Incidence and risk factors for immune effector cell-associated neurotoxicity syndrome in older patients with relapsed or refractory large B-cell lymphoma: A multicenter study

Abstract Introduction: Anti-CD19 chimeric antigen receptor T-cell (CART) therapy is feasible with an acceptable safety profile in older patients (pts) with relapsed/refractory (RR) large B-cell lymphoma (LBCL) (Tun et al, AJH 2024). However, immune effector cell-associated neurotoxicity syndrome (ICANS) is a frequent and challenging toxicity in older pts, and its characteristics and associated risk factors are not well defined. Methods: Seven centers participated in this retrospective study. Pts aged ≥65 years (yrs) with RR LBCL treated with a commercial CART product were included. Baseline characteristics, treatment, CART toxicity, and outcomes were collected. ICANS was graded by the ASTCT criteria in most pts. Cumulative incidences of ICANS were estimated using deaths/progressions as competing risks, and associations between incidences and variables were assessed by Gray's test. A 30-day landmark was set after infusion to reduce immortal time bias. Progression-free survival (PFS; time from the landmark to disease progression or death) and overall survival (OS; time from the landmark to death) were analyzed with the Kaplan-Meier method. Statistical analyses were done in JMP v18. Results: A total of 224 pts were included. Median age at infusion was 71 yrs (range 65–89; ≥80 yrs, 12%. 142 (63%) were male and 27 (13%) had an ECOG PS scale of ≥2. The median HCT CI was 1 (range 0–6). LDH was elevated in 110 (51%) pts, 23 (19%) had bulky disease ≥7 cm, 176 (82%) had advanced-stage, and 145 (71%) had extranodal disease. Median number of prior treatments was 2 (range 1–8), and 44 (20%) had prior bendamustine. Prior stem cell therapy was done in 47 (21%) pts (autologous stem cell transplant [SCT], n = 45; allogeneic SCT, n=2). Axicabtagene ciloleucel (axi-cel) was most frequently used (58%; n=131) followed by lisocabtagene maraleucel (liso-cel) (16%, n=36) and tisagenlecleucel (tisa-cel) (25%, n=57). Median duration of ICANS was 6 days (interquartile range [IQR] 3–11; range 1–303). Median time to ICANS onset was 6 days (IQR 3.8–8.0; range 0–24). The 30-day cumulative incidence of all grade ICANS was 50.9% (95% confidence interval [CI] 44.7–57.9) and grade ≥3 ICANS was 29.8% (95% CI 24.0–37.0). There was no significant difference in incidence of all grade (P=0.39) and grade ≥3 (P=0.49) ICANS as well as duration of ICANS (≥14 vs <14 days; P=0.08) according to the age groups (≥65–69 vs ≥70–74 vs ≥75–79 vs ≥80–89). In contrast, pts with an ECOG PS scale of ≥2 were associated with a higher incidence of all grade (30-day estimate, 66.7% vs 47.0%; P=0.02) and grade ≥3 ICANS (30-day estimate, 53.8% vs 25.6%; P=0.002). In addition, pts with an elevated LDH level had a higher incidence of grade ≥3 ICANS than those without (30-day estimate, 37.5% vs 18.8%;P=0.004). The incidence of ICANS varied among various CART products, with 30-day estimates of 64.9% vs 33.3% vs 29.8% (P<0.0001) for all grades and 40.1% vs 13.2% vs 18.0% (P=0.004) for grade ≥3 ICANS in pts treated with axi-cel vs tisa-cel vs liso-cel, respectively. A trend toward higher grade ≥3 ICANS was seen in pts treated with ≥3 prior lines than those treated with 2 or 1 (30-day estimate, 35.7% vs 28.1% vs 10.5%; P = 0.07). ICANS was managed with steroids in 47 (41%) pts, levetiracetam +/- other agents in 46 (40%) pts, biologic agents +/- other drugs in 15 (13%) pts, and supportive care in 6 (5%) pts. Median follow-up from the 30-day landmark post-infusion was 17.2 months (95% CI 14.2–22.4). Median PFS was 10.5 months (95% CI 5.7–18.2) and OS was 18.2 months (95% CI 13.3 vs 27.5). There was no difference in PFS and OS in pts who experienced ICANS vs no ICANS (median PFS 14.7 vs 10.1 months; P=0.65 and median OS 18.2 vs 24.7 months; P=0.49). However, there was a trend toward inferior PFS and OS in pts who experienced high-grade ICANS compared to those who had grade 0-2 ICANS (median PFS 9.2 vs 21.2; P=0.14 and median OS 11.7 =vs 22.9; P=0.39). Conclusions: This large study of older pts with RR LBCL demonstrated acceptable risks of ICANS, comparable to that in pivotal registration trials, with a relatively higher rate of grade ≥3 ICANS. The risks of ICANS were similar regardless of patient age, including those aged ≥80 yrs, but different among CART products. Similar to younger pts, high tumor burden disease and poor performance status at CART infusion were associated with higher risks of ICANS. A comprehensive neurologic and frailty assessment is warranted to identify suitable CART candidates.