Delays from Progression to Initial Appointment Occur with External Referrals for CAR T-Cell Therapy but Do Not Impact Survival
Authors: Bhella Sita D. , Hueniken Katrina , Jarallah Osamah Jamal S. , Maltez Melissa Teixeira , 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, provincial and national population. We sought to determine if patients referred from out of province (OOP) or from centres in province but external to our centre (EIP) experienced delays in treatment, inferior survival or increased toxicity compared to local populations (LIP).
Methods:
This is a single-centre retrospective review of consecutive patients with RR-LBCL referred for CART at PM from April 2020-November 2023 for ³ 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. Metrics to infusion were examined including dates of: CT demonstrating progression post 2L+ therapy, referral, intake, apheresis and infusion. Toxicity outcomes included rates of CRS, ICANS, use of tocilizumab/steroids/ICU and non-relapse mortality.
Results:
238 consecutive patients were included for analysis, with 183 receiving CART and 55 who were referred but did not receive CART (no CART). No significant difference in baseline characteristics between LIP,EIP and OOP cohorts were seen: median age(yrs) (58.6,60.1,61.8, p=0.19), % male (62,63,61, p=0.96), % stage 3-4 (81,75,88,p=0.27), % bulky disease &gt; 7 cm (46,42,33,p=0.30), % extranodal disease (59,54,59,p=0.78), % history of CNS disease (7,8,4,p=0.71, % refractory disease (59,66,64,p=0.67) and % treated with autologous stem cell transplant (29,24,27,p=0.78). EIP pts had a significantly higher ECOG 2+ population as % with ECOG 2+ was LIP 20%, EIP 38% and OOP 15% (p=0.001). 19% received tisa-cel, 58% received axi-cel and 23% received no CART (p=0.27).
167 (70%) pts were referred from Ontario (78 EIP and 89 LIP) and 71 (30%) were from out of province (OOP). When comparing Ontario to OOP pts, 77.8% v. 74.6% of referrals received CART. 84.3% of LIP compared to 70.5% of EIP referrals received CART (p=0.095). Bridging was used in 73% Ontario pts compared to 59% OOP pts (p=0.046).
Date of CT demonstrating progression to initial visit for the whole cohort was a median of 11 days (0-177) for LIP, 16 days (0-189) for EIP and 22 days (0-113) for OOP (p&lt;0.001). Date of CT demonstrating progression to initial visit for pts who received CART was similar and was a median of 11.5 days (0-177) for LIP, 18 days (0-73) for EIP and 21.5 days (0-113) for OOP. Median days from CT demonstrating progression to CART for LIP, EIP and OOP pts was 44(19-100), 45(33-85) and 48(20-88). (p=0.049) Median days from initial visit to CART for LIP, EIP and OOP pts was 49 (30-111),50 (24,94) and 56 (40,95) days (p=0.018). Median days from apheresis to CART for LIP, EIP and OOP pts was 35(27-107), 36(28-70) and 35(28,74) (p=0.736).
There was no OS difference from infused date for pts receiving CART between LIP, EIP and OOP pts (p=0.46). The 12-month OS of the whole cohort, all Ontario, LIP, EIP and OOP was 67.0% 95% CI (58.9%,76.1%), 66% 95% CI (57.2%,76.1%), 66.3% 95% CI (56.0%,78.6%), 66.9% 95% CI (52.0%,86.1%) and 68.8% 95% CI (50.1%,94.6%).
There was no PFS difference between LIP, EIP, OOP pts (p=0.075). The 6-month PFS of the whole cohort, all Ontario, LIP, EIP and OOP was 53.5% 95% CI (32.3%,88.6%), 49.6% 95% CI (28.8%,85.6%), 53.4% 95% CI (31.2%,91.4%), 41.7% 95% CI (31.2%,91.4%) and 68.2% 95% CI (42.7%,100.0%)
No significant differences in CRS Grade 3+ (p=0.26), ICANS (p=0.54), ICANS Grade 3+ (p=0.67), use of steroids (p=0.086) and non-relapse mortality (p=0.76) between LIP, EIP and OOP pts were noted. Significant differences in CRS (LIP 92%, EIP 78%, OOP 96% p=0.01), tocilizumab use (LIP 82%,60% EIP,70% OOP p=0.02) and ICU admission (LIP 9%, EIP 11%,0% OOP p=0.028) were seen.
Conclusions:
External patients were noted to have significant differences in time to progression to intake visit and time from intake visit to CART. There was no significant difference in patients receiving CART between groups. No differences in PFS or OS were noted between infused patients. More Ontario patients were admitted to the ICU than OOP pts. EIP pts had poorer intake ECOG, less CRS and tocilizumab use although analysis is limited by sample size. Initiatives to reduce time from progression to intake for external patients, such as local infrastructure and provider education, may be needed.