Real-world predictive model for immune checkpoint inhibitor-induced hepatitis using baseline cytotoxic T-lymphocyte counts

Table 1 Demographic and clinical characteristics of patients with or without immune-mediated hepatitis, n (%)/median interquartile ranges (P25, P75)

Variables	Total (n = 544)	No-IMH (n = 308)	IMH (n = 236)	P value
Gender				< 0.001
Female	144 (26.47)	64 (20.78)	80 (33.90)
Male	400 (73.53)	244 (79.22)	156 (66.10)
Primary cancer type				< 0.001
Malignant melanoma	9 (1.65)	5 (1.62)	4 (1.69)
Hepatocellular carcinoma	25 (4.60)	4 (1.30)	21 (8.90)
Lung cancer	297 (54.60)	188 (61.04)	109 (46.19)
Cholangiocarcinoma	19 (3.49)	8 (2.60)	11 (4.66)
Lymphoma	27 (4.96)	16 (5.19)	11 (4.66)
Head and neck cancer	29 (5.33)	25 (8.12)	4 (1.69)
Gastrointestinal cancer	90 (16.54)	40 (12.99)	50 (21.19)
Urologic cancer	7 (1.29)	4 (1.30)	3 (1.27)
Other types of tumors	41 (7.54)	18 (5.84)	23 (9.75)
ICI agent type				0.027
Anti PD-1	482 (88.60)	263 (85.39)	219 (92.80)
Anti PD-L1	60 (11.03)	44 (14.29)	16 (6.78)
Combination of anti PD-1 and anti CTLA-4	2 (0.377)	1 (0.32)	1 (0.42)
ICI treatment regimen				0.079
ICI monotherapy	58 (10.66)	36 (11.69)	22 (9.32)
ICI + targeted therapy	122 (22.43)	73 (23.70)	49 (20.76)
ICI + chemotherapy	245 (45.04)	124 (40.26)	121 (51.27)
ICI + chemotherapy + targeted therapy	119 (21.88)	75 (24.35)	44 (18.64)
Grade
Grade 1			177 (75.00)
Grade 2			26 (11.02)
Grade 3			26 (11.02)
Grade 4			7 (2.97)
Age (years)	59.00 (52.00, 66.00)	59.00 (54.00, 66.00)	57.00 (49.00, 66.00)	0.006
WBC (109/L)	5.80 (4.50, 7.80)	6.20 (4.60, 7.90)	5.60 (4.50, 7.60)	0.148
HB (g/L)	120.50 (106.00, 132.00)	119.00 (106.00, 132.00)	122.00 (108.00, 132.00)	0.476
PLT (109/L)	212.50 (163.00, 282.00)	218.50 (171.50, 280.25)	208.50 (152.00, 287.25)	0.163
N (109/L)	3.70 (2.80, 5.43)	4.05 (2.90, 5.60)	3.65 (2.70, 5.20)	0.238
LYM (109/L)	1.20 (0.90, 1.60)	1.20 (0.90, 1.60)	1.20 (0.80, 1.60)	0.518
MONO (109/L)	0.60 (0.40, 0.80)	0.60 (0.40, 0.80)	0.50 (0.40, 0.70)	0.050
ALB (g/L)	39.35 (36.18, 42.30)	39.10 (36.27, 41.92)	39.50 (35.90, 42.62)	0.688
GLB (g/L)	29.60 (26.40, 33.50)	30.05 (26.67, 33.23)	29.50 (25.90, 33.65)	0.524
TBIL (μmol/L)	8.50 (6.20, 11.60)	8.00 (5.97, 10.80)	9.10 (6.60, 12.62)	0.004
DBIL (μmol/L)	3.00 (2.20, 4.40)	2.80 (2.00, 4.03)	3.40 (2.40, 5.00)	< 0.001
TBA (μmol/L)	4.45 (2.60, 7.30)	4.25 (2.60, 7.10)	4.70 (2.60, 7.93)	0.555
ALT (U/L)	22.05 (15.00, 31.52)	17.95 (13.28, 27.22)	27.35 (20.65, 36.75)	< 0.001
AST (U/L)	23.85 (19.00, 32.32)	21.75 (17.78, 29.40)	26.85 (21.17, 36.40)	< 0.001
AKP (U/L)	93.00 (76.00, 127.60)	91.20 (74.00, 126.00)	94.30 (77.38, 134.43)	0.575
GGT (U/L)	39.80 (24.20, 79.00)	36.50 (23.40, 71.80)	42.65 (26.05, 87.68)	0.306
CRP (mg/dL)	9.70 (2.96, 29.84)	10.65 (3.28, 30.41)	8.80 (2.46, 26.70)	0.295
C4 (mg/L)	257.00 (207.00, 314.00)	273.00 (231.00, 331.00)	237.00 (179.00, 292.25)	< 0.001
C3 (mg/L)	999.00 (848.00, 1160.00)	1040.00 (864.00, 1170.00)	978.00 (828.00, 1150.00)	0.195
IgG (g/L)	12.80 (10.85, 15.40)	12.70 (10.80, 15.30)	13.00 (11.20, 16.00)	0.402
IgA (mg/L)	2570.00 (1737.50, 3157.50)	2350.00 (1730.00, 3130.00)	2780.00 (1760.00, 3210.00)	0.340
IgM (mg/L)	960.00 (676.25, 1287.50)	953.00 (684.00, 1260.00)	983.00 (676.00, 1350.00)	0.927
CD3+ CD4+ T cells (cells/μL)	475.00 (328.75, 625.50)	461.50 (314.75, 593.50)	499.00 (344.00, 771.00)	< 0.001
CD3+ CD8+ T cells (cells/μL)	326.50 (224.75, 495.75)	287.50 (203.00, 429.50)	396.50 (275.75, 649.25)	< 0.001
Th/Ts ratio	1.42 (0.97, 1.89)	1.56 (1.01, 2.15)	1.25 (0.92, 1.58)	< 0.001

The upper limit of normal for alanine transaminase is 40 U/L per the laboratory reference range. IMH: Immune-mediated hepatitis; ICI: Immune checkpoint inhibitor; PD-1: Programmed cell death-1; PD-L1: Programmed cell death ligand-1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; WBC: White blood cells; HB: Hemoglobin; PLT: Platelet; N: Neutrophil; LYM: Lymphocyte; MONO: Monocyte; ALB: Albumin; GLB: Globulin; TBIL: Total bilirubin; DBIL: Direct bilirubin; TBA: Total bile acid; ALT: Alanine transaminase; AST: Aspartate transaminase; AKP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; CRP: C-reactive protein; C4: Complement 4; C3: Complement 3; IgG: Immunoglobulin G; IgA: Immunoglobulin A; IgM: Immunoglobulin M; Th/Ts: T helper cell/T suppressor cell (cluster of differentiation 3+ cluster of differentiation 4+/cluster of differentiation 3+ cluster of differentiation 8+); CD: Cluster of differentiation.

Table 2 Clinical characteristics of the training and validation cohorts, n (%)/median interquartile ranges (P25, P75)

Variables	Training cohort (n = 380)	Validation cohort (n = 164)	P value
Gender			0.163
Female	94 (24.74)	50 (30.49)
Male	286 (75.26)	114 (69.51)
Primary cancer type			0.762
Malignant melanoma	6 (1.58)	3 (1.83)
Hepatocellular carcinoma	18 (4.74)	7 (4.27)
Lung cancer	201 (52.89)	96 (58.54)
Cholangiocarcinoma	13 (3.42)	6 (3.66)
Lymphoma	19 (5.00)	8 (4.88)
Head and neck cancer	20 (5.26)	9 (5.49)
Gastrointestinal cancer	63 (16.58)	27 (16.46)
Urologic cancer	6 (1.58)	1 (0.61)
Other types of tumors	34 (8.95)	7 (4.27)
Age (years)	58.00 (51.00, 65.00)	59.00 (53.00, 67.00)	0.141
WBC (109/L)	5.80 (4.60, 7.80)	5.85 (4.50, 7.93)	1.000
HB (g/L)	121.00 (106.00, 132.00)	119.00 (108.00, 130.00)	0.655
PLT (109/L)	214.50 (163.75, 282.25)	207.50 (163.00, 276.00)	0.770
N (109/L)	3.70 (2.80, 5.50)	3.85 (2.77, 5.32)	0.977
LYM (109/L)	1.20 (0.90, 1.60)	1.20 (0.80, 1.60)	0.821
MONO (109/L)	0.60 (0.40, 0.80)	0.50 (0.40, 0.80)	0.807
ALB (g/L)	39.20 (36.08, 42.42)	39.50 (36.30, 41.60)	0.738
GLB (g/L)	30.20 (26.78, 33.35)	28.60 (25.90, 33.80)	0.094
TBIL (μmol/L)	8.70 (6.38, 11.90)	8.00 (5.77, 10.72)	0.040
DBIL (μmol/L)	3.10 (2.20, 4.53)	2.80 (1.90, 4.03)	0.019
TBA (μmol/L)	4.35 (2.50, 7.62)	4.50 (2.70, 7.03)	0.512
ALT (U/L)	22.00 (15.00, 31.68)	22.30 (15.12, 31.42)	0.977
AST (U/L)	22.95 (18.90, 32.02)	24.90 (19.67, 32.38)	0.486
AKP (U/L)	93.10 (77.45, 125.30)	89.95 (70.60, 134.33)	0.322
GGT (U/L)	40.90 (25.50, 84.60)	34.30 (23.20, 75.95)	0.212
CRP (mg/dL)	9.78 (3.01, 26.03)	9.63 (2.95, 44.00)	0.668
C4 (mg/L)	251.00 (207.00, 310.00)	265.00 (211.00, 318.50)	0.692
C3 (mg/L)	985.00 (848.00, 1170.00)	1035.00 (859.25, 1122.50)	0.978
IgG (g/L)	13.10 (11.20, 16.00)	12.45 (10.06, 14.53)	0.082
IgA (mg/L)	2580.00 (1730.00, 3265.00)	2455.00 (1785.00, 3140.00)	0.585
IgM (mg/L)	985.00 (694.75, 1300.00)	922.50 (641.25, 1225.00)	0.267
CD3+ CD4+ T cells (cells/μL)	484.00 (341.00, 655.75)	443.00 (295.25, 553.00)	0.043
CD3+ CD8+ T cells (cells/μL)	313.50 (218.75, 483.75)	362.00 (239.75, 508.00)	0.361
Th/Ts (CD3+ CD4+/CD3+ CD8+)	1.48 (1.03, 2.00)	1.25 (0.91, 1.66)	0.052

The training and validation cohorts were generally comparable, with no significant differences in baseline characteristics (P > 0.05 for most variables). WBC: White blood cells; HB: Hemoglobin; PLT: Platelet; N: Neutrophil; LYM: Lymphocyte; MONO: Monocyte; ALB: Albumin; GLB: Globulin; TBIL: Total bilirubin; DBIL: Direct bilirubin; TBA: Total bile acid; ALT: Alanine transaminase; AST: Aspartate transaminase; AKP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; CRP: C-reactive protein; C4: Complement 4; C3: Complement 3; IgG: Immunoglobulin G; IgA: Immunoglobulin A; IgM: Immunoglobulin M; Th/Ts: T helper cell/T suppressor cell (cluster of differentiation 3+ cluster of differentiation 4+/cluster of differentiation 3+ cluster of differentiation 8+); CD: Cluster of differentiation.

Table 3 Logistic regression analysis of the risk factors for immune-mediated hepatitis in the training cohort, n (%)

Variables	OR (univariable)		OR (multivariable)
	P value	OR (95%CI)	P value	OR (95%CI)
Gender	< 0.001	0.44 (0.27-0.71)
Age (years)	0.223	0.99 (0.97-1.01)
Primary cancer type	0.128	1.08 (0.98-1.18)
ICI agent type	0.009	0.32 (0.14-0.76)
ICI treatment regimen	0.649	0.68 (0.13-3.55)
WBC (109/L)	0.361	0.98 (0.93-1.03)
HB (g/L)	0.906	1.00 (0.99-1.01)
PLT (109/L)	0.502	1.00 (1.00-1.00)
N (109/L)	0.433	1.00 (0.99-1.02)
LYM (109/L)	0.941	1.00 (0.91-1.11)
MONO (109/L)	0.489	1.09 (0.86-1.38)
ALB (g/L)	0.462	0.99 (0.97-1.01)
GLB (g/L)	0.789	0.99 (0.96-1.03)
TBIL (μmol/L)	0.577	1.22 (0.60-2.49)
DBIL (μmol/L)	0.375	0.99 (0.98-1.01)
TBA (μmol/L)	0.482	0.99 (0.97-1.02)
ALT (U/L)	0.046	1.01 (1.01-1.02)	0.028	1.04 (1.01-1.06)
AST (U/L)	0.634	1.00 (1.00-1.01)
AKP (U/L)	0.742	1.00 (0.99-1.00)
GGT (U/L)	0.460	1.00 (1.00-1.00)
CRP (mg/dL)	0.361	0.98 (0.93-1.03)
C4 (mg/L)	0.014	0.99 (0.99-0.99)	0.038	0.99 (0.97-1.00)
C3 (mg/L)	0.255	1.00 (1.00-1.00)
IgG (g/L)	0.546	0.99 (0.98-1.01)
IgA (mg/L)	0.230	1.00 (1.00-1.00)
IgM (mg/L)	0.695	1.00 (1.00-1.00)
CD3+ CD4+ T cells (cells/μL)	< 0.001	1.01 (1.01-1.01)
CD3+ CD8+ T cells (cells/μL)	< 0.001	1.01 (1.01-1.01)	0.002	1.01 (1.01-1.02)
Th/Ts (CD3+ CD4+/CD3+ CD8+)	0.005	0.57 (0.38-0.84)

OR: Odds ratio; CI: Confidence interval; ICI: Immune checkpoint inhibitor; WBC: White blood cells; HB: Hemoglobin; PLT: Platelet; N: Neutrophil; LYM: Lymphocyte; MONO: Monocyte; ALB: Albumin; GLB: Globulin; TBIL: Total bilirubin; DBIL: Direct bilirubin; TBA: Total bile acid; ALT: Alanine transaminase; AST: Aspartate transaminase; AKP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; CRP: C-reactive protein; C4: Complement 4; C3: Complement 3; IgG: Immunoglobulin G; IgA: Immunoglobulin A; IgM: Immunoglobulin M; Th/Ts: T helper cell/T suppressor cell (cluster of differentiation 3+ cluster of differentiation 4+/cluster of differentiation 3+ cluster of differentiation 8+); CD: Cluster of differentiation.