Table 1.

Clinical data and histopathologic findings of our cases and previously described cases (modified from7)

No. of patient/ Ref.	Age, gender (M – F)	Disease	Product	Cy/flu conditioning	Corticoids in last admission	Cause of Death	Time between CAR-T infusion and death	Neurologic signs	Autopsy findings	CAR T-cells in FFPE brain tissue
1	44, F	B-cell lymphoblastic leukemia	ARI-0001 (CAR T 19)	Yes	Yes	Disease progression and signs of pneumonia and pulmonary hemorrhage	23 days	Yes	Mild changes and occasional intravascular leukemia cells: Mild arteriosclerosis and arteriolar hyalinosis, minimal T-cell perivascular infiltrate, occasional intravascular infiltration by TdT positive atypical cells (leukemic cells), without remarkable parenchymal involvement.	Negative
2	19, F	Mediastinal diffuse large B-cell lymphoma	ARI-0001 (CAR T 19)	Yes	Yes	Disease progression and signs of pneumonia.	33 days	No	Mild changes: mild gliosis in basal ganglia and occasional perivascular hemosiderin deposits in parenchymal blood vessels of the white matter and basal ganglia.	Positive
3	19, M	B-cell acute lymphoblastic leukemia	ARI-0001 (CAR T 19)	Yes	Yes	Cytokine release syndrome	5 days	No	Mild changes: Mild white matter oedema with mild gliosis in basal ganglia and midbrain tegmentum. Cortical dark neurons suggestive of incipient hypoxic-ischemic alterations. Mild congestion and minimal arteriosclerosis of parenchymal blood vessels with occasional perivascular histiocytes.	Negative
4	63, M	Follicular lymphoma	ARI-0001 (CAR T 19)	Yes	Yes	Respiratory failure due to nosocomial pneumonia	5 months	No	Cortical gliosis in frontal and parahippocampal cortices, in possible relation to mild acute hypoxic-ischemic injury, with scattered foci of gliosis with minimal clasmatodendrosis in frontal and parahippocampal subcortical white matter. Mild arteriosclerosis and arteriolar hyalinosis.	Negative
5	28, M	B-cell acute lymphoblastic leukemia	ARI-0001 (CAR T 19)	Yes	Yes	Encephalomyelitis	43 days	Yes	Diffuse lymphocytic encephalomyelitis: Diffuse gliosis in basal ganglia, hippocampus, brainstem, and spinal cord. Severe interstitial and perivascular lymphocytic (CD3+ and predominantly CD8+) and histiocytic infiltrates in anterior horns and grey matter of spinal cord, as well as brainstem, limbic system, and basal ganglia. Mild focal clasmatodendrosis in hippocampal white matter.	Negative
6	71, F	Multiple Myeloma	ARI-0002 (CAR T BCMA)	Yes	Yes	Submassive liver necrosis of probable ischemic cause	19 days	No	Mild changes: Minimal diffuse gliosis and minimal microglial activation. Isolated perivascular T-cells. Mild arteriosclerosis.	Negative
Torre et al., 2018	21, M	B-ALL	JCAR015	Yes	Yes	Fulminant cerebral edema	4 days	Yes	Expansion of perivascular spaces attributed to blood-brain barrier dysfunction, clasmatodendrosis with perivascular distribution of damaged astrocytes within white matter, myelin pallor and vacuoles within white matter, few scattered intraparenchymal inflammatory cells and rare T-cells; perivascular macrophages clusters, microglia activation.	Negative
Gust et al., 2017	N/A	B-cell malignancy	CD19 CAR	N/A	N/A	Brainstem hemorrhage	13 days	N/A	Evidence of CAR T-cells in perivascular areas and CSF, with evidence of blood and blood-brain barrier alterations, with Intravascular vWF binding and CD61þ platelet microthrombi, and parenchymal lesions with multifocal microhemorrhages, patchy parenchymal necrosis and fibrinoid vessel wall necrosis. Reactive microglia without diffuse activation.	Positive
Gust et al., 2017	N/A	B-cell malignancy	CD19 CAR	N/A	N/A	Severe CRS, multiorgan failure, grade 4 neurotoxicity	N/A	N/A	Intravascular CD61þ platelet microthrombi.	N/A
Schuster et al., 2017	N/A	Follicular lymphoma	CTL019 (CD19/4- 1BB)	Yes	No	Progressive neurologic deterioration	N/A	Yes	Inflammatory process with dense macrophage infiltration of white matter, microglial activation and a moderate CD8+ T-cell infiltrate with white matter degeneration, gliosis, and neuronal loss. No evidence of herpes simplex virus 1 or 2, cytomegalovirus, varicella–zoster virus, JC virus, adenovirus, or Epstein–Barr virus	N/A

*Acronyms: M: male; F: female; N/A: not applicable. FFPE: Formalin fixed paraffin embedded.