Patients with Poor Functional Status at Intake Experience Early Failure of CAR T-Cell Therapy for Third Line Treatment of RR-LBCL
Authors: Bhella Sita D. , Hueniken Katrina , Aitken Rachel , Waldron Carmel , Crump Michael , Kuruvilla John , Prica Anca , Kukreti Vishal , Kridel Robert , Vijenthira Abi , Yang Chloe , Tsang Richard , Hodgson David , Rodin Danielle , Malik Nauman , Wells Woodrow , Chen Christine I 
Published: December 2024

Background:
Princess Margaret (PM) is the referral centre for antiCD19 CAR T-cell therapy (CART) for a large regional population and currently treats patients from other provinces in Canada. Better understanding of early CART failure may inform selection criteria.
Purpose:
We evaluated outcomes of all patients referred for CART and explored risk factors for early failure, as defined by failure to receive cells, death within 100 days of infusion or progressive disease (PD) prior to or at day 100 response assessment.
Methods:
This is a single-centre retrospective review of consecutive adult patients with RR-LBCL referred for CART at PM from April 2020-November 2023 for &gt; 3rd line therapy. Outcomes included progression-free survival (PFS) defined from date of cell infusion/ date of intake (for pts that failed to proceed with CART (PFPC)) to PD/death/last follow-up. Overall survival (OS) defined from date of cell infusion/date of intake (for PFPC) to death/last follow-up. To identify predictors for early failure, a univariate analysis examining the early failure and non-early failure cohort was conducted. Variables examined included: age, stage, ECOG, presence of bulky disease (&gt;7 cm), relapsed vs. refractory, lymphoma subtype, cell of origin, presence of double hit or triple hit lymphoma, and failure to undergo ASCT. Metrics to infusion were examined including dates of CT demonstrating progression post 2L+ therapy, intake, apheresis and infusion.
Results:
263 pts were referred for CART during the study period. 192 underwent CART (tisa-cel 47, axi-cel 145) and 71 were referred but did not undergo CART. Of these 71, 14 were found to be ineligible for CART at intake and were excluded. ITT analysis included 57 pts who did not receive CART.
For the 57 pts who did not proceed with CART, reasons for not proceeding were identified in 56. Reasons included: patient factors (choice 12(21%), poor functional status 7(13%)), product factors (collection 2(4%), manufacturing 5(9%) and disease factors (progression 22(39%), active CNS disease 5(9%), death 3(5%)). 52% did not proceed with apheresis.
Median time from date of progression noted on CT to intake appt was 19 days for tisa-cel (0-177) and 16.5 days for axi-cel (0-113). Median time from date of progression noted on CT to infusion was 50 days (19-100) for tisa-cel and 44 days (28-89) for axi-cel. Median time from apheresis to infusion was 43 days (35-107) for tisa-cel and 33 days (27-74) for axi-cel. There were no significant differences in median days from progression noted on CT to intake or referral to intake between early failure and non-early failure cohorts 15 v. 18 (p=0.603) and 10 v. 8.5 (p=0.128).
Response at 100 days post CART was assessed in 192 pts. 83 achieved CR/CMR (43%), 25 achieved PR (13%), 64 (34%) experienced progression, and 2(1%) died before 100 days from toxicity (ICH, frailty post ICU for ICANS); and 100-day status was unknown/pending in 18(9%) patients and were censored.
Median follow up time for all patients receiving CART was 12.02 mos (6.28-17.38) from infusion to censored. Median OS for the cohort receiving CART was not reached. 12-month OS for whole CART cohort, tisa-cel and axi-cel cohorts respectively were 66.9% (95% CI 58.9,76), 55.9% (95% CI 42.3, 73.7) and 72.8% (95% CI 63.7,83.2). Median PFS for all infused patients was 8.2 mos (95% CI 1.28, NYR). Median OS for the ITT cohort (CART and no CART) was 57.7 months (95% CI 50.5, 65.8) from intake date with median follow up 13.44 mos (95% CI 7.79,18.5). Median OS for the CART and no CART cohort was 68.8 mos (95% CI, 60.9,77.6) and 12.4 mos (95% CI 5.3, 28.9).
A univariate analysis of predictors for early failure was conducted. Those with unknown status at Day 100 were excluded. 234 referred pts were included for analysis and 121(52%) pts met the definition of early failure. Of those who experienced early failure post CART, 62 pts (97%) experienced relapse and 2 pts (3%) died from toxicity. ECOG 2+ at intake (p=0.011) was identified as a predictor. Refractory disease (p=0.056) and presence of double /triple hit lymphoma (p=0.059) trended close to significance.
Conclusions:
We present the early experience with SOC CART for RR-DLBCL from a large tertiary Canadian centre. Limited RW cohorts have provided ITT results. A large proportion of referred patients experienced early failure, with 23% not receiving CART and 52% experiencing early failure. Novel strategies are required to better outcomes in those at risk of early failure.