Table 2

Cases treated with additional immunosuppressive agents for steroid-resistant ir-hepatitis

StudyType of cancerType and duration of ICPIsN (age/sex) with grade 3–4 ir-hepatitisSteroids dose and duration (days)Type and duration of additional immunosuppressive treatmentsTime to recovery of liver testsManagement of ICPIsOutcomes and comments
Chmiel et al 39 Metastatic melanomaIpilimumab
(2 doses at 10 mg/kg)
1 (60/M)Methylprednisolone intravenous 500 mg/day (9 days) and reduction to oral prednisolone 150 mg/day (steroid-induced psychosis)MMF 2 g/day for 1 week,
ATG (4 doses) in 1 month
4 weeks from the start of ATG, LFTs normalized without relapseWithdrawnIr-thyroiditis was also diagnosed and treated with L-thyroxin 50 mg/day.
Secondary to steroids DM was developed.
Ahmed et al 43 Metastatic melanomaIpilimumab
(4 doses)
1 (50/F)Methylprednisolone on 2 mg/kg (2 days)Co-administration of MMF (2 g/day and subsequently halved and stopped in 2 weeks)
Methylprednisolone (120 mg/day and tapering up to weaning off in 6 weeks) and ATG (2 doses)
2 weeksCompletedLiver biopsy was considered unsafe in such an acutely unwell patient.
Spänkuch et al 44 Metastatic melanomaNivolumab/Ipilimumab (3 doses)1 (49/F)Methylprednisolone 100 mg/day (10 days)MMF 1 g/day for 2 days,
Prednisolone 1 g/day for 5 days, ATG with reduced prednisolone to 100 mg/day
After 5 daysWithdrawn and switched to pembrolizumab, when LFTs were normalizedNo hepatic recurrence.
McGuire et al 45 Metastatic melanomaPembrolizumab1 (57/F)Methylprednisolone at 2 mg/kg for 4 days (138 mg/day) followed by oral dexamethasone at equivalent dosePrednisone at 150 mg and MMF at 1 g/day,
ATG (2 doses) in 24 hours
After 162 daysN/AMultiple abnormalities in CD4+ T cell phenotype were present before melanoma onset, including high multidrug resistance type 1 transporter activity, probably implicated in steroid resistance.
Cheung et al 34 Metastatic melanomaNivolumab+ipilimumab1 (67/F)Prednisolone, MMF, infliximabCo-existed irAEs (colitis, rash, hypoadrenalism).
Metastatic melanomaIpilimumab and subsequently pembrolizumab1 (76/F)Prednisolone, MMF, tacrolimusCo-existed ir-colitis.
Metastatic melanomaNivolumab+ipilimumab1 (49/F)Methylprednisolone, prednisolone, MMF, infliximabAll patients were diagnosed and managed empirically without liver biopsy.
Huffman et al 50 Metastatic melanoma (previous diagnosis of AIH)Ipilimumab1 (N/A)SteroidsAZA (1 mg/kg)No exact date of recoveryContinuationHepatitis resolution—death due to PD.
Metastatic melanomaIpilimumab1 (N/A)Prednisone (0.5 mg/kg) for 2 weeksCiclosporin (100 mg twice daily)+prednisone (1 mg/kg)After 40 daysWithdrawnLFTs were normalized and immunosuppressants were discontinued.
Died from PD after two other chemotherapeutic lines.
Iwamoto et al,
Metastatic melanomaNivolumab
(10 doses)
1 (75/M)Methylpredonisolone (2 mg/kg/day)Co-administration of oral AZA (100 mg/day)After 4 weeksWithdrawnTumor size was increased.
The price of AZA at 100 mg/day is approximately seven times lower than that of MMF at 2 g/day.
Johncilla et al 17 Metastatic melanomaIpilimumab1 (N/A)Steroids6-MPN/AN/ARecovery from ir-hepatitis.
De Martin et al,24 Metastatic melanomaPembrolizumab (prior exposure)+ipilimumab
(1 dose)
1 (56/F)SteroidsHigh-dose steroids (2.5
No exact date of recoveryLiver biopsy: pattern of chronic hepatitis with portal fibrosis and severe periportal activity.
Nakano et al 41 HNSCC (laryngeal carcinoma)Nivolumab
(14 doses)
1 (50/M)Prednisolone
(5 mg/day)
Pulse steroid therapy—methylprednisolone (500 mg/day)+MMF (2 g/day)After 68 days of hospitalization (discharged with oral MMF 1.5 g/day and prednisolone 30 mg/day)WithdrawnLiver biopsy: lymphocyte infiltration to Glisson’s capsule and piecemeal necrosis, consistent with nivolumab-induced hepatitis
HNSCC progression with extensive lymphadenopathy and palliative radiotherapy.
Patient died 9.7 months after the hospitalization due to irAEs.
Tanaka et al 40 Metastatic melanomaNivolumab
(11 doses),
(1 dose)
1 (59/M)Pulse steroid therapy- Methylprednisolone (1000 mg/day)+tapering back to 1 mg/kg/day+empirical ceftazidimeSecond pulse steroid therapy—methylprednisolone (1000 mg/day)+MMF (2 g/day)On day 104, ALT/AST recovered to grade 1 (then dosage of prednisone: 0.5 mg/kg/day and MMF: 1 g/day)WithdrawnCT scans at ir-hepatitis diagnosis: no liver but multiple lung metastases.
Patients died, few days after the normalization of his LFTs (day 120) due to melanoma progression.
Doherty et al 32 Metastatic melanoma
(1 dose of 2 mg/kg)
1 (49/F)Prednisolone
(1 mg/kg/day)+UDCA
(1 mg/kg/day)+MMF (2 g/day)+UDCA
No exact date of complete recovery
Changed to BRAF/MEK inhibitorsLiver biopsy: pattern of vanishing bile duct syndrome.
MMF stopped due to profound neutropenia.
Patient died from progressive intracranial disease (8 months after hepatotoxicity diagnosis).
Metastatic mesotheliomaPembrolizumab
(1 dose)
1 (76/M)Methylprednisolone
(2 mg/kg/day)
(1 mg/kg/day)+MMF (1 g/day)+UDCA
No exact date of complete recovery
WithdrawnLiver biopsy: severe cholestasis and duct injury with evidence of parenchymal loss and regeneration.
MMF stopped due to marked lymphopenia.
Patient died from progressive disease.
Corrigan et al 46 Metastatic melanomaNivolumab/Ipilimumab
(3 doses)
1 (53/F)Methylprednisolone (200 mg/day)MMF (2 g/day)
Infliximab (5 mg/kg/dose, 2 doses)
Tacrolimus (target trough 3–5 ng/mL)
After 11 weeksWithdrawnThree liver biopsies performed, first report of administrating four distinct immunosuppressants in order to resolve ir-hepatitis.
No PD of melanoma, despite intensified immunosuppression.
Stroud et al 51 Lung cancer (88.2%)Nivolumab
(4 cycles)
1 (64 years, median/50% F)Prednisone (1 mg/kg/day) or equivalents, at time of tocilizumabTocilizumab
(4 mg/kg/dose, 2 doses)
4 days, median time of dischargeN/AHepatitis resolution.
Riveiro-Barciela et al 47 Metastatic vulvar melanomaNivolumab
(5 cycles)
(2 cycles)
1 (76/F)Steroids (2 mg/kg/day)MMF (1.5 g/day)
Plasma exchange (a course of five treatments)
After 2 weeks she was discharged
After 6 weeks, LFTs were normalized
WithdrawnMild ir-hepatitis already existed after nivolumab and retreatment with Ipilimumab was decided.
The scheduled liver biopsy was not performed, because of grade 2 hepatic encephalopathy.
First report of plasmapheresis as a feasible treatment for ipilimumab-induced hepatitis.
Our caseMetastatic melanomaNivolumab
(6 cycles)
(4 cycles)
1 (73/M)Intravenous methylprednisolone (1 mg/kg, after 2 days, increased to 2 mg/kg)MMF (1 g twice daily)
Tacrolimus (target trough 8–10 ng/mL)
After 9 weeksWithdrawnNo biopsy decided.
Melanoma relapse with lung metastasis.
  • AIH, autoimmune hepatitis; ALT, alanine transaminase; AST, aspartate transaminase; ATG, antithymocyte globulin; AZA, azathioprine; DM, diabetes mellitus; F, female; HNSCC, head and neck squamous cell carcinoma; ICPI, immune checkpoint inhibitor ; irAE, immune-related adverse event; LFT, liver function test; M, male; MMF, mycophenolate mofetil; 6-MP, 6-mercaptopurine; N/A, not available; PD, progressive disease; UDCA, ursodeoxycholic acid.