ICANS mitigation in high-risk elderly patients treated with CD28 co-stimulatory anti-CD19 CAR-T cells using a...

Area of Science:

• Oncology
• Neurology
• Immunotherapy

Background:

• Chimeric antigen receptor T-cell (CAR-T) therapy, particularly CD28-based products, has revolutionized relapsed/refractory large B-cell lymphoma (LBCL) treatment.
• However, these therapies are associated with high rates of immune effector cell-associated neurotoxicity syndrome (ICANS), especially in older adults who lack specific mitigation strategies.
• Existing data show overall and severe ICANS rates of 78% and 35% with approved CD28-based CAR-T agents.

Purpose of the Study:

• To develop and implement a standardized ICANS mitigation protocol tailored for older adults undergoing CD28-based anti-CD19 CAR-T therapy.
• To address the critical unmet need for managing neurotoxicity in this vulnerable patient population.

Main Methods:

• A single-arm prospective pilot study was conducted on patients aged 75 years or older, or 65 years or older with additional risk factors, receiving CD28-based CAR-T.
• The protocol incorporated levetiracetam and thiamine prophylaxis.
• Early, grade-based administration of corticosteroids and anakinra was used for grade 3 or higher and refractory ICANS (defined as no improvement within 24 hours).

Main Results:

• Forty-five patients were enrolled, with a median age of 75 years; 78% had an ECOG performance status of 2 or higher, and 42% had pre-existing neurologic comorbidities.
• The protocol resulted in overall, grade 3 or higher, and refractory ICANS rates of 67%, 31%, and 20%, respectively.
• The median duration of ICANS was 4 days, which is shorter compared to historical cohorts. Disease characteristics did not predict ICANS metrics, though LDH showed a trend towards severe ICANS.

Conclusions:

• The implemented standardized protocol effectively reduced the duration of ICANS in older adults receiving CD28-based CAR-T therapy.
• The findings suggest that proactive neuroprotection strategies can mitigate CAR-T-related neurotoxicity in vulnerable elderly populations.
• Further research is warranted to confirm these findings and optimize management strategies, considering the association of cumulative steroids with increased infection and non-relapse mortality.