Cases treated with additional immunosuppressive agents for steroid-resistant ir-hepatitis
| Study | Type of cancer | Type and duration of ICPIs | N (age/sex) with grade 3–4 ir-hepatitis | Steroids dose and duration (days) | Type and duration of additional immunosuppressive treatments | Time to recovery of liver tests | Management of ICPIs | Outcomes and comments |
| Chmiel et al 39 | Metastatic melanoma | Ipilimumab (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| MMF 2 g/day for 1 week, ATG (4 doses) in 1 month | 4 weeks from the start of ATG, LFTs normalized without relapse | Withdrawn | Ir-thyroiditis was also diagnosed and treated with L-thyroxin 50 mg/day. Secondary to steroids DM was developed. |
| Ahmed et al 43 | Metastatic melanoma | Ipilimumab (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 weeks | Completed | Liver biopsy was considered unsafe in such an acutely unwell patient. |
| Spänkuch et al 44 | Metastatic melanoma | Nivolumab/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| MMF 1 g/day for 2 days, Prednisolone 1 g/day for 5 days, ATG with reduced prednisolone to 100 mg/day | After 5 days | Withdrawn and switched to pembrolizumab, when LFTs were normalized | No hepatic recurrence. |
| McGuire et al 45 | Metastatic melanoma | Pembrolizumab | 1 (57/F) | Methylprednisolone at 2 mg/kg for 4 days (138 mg/day) followed by oral dexamethasone at equivalent dose | Prednisone at 150 mg and MMF at 1 g/day, ATG (2 doses) in 24 hours | After 162 days | N/A | Multiple 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 melanoma | Nivolumab+ipilimumab | 1 (67/F) | Prednisolone, MMF, infliximab | Co-existed irAEs (colitis, rash, hypoadrenalism). | |||
| Metastatic melanoma | Ipilimumab and subsequently pembrolizumab | 1 (76/F) | Prednisolone, MMF, tacrolimus | Co-existed ir-colitis. | ||||
| Metastatic melanoma | Nivolumab+ipilimumab | 1 (49/F) | Methylprednisolone, prednisolone, MMF, infliximab | All patients were diagnosed and managed empirically without liver biopsy. | ||||
| Huffman et al 50 | Metastatic melanoma (previous diagnosis of AIH) | Ipilimumab | 1 (N/A) | Steroids | AZA (1 mg/kg) | No exact date of recovery | Continuation | Hepatitis resolution—death due to PD. |
| Metastatic melanoma | Ipilimumab | 1 (N/A) | Prednisone (0.5 mg/kg) for 2 weeks | Ciclosporin (100 mg twice daily)+prednisone (1 mg/kg) | After 40 days | Withdrawn | LFTs were normalized and immunosuppressants were discontinued. Died from PD after two other chemotherapeutic lines. | |
| Iwamoto et al, 49 | Metastatic melanoma | Nivolumab (10 doses) | 1 (75/M) | Methylpredonisolone (2 mg/kg/day) | Co-administration of oral AZA (100 mg/day) | After 4 weeks | Withdrawn | Tumor 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 melanoma | Ipilimumab | 1 (N/A) | Steroids | 6-MP | N/A | N/A | Recovery from ir-hepatitis. |
| De Martin et al,24 | Metastatic melanoma | Pembrolizumab (prior exposure)+ipilimumab (1 dose) | 1 (56/F) | Steroids | High-dose steroids (2.5 mg/kg/day)+MMF | No exact date of recovery | Liver 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) | Withdrawn | Liver 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 melanoma | Nivolumab (11 doses), ipilimumab (1 dose) | 1 (59/M) | Pulse steroid therapy- Methylprednisolone (1000 mg/day)+tapering back to 1 mg/kg/day+empirical ceftazidime | Second 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) | Withdrawn | CT 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 (BRAF-mutant) | Pembrolizumab (1 dose of 2 mg/kg) | 1 (49/F) | Prednisolone (1 mg/kg/day)+UDCA | Prednisolone (1 mg/kg/day)+MMF (2 g/day)+UDCA | Imroved No exact date of complete recovery | Changed to BRAF/MEK inhibitors | Liver 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 mesothelioma | Pembrolizumab (1 dose) | 1 (76/M) | Methylprednisolone (2 mg/kg/day) | Prednisolone (1 mg/kg/day)+MMF (1 g/day)+UDCA | Improved No exact date of complete recovery | Withdrawn | Liver 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 melanoma | Nivolumab/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 weeks | Withdrawn | Three 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 tocilizumab | Tocilizumab (4 mg/kg/dose, 2 doses) | 4 days, median time of discharge | N/A | Hepatitis resolution. |
| Riveiro-Barciela et al 47 | Metastatic vulvar melanoma | Nivolumab (5 cycles) Ipilimumab (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 | Withdrawn | Mild 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 case | Metastatic melanoma | Nivolumab (6 cycles) Ipilimumab (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 weeks | Withdrawn | No 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.