Outcomes and toxicities in patients with CRS + HLH toxicities, HG-CRS without HLH toxicities, and NLG-CRS without HLH toxicities
| . | CRS + HLH-LT, n = 26 . | HG-CRS without HLH-LT, n = 17 . | NLG-CRS without HLH-LT, n = 141 . | P value . |
|---|---|---|---|---|
| Experienced CRS, n (%) | 26/26 (100) | 17/17 (100) | 75/141 (53.2) | <.0001∗∗∗∗ |
| ASTCT grade of CRS, median (IQR) | 4 (3.0-4.0), n = 25 | 3 (3-4), n = 17 | 1 (0-1), n = 141 | <.0001∗∗∗∗ |
| ASTCT grade of CRS, median (IQR) | 4 (3.0-4.0), n = 25 | 3 (3-4), n = 17 | .1696 | |
| ASTCT CRS grade, n (%) | ||||
| 0 | 0/25 (0) | 0/17 (0) | 67/141 (47.5) | |
| 1 | 0/25 (0) | 0/17 (0) | 45/141 (31.9) | |
| 2 | 3/25 (12) | 0/17 (0) | 29/141 (20.6) | |
| 3 | 7/25 (28) | 12/17 (70.6) | 0/141 (0) | |
| 4 | 14/25 (56) | 5/17 (29.4) | 0/141 (0) | |
| 5 | 1/25 (4.0) | 0/17 (0) | 0/141 (0) | |
| D between CAR T-cell infusion and CRS onset, median (IQR) | 2.5 (1-7.25), n = 24 | 3 (2-6), n = 17 | 5 (3-8), n = 67 | .10 |
| Duration of CRS, median (IQR), d | 11 (10-15), n = 19 | 5 (4-13), n = 15 | 3 (2-5), n = 65 | <.0001∗∗∗∗ |
| Experienced ICANS/neurotoxicity, n (%) | 13/24 (54.2) | 6/16 (37.5) | 20/140 (14.3) | <.0001∗∗∗∗ |
| Maximum grade ICANS/neurotoxicity∗, median (IQR) | 1.0 (0.0-2.0), n = 23 | 0.0 (0.0-2.5), n = 16 | 0.0 (0.0-0.0), n = 141 | <.0001∗∗∗∗ |
| Onset of HLH toxicities, median (range) | 12.0 (4.0-21.0), n = 7 | |||
| Duration of HLH toxicities, median (range) | 7.0 (4.0-25.0), n = 7 | |||
| Maximum ferritin (ng/mL), median (IQR) | 92 204 (38 305-221 638), n = 26 | 5 467 (2 186-14 614), n = 15 | 2 035 (855-4 048), n = 119 | <.0001∗∗∗∗ |
| Maximum ferritin (ng/mL), total (N), n (%) | 26 | 15 | 119 | |
| <10 000 | 0 (0.0) | 10 (66.7) | 103 (86.6) | <.0001∗∗∗∗ |
| ≥10 000 and <100 000 | 13 (50.0) | 4 (26.7) | 15 (12.6) | |
| ≥100 000 | 13 (50.0) | 1 (6.7) | 1 (0.8) | |
| Change in ferritin (ng/mL), median (IQR) | 83 874 (35 353-233 720), n = 25 | 4 753 (1 447-13 671), n = 13 | 325 (0-1 614), n = 106 | <.0001∗∗∗∗ |
| Maximum CRP (mg/dL), median (IQR) | 20.93 (11.61-30.53), n = 24 | 6.15 (4.02-16.78), n = 14 | 2.85 (0.87-10.83), n = 112 | <.0001∗∗∗∗ |
| Change in CRP (mg/dL), median (IQR) | 14.0 (7.8-20.5), n = 22 | 5.1 (3.3-9.2), n = 12 | 1.1 (0.2-9.5), n = 101 | <.0001∗∗∗∗ |
| Treatments received for CRS | ||||
| Doses of tocilizumab, median | 2 (1-2.75), n = 26 | 2 (1-2), n = 17 | 0 (0-0), n = 130 | <.0001∗∗∗∗ |
| Doses of tocilizumab, median | 2 (1-2.75), n = 26 | 2 (1-2), n = 17 | .50 | |
| D of steroid, median (IQR) | 4 (0-7), n = 25 | 0 (0-5.25), n = 16 | 0 (0-0), n = 127 | <.0001∗∗∗∗ |
| D of steroid, median (IQR) | 4 (0-7), n = 25 | 0 (0-5.75), n = 16 | .23 | |
| Other treatments, patients received, n | ||||
| Anakinra | 3 | 0 | 0 | |
| Siltuximab | 0 | 0 | 1 | |
| D hospitalized between CAR T-cell infusion and discharge, median (IQR) | 25 (17-38.5), n = 26 | 16 (13-23), n = 17 | 10 (2-17), n = 140 | <.0001∗∗∗∗ |
| D requiring intensive care unit–level care, median (IQR) | 10 (5-13), n = 26 | 5 (3-8), n = 17 | 0 (0-0), n = 139 | <.0001∗∗∗∗ |
| Experienced grade 4 neutropenia, n (%) | 21/24 (87.5) | 9/16 (56.3) | 88/134 (65.1) | .06 |
| Recovered from neutropenia, n (%) | 9/20 (45) | 7/9 (77.8) | 81/87 (93.1) | <.0001∗∗∗∗ |
| D to ANC recovery, median (IQR) | 34 (23-39), n = 9 | 13 (12-16.5), n = 7 | 13 (9-18), n = 88 | .008∗∗ |
| Required platelet transfusions after CAR T-cell infusion, n (%) | 23/24 (95.8) | 8/17 (47) | 35/134 (26.1) | <.0001∗∗∗∗ |
| Days after CAR T-cell infusion that last platelet transfusion administered, median (IQR) | 35 (25-50.5), n = 15 | 19 (9.5-25.75), n = 8 | 29 (21-49), n = 21 | .04∗ |
| Developed infection within 28 d of CAR T-cell infusion (%) | 14/22 (63.6%) | 3/17 (17.6%) | 19/137 (13.9%) | <.0001∗∗∗∗ |
| Onset of first infection (d from CAR T-cell infusion), median (IQR) | 13 (10-21.5), n = 15 | 73 (14.5-245.25), n = 8 | 50 (11-168.5), n = 47 | .04∗ |
| Refractory disease at d 28†,n (%) | 6/21 (28.6) | 3/17 (17.6) | 20/141 (14.2) | .20 |
| OS, median d | 128 | Undefined | Undefined | <.0001∗∗∗∗ |
| RFS, median d | 60 | Undefined | 701 | <.0001∗∗∗∗ |
| Relapse occurred, n (%) | 16/25 (64) | 5/17 (29.4) | 44/141 (31.2) | .007∗∗ |
| Time to relapse, median d | 60, n = 16 | 178, n = 5 | 101, n = 45 | .1033 |
| Death occurred, n (%) | 19/25 (76) | 3/17 (17.6) | 29/141 (20.6) | <.0001∗∗∗∗ |
| Time to death, median d | 85, n = 19 | 313, n = 3 | 221, n = 29 | .0261 |
| Relapse or death occurred, n (%) | 23/25 (92) | 7/17 (41.2) | 57/141 (40.4) | <.0001∗∗∗∗ |
| Causes of death, n (%) | ||||
| Leukemia | 12/19 (63.2) | 3/3 (100) | 23/29 (79.3) | |
| CRS | 1/19 (5.3) | 0/3 (0.0) | 1/29 (3.4) | |
| Neurotoxicity | 1/19 (5.3) | 0/3 (0.0) | 0/29 (0.0) | |
| Infection | 4/19 (21.1) | 0/3 (0.0) | 6/29 (20.7) | |
| Cardiopulmonary failure | 3/19 (15.8) | 0/3 (0.0) | 3/29 (10.3) | |
| Hematopoietic stem cell transplant-related complications | 0/19 (0.0) | 0/3 (0.0) | 3/29 (10.3) | |
| NRM‡, n (%) | 7/25 (28.0) | 0/17 (0.0) | 6/141 (4.3) | .0009∗∗∗ |
| CD19− relapse, n (%) | 10/14 (71.4) | 3/5 (60) | 13/39 (33.3) | .04∗ |
| Myeloid transformation of leukemia, n (%) | 3/16 (18.8) | 0/4 (0.0) | 1/41 (2.44) | .11 |
| . | CRS + HLH-LT, n = 26 . | HG-CRS without HLH-LT, n = 17 . | NLG-CRS without HLH-LT, n = 141 . | P value . |
|---|---|---|---|---|
| Experienced CRS, n (%) | 26/26 (100) | 17/17 (100) | 75/141 (53.2) | <.0001∗∗∗∗ |
| ASTCT grade of CRS, median (IQR) | 4 (3.0-4.0), n = 25 | 3 (3-4), n = 17 | 1 (0-1), n = 141 | <.0001∗∗∗∗ |
| ASTCT grade of CRS, median (IQR) | 4 (3.0-4.0), n = 25 | 3 (3-4), n = 17 | .1696 | |
| ASTCT CRS grade, n (%) | ||||
| 0 | 0/25 (0) | 0/17 (0) | 67/141 (47.5) | |
| 1 | 0/25 (0) | 0/17 (0) | 45/141 (31.9) | |
| 2 | 3/25 (12) | 0/17 (0) | 29/141 (20.6) | |
| 3 | 7/25 (28) | 12/17 (70.6) | 0/141 (0) | |
| 4 | 14/25 (56) | 5/17 (29.4) | 0/141 (0) | |
| 5 | 1/25 (4.0) | 0/17 (0) | 0/141 (0) | |
| D between CAR T-cell infusion and CRS onset, median (IQR) | 2.5 (1-7.25), n = 24 | 3 (2-6), n = 17 | 5 (3-8), n = 67 | .10 |
| Duration of CRS, median (IQR), d | 11 (10-15), n = 19 | 5 (4-13), n = 15 | 3 (2-5), n = 65 | <.0001∗∗∗∗ |
| Experienced ICANS/neurotoxicity, n (%) | 13/24 (54.2) | 6/16 (37.5) | 20/140 (14.3) | <.0001∗∗∗∗ |
| Maximum grade ICANS/neurotoxicity∗, median (IQR) | 1.0 (0.0-2.0), n = 23 | 0.0 (0.0-2.5), n = 16 | 0.0 (0.0-0.0), n = 141 | <.0001∗∗∗∗ |
| Onset of HLH toxicities, median (range) | 12.0 (4.0-21.0), n = 7 | |||
| Duration of HLH toxicities, median (range) | 7.0 (4.0-25.0), n = 7 | |||
| Maximum ferritin (ng/mL), median (IQR) | 92 204 (38 305-221 638), n = 26 | 5 467 (2 186-14 614), n = 15 | 2 035 (855-4 048), n = 119 | <.0001∗∗∗∗ |
| Maximum ferritin (ng/mL), total (N), n (%) | 26 | 15 | 119 | |
| <10 000 | 0 (0.0) | 10 (66.7) | 103 (86.6) | <.0001∗∗∗∗ |
| ≥10 000 and <100 000 | 13 (50.0) | 4 (26.7) | 15 (12.6) | |
| ≥100 000 | 13 (50.0) | 1 (6.7) | 1 (0.8) | |
| Change in ferritin (ng/mL), median (IQR) | 83 874 (35 353-233 720), n = 25 | 4 753 (1 447-13 671), n = 13 | 325 (0-1 614), n = 106 | <.0001∗∗∗∗ |
| Maximum CRP (mg/dL), median (IQR) | 20.93 (11.61-30.53), n = 24 | 6.15 (4.02-16.78), n = 14 | 2.85 (0.87-10.83), n = 112 | <.0001∗∗∗∗ |
| Change in CRP (mg/dL), median (IQR) | 14.0 (7.8-20.5), n = 22 | 5.1 (3.3-9.2), n = 12 | 1.1 (0.2-9.5), n = 101 | <.0001∗∗∗∗ |
| Treatments received for CRS | ||||
| Doses of tocilizumab, median | 2 (1-2.75), n = 26 | 2 (1-2), n = 17 | 0 (0-0), n = 130 | <.0001∗∗∗∗ |
| Doses of tocilizumab, median | 2 (1-2.75), n = 26 | 2 (1-2), n = 17 | .50 | |
| D of steroid, median (IQR) | 4 (0-7), n = 25 | 0 (0-5.25), n = 16 | 0 (0-0), n = 127 | <.0001∗∗∗∗ |
| D of steroid, median (IQR) | 4 (0-7), n = 25 | 0 (0-5.75), n = 16 | .23 | |
| Other treatments, patients received, n | ||||
| Anakinra | 3 | 0 | 0 | |
| Siltuximab | 0 | 0 | 1 | |
| D hospitalized between CAR T-cell infusion and discharge, median (IQR) | 25 (17-38.5), n = 26 | 16 (13-23), n = 17 | 10 (2-17), n = 140 | <.0001∗∗∗∗ |
| D requiring intensive care unit–level care, median (IQR) | 10 (5-13), n = 26 | 5 (3-8), n = 17 | 0 (0-0), n = 139 | <.0001∗∗∗∗ |
| Experienced grade 4 neutropenia, n (%) | 21/24 (87.5) | 9/16 (56.3) | 88/134 (65.1) | .06 |
| Recovered from neutropenia, n (%) | 9/20 (45) | 7/9 (77.8) | 81/87 (93.1) | <.0001∗∗∗∗ |
| D to ANC recovery, median (IQR) | 34 (23-39), n = 9 | 13 (12-16.5), n = 7 | 13 (9-18), n = 88 | .008∗∗ |
| Required platelet transfusions after CAR T-cell infusion, n (%) | 23/24 (95.8) | 8/17 (47) | 35/134 (26.1) | <.0001∗∗∗∗ |
| Days after CAR T-cell infusion that last platelet transfusion administered, median (IQR) | 35 (25-50.5), n = 15 | 19 (9.5-25.75), n = 8 | 29 (21-49), n = 21 | .04∗ |
| Developed infection within 28 d of CAR T-cell infusion (%) | 14/22 (63.6%) | 3/17 (17.6%) | 19/137 (13.9%) | <.0001∗∗∗∗ |
| Onset of first infection (d from CAR T-cell infusion), median (IQR) | 13 (10-21.5), n = 15 | 73 (14.5-245.25), n = 8 | 50 (11-168.5), n = 47 | .04∗ |
| Refractory disease at d 28†,n (%) | 6/21 (28.6) | 3/17 (17.6) | 20/141 (14.2) | .20 |
| OS, median d | 128 | Undefined | Undefined | <.0001∗∗∗∗ |
| RFS, median d | 60 | Undefined | 701 | <.0001∗∗∗∗ |
| Relapse occurred, n (%) | 16/25 (64) | 5/17 (29.4) | 44/141 (31.2) | .007∗∗ |
| Time to relapse, median d | 60, n = 16 | 178, n = 5 | 101, n = 45 | .1033 |
| Death occurred, n (%) | 19/25 (76) | 3/17 (17.6) | 29/141 (20.6) | <.0001∗∗∗∗ |
| Time to death, median d | 85, n = 19 | 313, n = 3 | 221, n = 29 | .0261 |
| Relapse or death occurred, n (%) | 23/25 (92) | 7/17 (41.2) | 57/141 (40.4) | <.0001∗∗∗∗ |
| Causes of death, n (%) | ||||
| Leukemia | 12/19 (63.2) | 3/3 (100) | 23/29 (79.3) | |
| CRS | 1/19 (5.3) | 0/3 (0.0) | 1/29 (3.4) | |
| Neurotoxicity | 1/19 (5.3) | 0/3 (0.0) | 0/29 (0.0) | |
| Infection | 4/19 (21.1) | 0/3 (0.0) | 6/29 (20.7) | |
| Cardiopulmonary failure | 3/19 (15.8) | 0/3 (0.0) | 3/29 (10.3) | |
| Hematopoietic stem cell transplant-related complications | 0/19 (0.0) | 0/3 (0.0) | 3/29 (10.3) | |
| NRM‡, n (%) | 7/25 (28.0) | 0/17 (0.0) | 6/141 (4.3) | .0009∗∗∗ |
| CD19− relapse, n (%) | 10/14 (71.4) | 3/5 (60) | 13/39 (33.3) | .04∗ |
| Myeloid transformation of leukemia, n (%) | 3/16 (18.8) | 0/4 (0.0) | 1/41 (2.44) | .11 |
ICANS/neurotoxicity grading was not standardized, but performed with ASTCT, CAR T‑cell therapy–associated toxicity neurological assessment, National Cancer Institute, National Institutes of Health/Common Terminology Criteria for Adverse Events version 4.03 and version 5.0 criteria.
Deaths from leukemia before day 28 and all with persistent disease at 1 month assessment after tisagenlecleucel counted as refractory disease.
NRM defined as death without recurrent or progressive disease. P values: comparisons between groups were via Kruskal-Wallis tests for continuous variables and Fisher exact tests for categorical variables, with a 2-tailed significance level of .05.