Table 1.
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 | Auto | 17 (68) | 5 (20) | 3 (12) | 25 | 0.5 | |
| HISTORY, n (%) | 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 | |||
| PRE-EXISTING 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 | Cy/Flu | 58 (56) | 23 (22) | 23 (22) | 104 | 0.11 | 0.0259 |
| REGIMENl, n (%) | 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 | <.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 | None (G 0) | 35 (88) | 5 (13) | 0 | 40 | <0.0001 | n/a |
| SYNDROME, n (%) | Mild (G 1–2) | 44 (57) | 19 (25) | 14 (18) | 77 | ||
| Severe (G 3–5) | 1 (6) | 1 (6) | 14 (88) | 16 | |||
Percentages are shown in parentheses.
Two-sided p-values calculated based on Kruskal-Wallis test for continuous variables, and based on Fisher’s Exact test for categorical variables.
Stepwise 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 impact 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 pre-treatment 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 pre-treatment variable. The percentage of all CD19+ cells in bone marrow was not included in the stepwise multivariable model since it strongly correlates with the percentage of marrow CD19+ abnormal B cells (r = 0.99, p<0.0001). Only variables with a p-value <0.05 were retained in the final model.
White versus non-white
Karnofsky performance score prior to lymphodepletion
Peripheral neuropathy
None versus any
Intracranial hemorrhage
Cognitive impairment
CNS toxicity from prior intra-thecal methotrexate use
CAR-T cells manufactured from CD4+ T cells and central memory enriched CD8+ T cells
Cy/Flu regimens include both cyclophosphamide and fludarabine