Background: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a frequent complication of CAR T-cell therapy, incidence varies by disease and CAR-T product. ICANS is reported in up to 64% of non-Hodgkins's lymphoma (NHL) patients (grade ≥3 in 10–28%, highest with Axi-cel) and 18% of multiple myeloma (MM) patients (grade ≥3 in 3%, Cilta-cel may cause delayed neurotoxicity). The impact of ICANS on long-term survival is unclear. We evaluated predictors and the impact of ICANS on overall survival (OS) in a large single-center cohort of NHL and MM patients treated with CAR-T therapy.

Methods: We retrospectively analyzed 330 patients (NHL = 263; MM = 67) treated with commercial CAR-T therapies from 2017–2024. ICANS and cytokine release syndrome (CRS) were graded using ASTCT criteria. Demographic, clinical, and laboratory variables were assessed; significant univariate predictors of OS were entered into multivariable Cox regression stratified by disease type. This study was approved by the institutional review board and conducted as a retrospective chart review.

Results: Median age was 65 years (MM: 66 vs. NHL: 63); 62% were male. MM patients were more frequently Black (37% vs. 16%; p=0.003), had poorer baseline ECOG performance status (≥2 in 83.6% vs. 65.8%, p=0.008), more prior therapies (>4 lines: 91% vs. 16%, p<0.001) and stem cell transplant (SCT) (75% vs. 19%, p<0.001) compared to NHL patients. All NHL and MM patients had active disease at infusion (98%); CNS involvement was uncommon (7%). Abnormal brain MRI was more common in MM (65% vs. 54.2%). NHL subtypes were predominantly diffuse large B-cell lymphoma (76%). Most NHL patients received Axi-cel (73%), while MM patients received Ide-cel (54%) or Cilta-cel (46%). Baseline labs showed higher LDH (509 vs. 228 U/L, p<0.001), and ferritin (157 vs. 62 ng/mL, p=0.02) in NHL.

ICANS Occurred in 40% of patients with greater severity in NHL (grade ≥2: 38% vs. 21%; p=0.02). The Median onset was 5 days. Younger age (p=0.005), elevated creatinine (NHL; OR=1.81, p=0.05), and pre-infusion lymphocyte count <1.0×10⁹/L (OR=0.32, p=0.004) were independent predictors of ICANS. Absolute lymphocytes count on days 7 and 14 did not correlate with ICANS. Most ICANS followed CRS onset which occurred in 80% of patients, making causative correlation difficult. Only 11 patients developed ICANS without CRS. Black patients had higher CRS rates (90% vs. 76%, p=0.01), but similar rates of ICANS to Caucasians.

Survival: The median follow-up was 2.16 years (95%CI: 1.99-2.32) for MM and 3.75 years (95% CI: 3.343-4.25) for NHL. Median OS for the entire cohort was 4.5 years; 5-year OS was 50%.

MM

ICANS predicted inferior survival (median OS: 1.6 vs. 5.7 years; HR=3.9, p=0.002). Early-onset ICANS (≤6 days) also worsened OS (HR=1.76, p=0.04). Age ≥70 (HR=3.06, p<0.001), ECOG ≥2 (5-year OS: 17% vs. 57%; p=0.015), and CNS involvement (5-year OS: 0% vs. 58%; p=0.02) were adverse prognostic factors.

NHL

Presence of ICANS reduced OS (median: 2.2 vs. 5.7 years; HR=1.57, p=0.014). ICANS lasting 7–14 days predicted worse outcomes than 0–6 days (HR=1.91, p=0.02). ECOG ≥2 remained highly prognostic (median OS: 0.4 vs. 5.7 years; HR=3.34, p<0.0001). Female sex was associated with improved 5-year OS (59% vs. 44%; p=0.02).

Multivariable analysis confirmed that age ≥70 (HR=3.21, p<0.001), presence of ICANS (HR=1.54, p=0.03), and CRP >5 mg/dL (HR=2.12, p=0.002) were independent predictors of inferior OS, whereas ECOG >2 was no longer statistically significant.

Conclusions: ICANS occurs in 40% of CAR T-cell recipients, with similar incidence in NHL and MM but greater severity in NHL. Its occurrence, early onset, and prolonged duration are associated with significantly reduced OS, regardless of disease type. Age ≥70 and high CRP further identify high-risk patients. Early recognition and intervention may improve survival and tolerability of CAR T-cell therapy.

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2025
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