Factors associated with neurotoxicity
| Neurotoxicity CTCAE grade | Grade 0a | Grade 1–2a | Grade 3–5a | Total | Univariateb | Multivariablec | ||
|---|---|---|---|---|---|---|---|---|
| Overall, n (%) | 80 (60) | 25 (19) | 28 (21) | 133 (100) | ||||
| Age, n (%) | <40 years | 11 (41) | 10 (37) | 6 (22) | 27 | 0.094 | ||
| 40–60 years | 42 (66) | 8 (13) | 14 (22) | 64 | ||||
| >60 years | 27 (64) | 7 (17) | 8 (19) | 42 | ||||
| Sex, n (%) | Male | 59 (63) | 17 (18) | 17 (18) | 93 | 0.4 | ||
| Female | 21 (53) | 8 (20) | 11 (28) | 40 | ||||
| Diagnosis, n (%) | ALL | 22 (47) | 11 (23) | 14 (30) | 47 | 0.084 | ||
| CLL | 16 (67) | 2 (8) | 6 (25) | 24 | ||||
| NHL | 42 (68) | 12 (19) | 8 (13) | 62 | ||||
| Race, n (%) | White | 62 (56) | 22 (20) | 26 (24) | 110 | 0.17d | ||
| Not white | 18 (78) | 3 (13) | 2 (9) | 23 | ||||
| Prior therapies | Median (range) | 4 (1–11) | 4 (1–10) | 4 (1–11) | 4 (1–11) | 0.5 | ||
| Transplant history, n (%) | Auto | 17 (68) | 5 (20) | 3 (12) | 25 | 0.5 | ||
| Allo | 14 (50) | 8 (29) | 6 (21) | 28 | ||||
| Karnofsky scoree, n (%) | 60–70 | 7 (50) | 3 (21) | 4 (29) | 14 | 0.5 | ||
| 80–90 | 65 (61) | 18 (17) | 23 (22) | 106 | ||||
| 100 | 8 (62) | 4 (31) | 1 (8) | 13 | ||||
| Preexisting neurologic comorbidities, n (%) | Any | 26 (45) | 16 (28) | 16 (28) | 58 | 0.0059g | 0.0023g | |
| PNf | 14 (47) | 7 (23) | 9 (30) | 30 | 0.2 | |||
| CNS involvement | 6 (43) | 5 (36) | 3 (21) | 14 | 0.2 | |||
| Headache disorder | 6 (43) | 5 (36) | 3 (21) | 14 | 0.2 | |||
| Other | 5 (50) | 2 (20) | 3 (30) | 10 | 0.7 | |||
| ICHh | 4 (67) | 1 (17) | 1 (17) | 6 | 1 | |||
| Seizures | 2 (33) | 2 (33) | 2 (33) | 6 | 0.3 | |||
| Cog impairmenti | 1 (25) | 2 (50) | 1 (25) | 4 | 0.1 | |||
| MTX CNS toxicityj | 1 (50) | 1 (50) | 0 | 2 | 0.4 | |||
| Marrow disease, % | Median (range) | 0.6 (0–97) | 0.4 (0–93) | 25.8 (0–97) | 1.3 (0–97) | 0.072 | 0.0165 | |
| 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 (%) | Selected | 48 (67) | 11 (15) | 13 (18) | 72 (54) | 0.242 | ||
| Lymphodepletion regimenl, n (%) | Cy/Flu | 58 (56) | 23 (22) | 23 (22) | 104 | 0.11 | 0.0259 | |
| Non-Cy/Flu | 22 (76) | 2 (7) | 5 (17) | 29 | ||||
| CAR-T cell dose, n (%) | 2 × 105 cells/kg | 20 (57) | 10 (29) | 5 (14) | 35 | <0.0001 | 0.0009 | |
| 2 × 106 cells/kg | 55 (64) | 15 (17) | 16 (19) | 86 | ||||
| 2 × 107 cells/kg | 5 (42) | 0 | 7 (58) | 12 | ||||
| Cytokine release syndrome, n (%) | None (G 0) | 35 (88) | 5 (13) | 0 | 40 | <0.0001 | n/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.