Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

Table 1 Baseline patient characteristics, n (%)

Variable	Category	No AEs or AEs grade < 2	AEs grade ≥ 2	OR	95%CI	P value
n = 361		274 (76)1	87 (24)
Age (Median)		65	64	0.99	(0.97, 1.01)	0.450
Sex	Male	222 (61)	65 (18)	1.00
	Female	52 (14)	22 (7)	1.44	(0.82, 2.56)	0.206
AFP (Median)		115	29	1.00	(1, 1)	0.850
Known cirrhosis	Yes	201 (56)	62 (17)	0.90	(0.53, 1.54)	0.702
	No	73 (20)	25 (7)	1.00
Known PVT	Yes	61 (17)	18 (5)	0.60	(0.33, 1.1)	0.100
	No	124 (34)	61 (17)	1.00
NLR	NLR ≤ 5	122 (34)	62 (17)	1.00
	NLR > 5	54 (15)	16 (5)	0.58	(0.31, 1.1)	0.096
	Unknown	98 (27)	9 (2)
PLR	PLR ≤ 300	145 (40)	72 (20)	1.00
	PLR > 300	31 (9)	6 (2)	0.39	(0.16, 0.98)	0.044
	Unknown	98 (27)	9 (2)
Child pugh class	A	202 (56)	74 (20)	1.00
	B	61 (17)	13 (4)	0.58	(0.3, 1.12)	0.105
	C	7 (2)	0 (0)	0.00	(0, Inf)	0.986
	Unknown	4 (1)	0 (0)
HCV	Yes	112 (31)	41 (11)	1.29	(0.79, 2.09)	0.305
	No	162 (45)	46 (13)	1.00
HBV	Yes	59 (16)	18 (5)	0.95	(0.53, 1.72)	0.867
	No	215 (60)	69 (19)	1.00
EtOH	Yes	48 (13)	17 (5)	1.14	(0.62, 2.11)	0.669
	No	226 (63)	70 (19)	1.00
NASH	Yes	37 (10)	8 (2)	0.65	(0.29, 1.45)	0.292
	No	237 (66)	79 (22)	1.00
BCLCs	A	9 (2)	1 (1)	1.00
	B	66 (18)	25 (7)	3.41	(0.41, 28.31)	0.256
	C	194 (53)	61 (17)	2.83	(0.35, 22.79)	0.328
	D	4 (1)	0 (0)	0.00	(0, Inf)	0.985
	Unknown	1 (1)	0 (0)
Extra Hepatic Disease	Yes	100 (28)	36 (10)	0.73	(0.43, 1.23)	0.239
	No	87 (24)	43 (12)	1.00
	Unknown	87 (24)	8 (2)
ECOG	0	168 (47)	77 (21)	1.00
	1	18 (5)	2 (1)	0.24	(0.05, 1.07)	0.062
	Unknown	88 (24)	8 (2)
Steroid use	Yes	57 (16)	37 (10)	2.74	(1.61, 4.64)	0.0002
	No	190 (53)	45 (12)
	Unknown	27 (7)	5 (2)
Antibiotic use	Yes	42 (12)	14 (4)	1.01	(0.52, 1.98)	0.95
	No	205 (56)	67 (19)
	Unknown	27 (7)	6 (2)
Treatment	PD-1	244 (68)	61 (17)
	PD-1/CLTA-4	16 (4)	12 (3)	3.00	(1.35, 6.67)	0.007
	PD-1/TKI	12 (3)	12 (3)	4.00	(1.71, 9.34)	0.001
	PD-1/other	1 (0)	1 (0)	4.00	(0.25, 64.86)	0.329
	CTLA-4	1 (0)	1 (0)	4.00	(0.25, 64.86)	0.32

¹Of 274 (76%) with no adverse events (AEs) or AEs grade < 2, 80 (22%) had grade 1 AEs and 194 (54%) had no AEs.

OR: Odds ratio; CI: Confidence Interval; AEs: Adverse events; AFP: Alpha-fetoprotein; ECOG: Eastern cooperative oncology group; BCLCs: Barcelona clinic liver cancers; NASH: Nonalcoholic steatohepatitis; HBV: Hepatitis B virus; HCV: Hepatitis C virus infection; PLR: Platelet-lymphocyte ratio; NLR: Neutrophil-lymphocyte ratio; PVT: Portal vein thrombosis; PD-1: Programmed cell death ligand 1; CLTA-4: Cytotoxic T-lymphocyte antigen-4; TKI: Tyrosine kinase inhibitor.

Table 2 Immune-related adverse events incidence by groups¹, n (%)

IrAE by organ system n = 167	Grade < 2	Grade ≥ 2
Dermatological	43 (26)	15 (9)
Colitis	19 (11)	10 (6)
Hepatitis	40 (24)	29 (17)
Endocrine	18 (11)	11 (7)
Polyarthritis	3 (1)	1 (0)
Pneumonitis	10 (6)	9 (5)
Constitutional	52 (31)	15 (9)
Other	15 (9)	22 (13)

¹The incidence of immune-related adverse events (IrAEs) has been presented by patient groups categorized as those with IrAEs of grade < 2 and those with IrAEs of grade ≥ 2, stratified by the affected organ systems. IrAE: Immune-related adverse events.

Table 3 Univariable and multivariable models to predict grade 2 or higher adverse events

	Odds ratio	95%CI	P value
Univariable model:
PLR (> 300)	0.40	(0.16, 0.98)	0.044
NLR (> 5)	0.58	(0.31, 1.10)	0.097
Steroid use	2.74	(1.62, 4.64)	< 0.001
Antibiotics use	1.02	(0.52, 1.98)	0.954
Treatment
PD-1 CLTA-4	3	(1.35, 6.67)	0.007
PD-1 TKI	4	(1.71, 9.34)	0.001
Other1	4	(0.55, 28.97)	0.170
Multivariable model:
PLR (> 300)	0.26	(0.09, 0.74)	0.011
Steroid use	4.43	(2.21, 8.88)	< 0.001
Treatment
PD-1/CLTA-4	2.57	(1.06, 6.24)	0.037
PD-1/TKI	3.39	(1.34, 8.56)	0.01
Other1	3.50	(0.21, 57.86)	0.381

¹Other include single agent cytotoxic t-lymphocyte antigen-4 and other immune checkpoint inhibitors/tyrosine kinase inhibitor combinations. CI: Confidence interval; PLR: Platelet-lymphocyte ratio; NLR: Neutrophil-lymphocyte ratio; PD-1: Programmed cell death ligand 1; CLTA-4: Cytotoxic t-lymphocyte antigen-4; TKI: Tyrosine kinase inhibitor.