Immune Checkpoint Inhibition in Classical Hodgkin Lymphoma: From Early Achievements towards New Perspectives

Table 3

Adverse Events linked to immune checkpoint inhibitors in cHL.

Agent	Reference / Phase	No. of patients	Most Common AE	Grade 3 or 4 AEs	Comments
Nivolumab	Ansell et al. (Checkmate 039) [7]	23	78 Drug-related adverse events of any grade; the most common (>10): (i) Rash (22%); (ii) Thrombocytopenia (17%); (iii) Pyrexia (13%); (iv) Fatigue (13%); (v) Diarrhea (13%); (vi) Nausea (13%); (vii) Pruritus (13%)	22 Drug-related adverse events of grade 3: (i) Myelodysplastic syndrome; (ii) Pancreatitis; (iii) Pneumonitis; (iv) Stomatitis; (v) Colitis; (vi) Gastrointestinal inflammation; (vii) Thrombocytopenia; (viii) Increased lipase levels; (ix) Decrease lymphocyte level; (x) Leukopenia	(i) Two patients discontinued treatment because of drug toxicity.; (ii) AE reversible in all the patients except the 2 who discontinued.
	Younes and al. (Checkmate 205) [8]	80	89 Drug-related adverse events of any grade; the most common (>10): (i) Fatigue (25%); (ii) IRR (20%); (iii) Rash (15%); (iv) Arthralgie (14%); (v) Pyrexia (14%); (vi) Nausea (13%); (vii) Diarrhea (10%); (viii) Pruritus (10%)	21 Drug related grade 3: (i) Neutropenia (5%); (ii) Increased lipase levels (3%); (iii) Increased ALT (3%); (iv) Increased AST (3%); (v) Abdominal pain (3%); (vi) Dyspnea (1%); (vii) Pneumonia (1%); (viii) Hepatitis (1%); (ix) Rash (1%); (x) Arthritis (1%); (xi) Syncope (1%); 4 Drug-related AE grade 4: (i) Increased lipase (3%); (ii) Decreased neutrophil count (1%)	AE leading to discontinuation: (i) Treatment related autoimmune hepatitis (1 patient); (ii) Treatment related increased ALT and ASAT concentrations (1 patient); (iii) Death from multi-organ failure (1 patient) not treatment-related.
	Armand et al. (Checkmate 205) [57]	243	Drug-related AE any grade: (i) Fatigue (23%); (ii) Diarrhea (15%); (iii) Infusion-related reaction (14%); (iv) Rash (12%); (v) Pruritus (10%); (vi) Nausea (10%); Immune-mediated AE: (i) Hypothyroidism /thyroiditis (12%); (ii) Rash (9%); (iii) Hepatitis (5%); (iv) Pneumonitis (4%); (v) Hyperthyroidism (2%); (vi) Diabetes mellitus <1%	Drug-related AE grade 3-4: (i) Lipase increased (5%); (ii) Neutropenia (3%); (iii) ALT increased (3%); (iv) AST increased (2%)	7% discontinue treatment because of drug-related AE: (i) Pneumonitis (2%); (ii) Autoimmune hepatitis (1%)
	Maruyama and al. [60]	17	Most common adverse events; (i) Pyrexia (41.2%); (ii) Pruritus (35.3%); (iii) Rash (35.3%); (iv) Hypothyroidism (29.4%)	23.5 grade 3 or 4 AEs: (i) Anemia; (ii) Lymphopenia; (iii) Thrombocytopenia; (iv) Pyrexia; (v) Hepatic function abnormal; (vi) Pneumonia; (vii) Hyponatremia; (viii) Fulminant type 1 diabetes mellitus; (ix) Interstitial lung disease; (x) Rash	6 serious AE in 3 patients (all judged drug-related): (i) Pyrexia; (ii) Hepatic function abnormal; (iii) Hyponatremia; (iv) Fulminant type 1 diabetes mellitus∗; (v) Interstitial lung disease∗; (vi) Rash; ∗ Led to treatment discontinuation
Pembrolizumab	Armand et al. (Keynote 013) [61]	31	68 Drug-related AE; (i) Hypothyroidism (16%); (ii) Nausea (13%); (iii) Diarrhea (16%); (iv) Pneumonitis (10%)	16 Drug-related grade 3 AEs: (i) Colitis; (ii) Increased ALT and AST levels; (iii) Nephrotic syndrome; (iv) Joint swelling; (v) Back pain; (vi) Axillary pain	(i) Two patients discontinued due to grade 2 pneumonitis and grade 3 nephrotic syndrome
	Chen and al. (Keynote 087) [62]	210	TRAE grade 1 or 2: (i) Hypothyroidism (11.9%); (ii) Pyrexia (10%); (iii) Fatigue (8.6%); (iv) Rash (7.6%); (v) Diarrhea (6.2%)	6.4 TRAE grade 3/4: (i) Neutropenia (2.4%); (ii) Dyspnea (1%); (iii) Diarrhea (1%); (iv) Pyrexia (0.5%); (v) Cough (0.5%); (vi) Fatigue (0.5%); (vii) Hypothroidism (0.5%)	(i) 4.3% discontinued because of TRAEs; (ii) 12.4% experienced TRAEs resulting in treatment interruptions.
	Zinzani et al. Keynote 087 updated results (ASH 2018) [63]	210	72.9 TRAE of any grade: (i) Hypothyroidism (14.3%); (ii) Pyrexia (11.4%); (iii) Fatigue (11%); (iv) Rash (11%)	11.9 TRAE grade 3/4: (i) Neutropenia (2.4%); (ii) Diarrhea (1.4%)	6.7% of patients discontinued treatment due to TRAE
Avelumab	Chen et al. [91]	31	Treatment-related AE of any grade: (i) IRR (26.7%); (ii) Nausea (20%); (iii) Rash (20%); (iv) Fatigue (13.3%)	36.7 grade ≥3 AEs – details NA	2 patients (6.7%) discontinued treatment due to IRR
Sintilimab	Shi et al. (ORIENT-1) [68]	96	93 treatment-related AE of any grade: (i) Pyrexia 41%; (ii) Hypothyroidism 20%; (iii) Increased ALT 14%; (iv) Pneumonitis 11%; (v) Infusion reaction 9%; (vi) Rash 11%; (vii) Increase AST 8%; (viii) Decreased platelet counts 10%; 54 immune-related AE	18 treatment-related AE grade 3 or 4; 11 Drug-related serious adverse events: (i) Pneumonitis 3%; (ii) Lung infection 3%; (iii) Infusion reaction 2%; (iv) Upper respiratory tract infection 1%; (v) Liver function abnormality 1%; (vi) Decreased platelet counts 1%; (vii) Peripheral neuropathy 1%; (viii) Hyperthyroidism 1%	3% (3 patients) discontinued treatment due to adverse events; (i) 1 patient with grade 2 pneumonitis; (ii) 1 patient with grade 4 liver function abnormality; (iii) 1 patient with grade 3 pneumonitis and grade 4 decreased platelet count.

IRR = infusion related reactions; AE = adverse event; TRAE = treatment-related AE; NA = not available.