Table 1.

Factors associated with neurotoxicity

Neurotoxicity CTCAE gradeGrade 0aGrade 1–2aGrade 3–5aTotalUnivariatebMultivariablec
Overall, n (%)80 (60)25 (19)28 (21)133 (100)
Age, n (%)<40 years11 (41)10 (37)6 (22)270.094
40–60 years42 (66)8 (13)14 (22)64
>60 years27 (64)7 (17)8 (19)42
Sex, n (%)Male59 (63)17 (18)17 (18)930.4
Female21 (53)8 (20)11 (28)40
Diagnosis, n (%)ALL22 (47)11 (23)14 (30)470.084
CLL16 (67)2 (8)6 (25)24
NHL42 (68)12 (19)8 (13)62
Race, n (%)White62 (56)22 (20)26 (24)1100.17d
Not white18 (78)3 (13)2 (9)23
Prior therapiesMedian (range)4 (1–11)4 (1–10)4 (1–11)4 (1–11)0.5
Transplant history, n (%)Auto17 (68)5 (20)3 (12)250.5
Allo14 (50)8 (29)6 (21)28
Karnofsky scoree, n (%)60–707 (50)3 (21)4 (29)140.5
80–9065 (61)18 (17)23 (22)106
1008 (62)4 (31)1 (8)13
Preexisting neurologic comorbidities, n (%)Any26 (45)16 (28)16 (28)580.0059g0.0023g
PNf14 (47)7 (23)9 (30)300.2
CNS involvement6 (43)5 (36)3 (21)140.2
Headache disorder6 (43)5 (36)3 (21)140.2
Other5 (50)2 (20)3 (30)100.7
ICHh4 (67)1 (17)1 (17)61
Seizures2 (33)2 (33)2 (33)60.3
Cog impairmenti1 (25)2 (50)1 (25)40.1
MTX CNS toxicityj1 (50)1 (50)020.4
Marrow disease, %Median (range)0.6 (0–97)0.4 (0–93)25.8 (0–97)1.3 (0–97)0.0720.0165
Total CD19+ cells in marrow, %Median (range)5.3 (0–99)12.4 (0–93)29.1 (0–97)8.8 (0–99)0.062
CD8+ central memory enriched CAR-T cellsk, n (%)Selected48 (67)11 (15)13 (18)72 (54)0.242
Lymphodepletion regimenl, n (%)Cy/Flu58 (56)23 (22)23 (22)1040.110.0259
Non-Cy/Flu22 (76)2 (7)5 (17)29
CAR-T cell dose, n (%)2 × 105 cells/kg20 (57)10 (29)5 (14)35<0.00010.0009
2 × 106 cells/kg55 (64)15 (17)16 (19)86
2 × 107 cells/kg5 (42)07 (58)12
Cytokine release syndrome, n (%)None (G 0)35 (88)5 (13)040<0.0001n/a
Mild (G 1–2)44 (57)19 (25)14 (18)77
Severe (G 3–5)1 (6)1 (6)14 (88)16
  • aPercentages are shown in parentheses.

  • bTwo-sided P values calculated on the basis of Kruskal–Wallis test for continuous variables, and based on Fisher exact test for categorical variables.

  • cStepwise multivariable proportional odds models were performed to assess the impact of baseline factors on the occurrence of neurotoxicity (grade 0 vs. 1–2 vs. 3–5), where log10 values were used to transform data as appropriate, with 0.001 substituting for marrow disease values of 0. Although the lymphodepletion regimen did not significantly affect the risk of neurotoxicity in the univariate model, it was included in the multivariable model because of its association with increased in vivo CAR-T cell proliferation. After controlling for CAR-T cell dose and pretreatment tumor burden, the lymphodepletion regimen was found to have a significant impact on the risk of neurotoxicity. CRS was not included in the stepwise multivariable model, because it is not a pretreatment variable. The percentage of all CD19+ cells in bone marrow was not included in the stepwise multivariable model, as it strongly correlates with the percentage of marrow CD19+ abnormal B cells (r = 0.99, P < 0.0001). Only variables with P < 0.05 were retained in the final model.

  • dWhite versus nonwhite.

  • eKarnofsky performance score prior to lymphodepletion.

  • fPeripheral neuropathy.

  • gNone versus any.

  • hIntracranial hemorrhage.

  • iCognitive impairment.

  • jCentral nervous system (CNS) toxicity from prior intrathecal methotrexate (MTX) use.

  • kCAR-T cells manufactured from CD4+ T cells and central memory enriched CD8+ T cells.

  • lCy/Flu regimens included both cyclophosphamide and fludarabine.