Lazarus: IT Therapy for ICANS

PRIMARY OBJECTIVE: I. Efficacy of IT therapy to reduce high-grade ICANS in participants who receive axi-cel in NHL compared to historical experience. OUTLINE: This is an open label, phase 2 study of early intervention using IT cytarabine 100mg and IT hydrocortisone 100mg to treat ICANS after brexu-cel and axi-cel in NHL. Participants will be screened within 30 days prior to start of lymphodepletion chemotherapy. Lymphodepleting Chemotherapy and CAR T Cell Administration Period- Participants will receive standard fludarabine and cyclophosphamide-based LD chemotherapy starting day-5 followed by CAR T infusion on day 0. Participant must meet institutional criteria to start LD chemo on day -5. Grading for CRS and ICANS must follow ASTCT guidelines (appendix 4). Participants will get daily CRS and ICANS grading from D0 to D+7 then with each visit through day+28 and these grades will be documented in EMR by treating provider. Providers performing CRS and ICANS assessment should be familiar with ASTCT grading and study physician is responsible for verifying accuracy of final toxicity grading. CAR T INFUSION PHASE (4-5 WEEKS): Patients receive brexu-cel IV on day 0. POST CAR T PHASE (UP TO 24 MONTHS): Starting around day 28 or later after brexu-cel infusion, patients without progressive disease (PD) receive nemtabrutinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 24 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Early treatment of ICANS: IT hydrocortisone 100mg plus cytarabine 100mg at onset of grade 1/2 ICANS. This will be done along with the early intervention protocol as stated in Zuma 1, cohort 4 and 6 (1, 2) with prophylactic dexamethasone 10 mg daily on days 0, +1 and +2 per institutional protocol. Each participant may receive up to two intrathecal therapies for persistent ICANS. After completion of study treatment, patients are followed up at 30 days, 12 weeks, then every 6 months for up to 5 years.