ICANS mitigation in high-risk elderly patients treated with CD28 co-stimulatory anti-CD19 CAR-T cells using a standardization protocol: a pilot study

Chimeric antigen receptor T-cell therapy (CAR-T) has transformed the treatment of relapsed/refractory large B-cell lymphoma (LBCL), with CD28-based products yielding rapid responses but higher rates of immune effector cell-associated neurotoxicity syndrome (ICANS). With axicabtagene-ciloleucel and brexucabtagene-autoleucel, overall and severe ICANS reach 78% and 35%, respectively. Older adults are vulnerable, yet mitigation strategies are still lacking. To address this critical gap, we aimed to develop and implement a standardized ICANS mitigation protocol for older adults receiving CD28-based anti- CD19 CAR-T. We conducted a single-arm prospective pilot study in patients ≥75 or ≥65 years with additional risk factor receiving CD28-based CAR-T. The protocol included levetiracetam and thiamine prophylaxis, early grade-based corticosteroids and anakinra for grade ≥3 and refractory ICANS, which was defined as no improvement within 24 hours. Endpoints were ICANS duration, refractoriness, response, and toxicity. Forty-five patients met eligibility criteria. Median age was 75 years (range: 65-86 years); 78% had Eastern Cooperative Oncology Group (ECOG) ≥2 and 42% had neurologic comorbidity. Grade ≥3 and refractory ICANS developed in 67% overall, with grade ≥3 in 31%, and refractory ICANS in 20%. Median ICANS duration was four days, which was shorter than previous cohorts. Disease and patients' characteristics did not predict ICANS metrics, excluding lactate dehydrogenase which showed a trend for severe ICANS (P=0.07). modified Endothelial Activation and Stress Index (mEASIX) and ICANS-Prognostic Scoring System (PSS) scores were not predictive and expansion was not compromised. Cumulative steroids associated with infections (P=0.002) and non-relapse mortality (P<0.0001). Sixmonth progression-free survival and overall survival were 46% and 59%, respectively. In this high-risk cohort, the ICANS mitigation protocol using anakinra in a graded approach (vs. prophylaxis or salvage therapy) and a pragmatic definition of refractory disease was associated with shorter ICANS duration, despite severe event rates. Steroid-related toxicity remains a concern, and future efforts should focus on steroid-sparing mitigation to optimize outcomes in older adults undergoing CAR-T.