1. during cancer immunotherapy
목요세미나
Liver injury
during cancer immunotherapy
분당서울대병원 소화기내과
장은선

2. Case 1. F/61 NSCLC M/adrenal gl, LN on Nivolumab+Ipilimumab #30
TTF1+, ALK IHC2+, EGFR ; wt, ALK FISH (-)
PD-L1 90%
s/p Unilateral adrenalectomy
on Nivolumab+Ipilimumab #30

3. Liver, needle biopsy : Lobular hepatitis with
Nivolumab 시작
Nivolumab 중단
Liver, needle biopsy : Lobular hepatitis with
1) perivenular zone cell loss
2) milder degree of portal tract changes
3) no evident fibrosis
4) iron deposition in hepatocytes and Kupffer cells (1+)
Steroid
Q1. Is this ‘Immune-related’ hepatitis?

4. Pathologic features of Autoimmune hepatitis

5. Checkpoint inhibitor related liver injury vs. AIH vs. DILI
Histopathological features
Checkpoint inhibitor related liver injury, Autoimmune hepatitis, DILI 모두 lobular injury, portal inflammation 정도에서는 차이가 없었으나
Checkpoint inhibitor로 인한 liver injury는 다른 두가지 원인보다 confluent necrosis가 유의미하게 적었고
Autoimmune hepatitis보다 plasmacytosis가 적고
DILI보다 eosinophilic infiltration이나 bile plug가 유의미하게 적게 관찰되었습니다.
또 AIH(8)나 DILI(4)에서 보이는 Hepatocellular rosettes나 emperipolesis는 checkpoint inhibitor related liver injury에서는 관찰되지 않았습니다.

7. Anti-CTLA4 induced hepatitis in malignant melanoma patients
So far, specific feature of ‘immune-mediated hepatitis’ during immunotherapy is not determined.

8. Nivolumab induced AE in phase 3 trial for HCC patients

9. Anti-CTLA4 induced hepatitis in HCV related HCC patients
A pilot study with tremelizumab for HCV related advanced HCC patients (n=21)
LFT abnormality
AST elevation : n=14 (70%)
>gr 3, 9 (45%)
ALT elevation : n=11 (55%)
>gr 3, 5 (25%)

10. Case 2. F/45 Rectal cancer, M/LNs, liver, lung, bone (T3)
MSS, KRAS WT, NRAS MT, BRAF WT
on pall FOLFOX#6+avastin : PR
on NK Cell therapy & Nivolumab #3

11. Q2. Is steroid treatment mandatory?
Nivolumab 시작
Nivolumab #3
FOLFOX 중단
FOLFOX
다시 시작
FOLFOX
Dose reduction
FOLFOX 시작
Liver, needle biopsy :
Predominantly perivenular confluent hepatocyte necrosis
with 1) milder degree of portal inflammation (mixed infiltrates)
2) no evident fibrosis
3) no steatosis
Q2. Is steroid treatment mandatory?

12. ESMO Clinical Practice Guidelines: Management of ICPi-related hepatitis

13. Concerns over treatment for immune-related hepatitis patients with cancer
Re-administration of immunotherapy
Antitumor effect
Degree of immunosuppression
Possible reactivation of viral hepatitis

14. 38% were recovered without any corticosteroid therapy
3 were rechallenged with anti-PD1 mAb
1 died of tumor progression
1 experienced gr 1 liver enzyme elevation
1 had no recurrence of hepatitis
High dose steroid therapy might be not mandatory in most ICPi related hepatitis patients.

15. Summary & Conclusion
Immune related hepatitis will be not rare complication during immune checkpoint inhibitor (ICPi) therapy in cancer patients, especially with HCC.
Treatment strategy for ICPi related hepatitis is still not established and needed more clinical experiences.