Hemophagocytosis in cerebrospinal fluid after CAR T-cell therapy

The patient is a 66-year-old woman with chemorefractory diffuse large B-cell lymphoma who received axicabtagene ciloleucel anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. On day +1 after CAR infusion she developed a fever consistent with grade 1 cytokine release syndrome (CRS). She received 2 doses of tocilizumab, 8 mg/kg, on days +6 and +7 for persistent CRS. On day +8 she developed word finding difficulty and started IV dexamethasone, 10 mg every 6 hours. On day +9 she progressed with grade 2 ICANS (immune effector cell–associated neurotoxicity syndrome). Brain magnetic resonance imaging was unrevealing. Lumbar puncture with cerebrospinal fluid (CSF) analysis revealed an elevated white blood cell count (39/μL) without evidence of lymphoma. Immunophenotypic analysis demonstrated 55% T cells and no B cells. Wright-stained CSF cytospin revealed many hemophagocytic histiocytes (panel A, original magnification ×100; panel B, ×1000) consistent with a dysregulated immune response after CAR T-cell therapy. She received intrathecal hydrocortisone, 100 mg, with improvement. On day +13 she had recurrent grade 3 ICANS and received intrathecal hydrocortisone+methotrexate+cytarabine with full neurological recovery by day +14. Peak levels of ferritin, C-reactive protein, and lactate dehydrogenase in the first 28 days were 387 ng/mL, 14.93 mg/dL, and 287 U/L, respectively. She achieved remission and remains relapse free at 4 months posttreatment.

ICANS remains a clinical challenge of CAR T-cell therapy. The image demonstrates the role of macrophage activation in the development of ICANS and the ability of intrathecal treatment to reverse toxicity.