 94.4% received bridging therapy (n=67) with an overall response rate (ORR) of 33.3% (n=21/63). Median time from approval and 1st harvest to cell infusion was 56 (range 41-245) and 38 days (range 28-120) respectively. CRS and ICANS were observed in 94% (12%≥grade 3) and 56% (24%≥grade 3) respectively. 77.6% (n=38) received tocilizumab, and steroids were used in 59.2% (n=29), administered at day 7 (median; range 1-17), at a median dose of 165mg (range 10-1085) over a median of 8 days (range 1-270). 16.3% (n=8) received anakinra as an adjunctive agent for ICANS. 12 (24.5%) were admitted to ICU. Non-relapse mortality was 6.1% (n=3; COVID n=1, other infection n=2). Best ORR was 89.6% (83.3% complete remission, 6.3% partial remission). At a median follow-up of 9.1 months (range 0-14.8) from approval, median PFS was 9.9 months (95% CI 5.1-N/A). Median PFS from infusion was not reached at median follow-up of 7.4 months (range 0.9-13.2) with 6 and 12-month PFS rates of 82.5% (95% CI 67.9%-90.9%) and 56.1% (95% CI 34.1%-73.3%) respectively. In UVA, inferior PFS from infusion was associated with ≥3 sites of extra-nodal disease (HR 3.92, 95% CI 1.30-11.81, p=0.02) and the presence of circulating disease at T-cell harvest (HR 7.05, 95% CI 2.17-22.90, p=0.001) ; ICANS (any grade) with a superior PFS (HR 0.28, 95% CI 0.09-0.83, p=0.02) (Table 1). Median OS from infusion was also not reached with 6-month and 12-month OS rates of 92.8% (95% CI 79.2%-97.6%) and 72.3% (95% CI 47.1%-86.9%) respectively. Conclusion: Efficacy and safety outcomes for those infused with brexu-cel in the UK are comparable with ZUMA-2 and real-world datasets. However, prospective ITT analysis highlights the challenge of disease control in r/r MCL. Earlier referral with lower disease burden and better bridging strategies may reduce ITT failures, improve manufacturing success and overall outcomes. British Society of Haematology MCL guidance proposes a risk-based surveillance strategy for potential CAR T candidates at first relapse (O'Reilly et al, doi: 10.1111/bjh.18378 ). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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