Journée Hépatologie 2022

1. PROGRAMME
JOURNÉES DU CENTRE HÉPATO-BILIAIRE
CHIRURGIE|HÉPATOLOGIE|INFIRMIÈRES|RADIOLOGIE
4 réunions thématiques
RADIOLOGIE
CHIRURGIE
HÉPATOLOGIE
INFIRMIÈRES
7/8 AVRIL
UIC-P ESPACES CONGRÈS - PARIS 15E
INVITÉ D’HONNEUR :
Toxicité hépatique de l’immunothérapie
Eleonora De Martin
Centre Hépato-Biliaire, Paul Brousse
Villejuif, France

2. Chimiothérapie versus Immunothérapie
Paradigm Shift in Cancer Therapy
Tumor Cell
Historical Paradigm:
Targeting Tumor Cells
Lymphocyte
New Paradigm:
Targeting Immune Cells
Cellule tumorale
Paradigme historique:
Cible la cellule tumorale
Nouveau paradigme:
Cible le lymphocyte

3. De Martin, JHEP Reports 2021
Prévalence de toxicité hépatique de ICI
Patients treated for non-liver
Live toxicity can occur in patien
malignancies. For example, in
monotherapy for advanced me
any grade were reported in 4% t
elevation of ALT was reported i
study, among patients treated
ALT elevations of any grade and
2% of patients, respectively.33
T
creases in patients who receiv
tients treated with anti-PD-1
kinase inhibitor (TKI) for advan
tions of any grade were report
grade >
−3 elevations were found
patients receiving a combinatio
therapy for metastatic melanom
and of grade >
−3 were reporte
respectively36
(Fig. 2A and B).
Patients treated for hepatocel
Among patients who receive ICI
Anti-PD-1 + anti-CTLA-4
Anti-CTLA-4
Anti-PD-1
%
of
patients
with
irAEs
0
5
10
15
20
25
30
35
40
45
G
I
S
k
i
n
E
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.
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Fig. 1. Distribution of irAEs for organ categories according to treatment in
the main clinical trials of ICIs. Patients were treated with anti-PD-1 + anti-
CTLA-4,4,33,36
anti-CTLA-44,33,104,124
and anti-PD-1.33,34,124
The values quoted
are mean irAE rates of clinical trials as a whole. CTLA-4, cytotoxic T
lymphocyte-associated protein 4; Endoc, endocrine (hypo/hyper-thyroidism);
normal liver and cirrhotic liver?
What are the best markers to evaluate the severity of
ICI-induced liver toxicity?
Avoid overestimation of severity and iden
corticosteroids
Do corticosteroids shorten the interval to liver test
normalisation compared to spontaneous remission?
Decide on corticosteroid introduction and
Does immunosuppression have an impact on ICI efficacy? Modulate the dose of immunosuppressive
immunosuppression and type of cancer
Is UDCA enough to treat ICI-induced cholangitis? Avoid unnecessary corticosteroid therapy
What are the criteria to safely re-introduce an ICI after an
episode of immune-mediated hepatitis?
Identify biomarkers of activity resolution
ICI, immune checkpoint inhibitor; UDCA, ursodeoxycholic acid.
Distribution de toxicité de ICI par organe en fonction du type de traitement

4. N=16
Age, years 63 [33-84]
Sex, F 9 (56)
Interval time immunotherapy and
hepatitis, weeks
5 [1-49]
AST, UI/L 399 [117-2289]
ALT, UI/L 416 [266-3137]
Total Bilirubin, μmol/L 18 [6-324]
GGT, UI/L 317 [39-1252]
ANA ≥ 1:80 8 (50)
IgG, g/L 9 [6-18]
Le développement
de l’hépatite peux
survenir après
l’arrêt de
l’immunothérapie
Caractéristiques d’une population avec hépatite de grade ≥ 3
Variabilité et imprévisibilité
De Martin, J Hepatol 2018

5. CMV - Cellules T CD4+ effectrices mémoires
Hutchinson, Nature Comm 2021
e
No
Hepatitis
CMV ELISPOT + +
-
-
CD4
+
T
EM
ce
Hepatitis
f
Area = 0.885
Area = 0.700
CD4+ TEM (%)
PPV = 88.2 %
NPV = 82.6 %
p < 0.001
Hepatitis
No Hepatitis
3
26 4
4
19
16 15
2
≥ 16
CMV IgG- CMV IgG+
CD4+ TEM (%)
< 16 ≥ 16
< 16
PPV = 42.9 %
NPV = 61.9 %
p = 1.0
0.0 0.5 1.0
0.0
0.5
1.0
1 - Specificity
All cases (n=89)
CMV IgG+
cases (n=40)
nity to cytomegalovirus. a Seasonal presentation of CD4+ TEM
≥21% patients between 2017 and
of CD4+ TEM ≥ 21%. b CD4+ TEM
≥21% status was associated with high serum levels of anti-CMV
d line indicates a cut-off of CD4+ TEM ≥ 21%. c CD4+ TEM
≥21% status was associated with CMV-
). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. d Development of hepatitis was
Classification des patients ayant un mélanome métastatique avec ou sans hépatite au
anti-PD1/anti-CTLA4 en fonction du statu CMV IgG+ et des cellules CD4+TEM
34/40 (85%)
correctement classifiés

6. Diagnostic
Evaluation de la sévérité
Prise en charge thérapeutique
Toxicité hépatique de l’immunothérapie

7. Diagnostic
Evaluation de la sévérité
Prise en charge thérapeutique
Toxicité hépatique de l’immunothérapie

8. Le diagnostic : d’exclusion Adapté Navarro and Senior N Engl J Med 2006
Anomalies du bilan hépatique
Hépatite virale
VHA Ac IgM
VHB AgHBs
VHC Ac
VHE Ac IgM+PCR
CMV/EBV/HSV
Alcool
Autre médicaments
Syndrome métabolique
Hémodynamique
Hypotension
Choc
Insuffisance cardiaque
Thrombose
Anomalies biliaires/
Infiltration tumorale
Echographie
Scanner
IRM/cholangioIRM
Hépatite auto-immune
Ac anti-tissu
IgG
Maladie métabolique
et génétique
Fer, Ferritine
Céruloplasmine
a-1-antitrypsine
Possible toxicité hépatique

9. RUCAM:Roussel-UCLAF Causality Assessment Method

10. RUCAM:Roussel-UCLAF Causality Assessment Method
0 ou moins = exclu
1 à 2 = improbable
3 à 5 = possible
6 à 8 = probable
>8 = fortement probable

11. LiverTox - website
LiverTox® provides up-to-date,
unbiased and easily accessed
information on the diagnosis,
cause, frequency, clinical patterns
and management of liver injury
attributable to prescription and
nonprescription medications and
selected herbal and dietary
supplements.

12. Granulomes à anneaux de fibrine
Exemple: anti-CTLA4 et anti-PD1
Courtoisie Prof. C. Guettier

13. Cholangite aiguë destructrice
Figure 6. Biopsie hépatique d’un patient sous anti-PD-L1 :
lésions des canaux biliaires. Infiltrat portal dense de composition
mixte avec activité périportale et prolifération cholangiolaire (a :
HES × 100). Lésion de cholangite aiguë destructrice (b : HES × 400).
Liver biopsy of a patient treated with anti-PD-L1: lesions of bile
ducts. Mixed portal inflammation with severe periportal activity
Figure 7. Biopsies
d’intervalle d’une pati
sans fibrose portale (a
active avec apparition d’
Sequential hepatic biops
with Ipilimumab. Acute
Sirius × 35). Active chron
(b: Picro Sirius × 35).
transitoire d’hépatite
la réintroduction d’IC
prenant en compte la
vations incitent à prop
carte » des patients re
histologique systémat
tique.
Conclusion
Les effets secondaires
Exemple: anti-PDL1
Courtoisie Prof. C. Guettier

14. Hyperplasie nodulaire régénérative
LoPiccolo, Hepatol 2018
HEPATOLOGY, Vol.68, No.6, 2018 LOPICCOLO ET AL.
Regardless of the mechanism of drug-induced checkpoin
FIG. 2. (A) Hematoxylin and eosin stain showing hepatic parenchyma with mild
inflammation in the portal triads and lobules (100×). (B) Trichrome stain showi
highlighting a nodule of hypertrophic hepatocytes, with surrounding plates of at
confirming the diagnosis of nodular regenerative hyperplasia (100×). (D) Anti-
indicative of capillarization in the periportal area (arrows).

15. De Martin
JHEP
Reports
2021
Toxicité hépatique vs HAI

16. Pas de corrélation entre le patterns histologique et
la réponse aux corticoïdes
Cohen Mod Pathol 2021
Author
Manuscript
Author
Manuscript
Author
Manuscript
Author
Manuscript
Table 3:
Clinical features in 60 patients with suspected immune checkpoint inhibitor liver injury by histologic pattern
Hepatitic Pattern (n=36) Cholangitic pattern (n=16) Steatotic pattern (n=4) Mild and nonspecific changes (n=4)
Checkpoint therapy
Anti-PD1 only 7 5 2 1
Anti-CTLA4 only 4 0 0 0
Combination ICI 13 7 0 0
Sequential ICI 5 1 1 1
ICI and other 7 3 1 2
Pattern of LFTs
Hepatitic 24 2 1 3
Cholestatic 9 12 3 0
Mixed 3 2 0 1
ICI and other 7 3 1 2
Pattern of LFTs
Hepatitic 24 2 1 3
Cholestatic 9 12 3 0
Mixed 3 2 0 1
Grade of liver toxicity (CTCAE)
1 0 1 1 0
2 4 1 0 0
3 25 12 3 4
4 7 2 0 0
Radiologic findings
Normal 22 5 3 1
Hepatic metastases 7 7 0 1
Bile duct dilatation/narrowing 1 4 0 0
Gallbladder thickening 2 2 1 0
Duration of steroids
Not given 3 2 2 1
< 1 month 10 6 1 2
1 to 3 months 10 4 0 0
> 3 months 12 4 1 1
Uncertain 1 0 0 0
Pathol
.
Author
manuscript;
available
in
PMC
2021
August
30.
Caractéristiques de 60 patients avec toxicité hépatique au ICI en fonction du pattern histologique
Pas de corrélation entre l’aspect histologique et la
réponse aux corticoïdes

17. Utilité de la PBH
Li, JAMA Oncology 2022
213 patients traités par ICI avec hépatite de Grade >= 3
107 (50.2%) biopsie hépatique
La PBH était associe
• avec un plus longue temps de normalisation des
ALAT en médian (IQR) (42 [33-55] vs 33 [28-39]
jours; P = .01)
Table 2. Patients Who Received Liver Biopsy Stratified by Final Diagnosis
Characteristic
ICI hepatitis, No. (%)
P value
No (n = 12) Yes (n = 95)
Ultimate non-ICI hepatitis diagnosis
Malignant biliary obstruction 4 (33.3) NA
NA
Non-ICI drug-induced liver injury 4 (33.3) NA
Tumor infiltration of liver 2 (16.7) NA
Unknown 2 (16.7) NA
Major patterns of inflammationa
Inflammation
Panlobular 1 (8.3) 61 (64.9) <.001
Lobular 0 (0) 18 (19.2) .21
Portal 6 (50.0) 8 (8.5) .001
Central vein endothelialitis (sparing rest of lobule) 0 (0) 2 (2.1) >.99
Lette
Patients avec PBH stratifiés en fonction du diagnostic
Caractéristiques biologiques des patients
that were compatible with ICI hepatitis as documented by
hepatopathologists. There were 2 major biopsy-related com-
plications (splenic biopsy, hemothorax). The remaining 106
patients (49.8%) received a diagnosis of ICI hepatitis after
exclusion of other causes of liver injury (eg, viral hepatitis,
ischemia, other medications) and appropriate response to
therapy, liver metastases, steroid-refractory hepatitis,
and prior immune-related adverse events using a Cox
regression.
The most common pattern of liver injury in patients
with ICI hepatitis was panlobular inflammation (61 [64.9%])
(Table 2). Of the 12 patients who underwent a biopsy who
Table 1. Clinical Characteristics and Laboratory Values (continued)
Characteristic
Biopsy, No. (%)
P value
No Yes
Baseline laboratory values, median (IQR)
AST, U/L 20 (16-27) 21 (17-26) >.99
ALT, U/L 18 (14-26) 19 (15-27) .63
Alkaline phosphatase, U/L 77 (32-96) 77 (61-93) .69
Total bilirubin, mg/dL 0.5 (0.3-0.6) 0.4 (0.3-0.7) .29
Albumin, g/dL 4.2 (3.9-4.5) 4.2 (3.9-4.4) .96
Creatinine, mg/dL 0.9 (0.7-1.0) 0.9 (0.7-1.0) .85
Platelet count, ×103
/μL 221 (200-265) 227 (195-267) .83
Laboratory values at time of peak ALT, median (IQR)
AST, U/L 262 (181-426) 329 (213-535) .06
ALT, U/L 412 (289-613) 499 (317-818) .04
Alkaline phosphatase, U/L 216 (100-452) 216 (116-375) .94
Total bilirubin, mg/dL 0.7 (0.4-1.4) 0.9 (0.5-1.6) .25
Albumin, g/dL 3.8 (3.4-4.1) 3.7 (3.4-4.0) .85
Creatinine, mg/dL 0.8 (0.7-1.1) 0.9 (0.7-1.0) .71
Platelet count, ×103
/μL 233 (174-272) 207 (150-207) .03
Abbreviations: ALT, alanine
aminotransferase; AST, aspartate
aminotransferase; IQR, interquartile
range; NA, not applicable.
SI conversion factors: To convert
albumin to g/L, multiply by 10;
alkaline phosphatase, ALT, and AST to
μkat/L, multiply by 0.0167; bilirubin
to μmol/L, multiply by 17.104;
creatinine to μmol/L, multiply by
88.49; platelet count to ×109
/L,
multiply by 1.
a
Smokers defined as having a 10 or
greater pack-year history.
b
Alcohol use defined as 2 drinks or
more per day for men and 1 or more
drink per day for women.
Letters
that were compatible with ICI hepatitis as documented by
hepatopathologists. There were 2 major biopsy-related com-
plications (splenic biopsy, hemothorax). The remaining 106
patients (49.8%) received a diagnosis of ICI hepatitis after
exclusion of other causes of liver injury (eg, viral hepatitis,
ischemia, other medications) and appropriate response to
corticosteroids. Most patients had melanoma (115 [54%]).
Patients who underwent biopsy (Table 1) had higher peak
aminotransferase levels (ALT, 499 U/L vs 412 U/L; P = .04;
aspartate aminotransferase levels, 329 U/L vs 262 U/L [to
convert to μkat/L, multiply by 0.0167]; P = .06), were more
likely to develop steroid-refractory hepatitis (39.3% vs
17.0%; risk ratio, 2.32; 95% CI, 1.41-3.79; P < .001), and were
less likely to have a prior immune-related adverse event
(38.3% vs 56.6%; risk ratio, 0.7; 95% CI, 0.5-0.9; P = .01).
therapy, liver metastases, steroid-refractory hepatitis,
and prior immune-related adverse events using a Cox
regression.
The most common pattern of liver injury in patients
with ICI hepatitis was panlobular inflammation (61 [64.9%])
(Table 2). Of the 12 patients who underwent a biopsy who
were determined not to have ICI hepatitis, 4 received a diag-
nosis of malignant biliary obstruction, 4 were judged to
have liver injury from a contemporaneous drug, and 2 had
diffuse malignant infiltration. The cause of injury remained
unclear in the final 2 patients. Patients without ICI hepatitis
were more likely to have portal-predominant inflammation
(50.0% vs 8.5%; P = .001) and less likely to have panlobular
hepatitis (8.3% vs 64.9%; P < .001) compared with patients
with ICI hepatitis. Patients without ICI hepatitis also were
Table 1. Clinical Characteristics and Laboratory Values (continued)
Characteristic
Biopsy, No. (%)
P value
No Yes
Baseline laboratory values, median (IQR)
AST, U/L 20 (16-27) 21 (17-26) >.99
ALT, U/L 18 (14-26) 19 (15-27) .63
Alkaline phosphatase, U/L 77 (32-96) 77 (61-93) .69
Total bilirubin, mg/dL 0.5 (0.3-0.6) 0.4 (0.3-0.7) .29
Albumin, g/dL 4.2 (3.9-4.5) 4.2 (3.9-4.4) .96
Creatinine, mg/dL 0.9 (0.7-1.0) 0.9 (0.7-1.0) .85
Platelet count, ×103
/μL 221 (200-265) 227 (195-267) .83
Laboratory values at time of peak ALT, median (IQR)
AST, U/L 262 (181-426) 329 (213-535) .06
ALT, U/L 412 (289-613) 499 (317-818) .04
Alkaline phosphatase, U/L 216 (100-452) 216 (116-375) .94
Total bilirubin, mg/dL 0.7 (0.4-1.4) 0.9 (0.5-1.6) .25
Albumin, g/dL 3.8 (3.4-4.1) 3.7 (3.4-4.0) .85
Creatinine, mg/dL 0.8 (0.7-1.1) 0.9 (0.7-1.0) .71
Platelet count, ×103
/μL 233 (174-272) 207 (150-207) .03
Abbreviations: ALT, alanine
aminotransferase; AST, aspartate
aminotransferase; IQR, interquartile
range; NA, not applicable.
SI conversion factors: To convert
albumin to g/L, multiply by 10;
alkaline phosphatase, ALT, and AST to
μkat/L, multiply by 0.0167; bilirubin
to μmol/L, multiply by 17.104;
creatinine to μmol/L, multiply by
88.49; platelet count to ×109
/L,
multiply by 1.
a
Smokers defined as having a 10 or
greater pack-year history.
b
Alcohol use defined as 2 drinks or
more per day for men and 1 or more
drink per day for women.
Letters

18. La biopsie hépatique
• Confirmer la toxicité hépatique
• Faire la part de choses entre toxicités des molécules différents
• Evaluer la présence d’une hépatopathie chronique sous-jacente
1. La biopsie hépatique est conseillée chez les patients les plus sévères
2. Les rôles de la PBH:

19. Diagnostic
Evaluation de la sévérité
Prise en charge thérapeutique
Toxicité hépatique de l’immunothérapie

20. La sévérité – selon l’hépatologue
Grade 1
Faible
Grade 2
Modéré
Grade 3
Modère à sévère
Grade 4
Sévère
Grade 5
Mortel
Augmentation
ASAT/ALAT ou
PAL ou les
deux mais
bilirubine
totale < 2.5
mg/dL et INR <
1.5
Augmentation
ASAT/ALAT ou PAL
ou les deux et
bilirubine totale
³2.5 mg/dL ou
INR ³1.5 sans
hyper-
bilirubinémie
Augmentation
ASAT/ALAT ou
PAL ou les deux
et bilirubine
totale ³2.5
mg/dL et
hospitalisation à
cause de la
toxicité
hépatique
Augmentation
ASAT/ALAT ou PAL ou
les deux et bilirubine
totale ³2.5 mg/dL et
au moins 1 des
suivant :
1) Ictère pendant >
3mois
2) décompensation
hépatiques (INR³1.5,
ascite,
encéphalopathie
hépatique)
3) une autre
défaillance d’organe
à cause de la toxicité
Décès ou
transplantation
hépatique à
cause de la
toxicité
hépatique
Classification Drug-Induced Liver Injury Network (DILI-N).

21. La sévérité – selon l’oncologue
Classification Common Terminology Criteria for Adverse Events (CTCAE)
développée par le National Cancer Institute Version 5.0.
Grade 1 Grade 2 Grade 3 Grade 4
ASAT ou ALAT
normales à
baseline
> LSN – 3 x LSN >3- 5 x LSN >5 – 20 x LSN >20 x LSN
ASAT ou ALAT
élevées à
baseline
1.5 – 3 x
baseline
>3- 5 x
baseline
>5 – 20 x
baseline
>20 x
baseline
Bilirubine
normale à
baseline
>LSN – 1.5 x LSN >1.5 – 3 x LSN >3 – 10 x LSN >10 x LSN
Bilirubine
élevée à
baseline
>1.0 – 1.5 x
baseline
>1.5 – 3 x
baseline
>3 – 10 x
baseline
>10 x
baseline

22. La sévérité – selon l’oncologue
Classification Common Terminology Criteria for Adverse Events (CTCAE)
développée par le National Cancer Institute Version 5.0.
Grade 1 Grade 2 Grade 3 Grade 4
ASAT ou ALAT
normales à
baseline
> LSN – 3 x LSN >3- 5 x LSN >3 – 20 x LSN >20 x LSN
ASAT ou ALAT
élevées à
baseline
1.5 – 3 x
baseline
>3- 5 x
baseline
>3 – 20 x
baseline
>20 x
baseline
Bilirubine
normale à
baseline
>LSN – 1.5 x LSN >1.5 – 3 x LSN >3 – 10 x LSN >10 x LSN
Bilirubine
élevée à
baseline
>1.0 – 1.5 x
baseline
>1.5 – 3 x
baseline
>3 – 10 x
baseline
>10 x
baseline
Surestimation de la sévérité

23. Diagnostic
Evaluation de la sévérité
Prise en charge thérapeutique
Toxicité hépatique de l’immunothérapie

24. Recommandations de l’ESMO
Sévérité Traitement
Grade 1
ASAT ou ALAT >LSN-3xLSN
Pas de traitement
Grade 2
ASAT ou ALAT >3-5xLSN Si ASAT ou ALAT élevées au deuxième contrôle
Introduire predniso(lo)ne 1mg/kg/jour
Grade 3
ASAT ou ALAT >5-20xLSN ASAT ou ALAT < 400 et bilirubine
totale/INR/diminution de l’albumine introduire
prednisolone 1mg/kg/jour
ASAT o uALAT > 400 ou augmentation de la
bilirubine/INR/diminution de l’albumine :
(methyl)prednisolone 2mg/kg/jour i.v.
Grade 4
ASAT ou ALAT >20xLSN
(methyl)prednisolone 2mg/kg/jour i.v.
Haanen, Ann of Oncology 2018

25. Amélioration spontanée
38%
All ≥G3
De Martin, J Hepatol 2018

26. Management of liver toxicity
De Martin, JHEP Rep. 2020
IMPROVEMENT YES
NO
Cytolysis and/or cholestasis grade ≥3
Rule out common causes of acute hepatitis/tumour
infiltration/biliary obstruction
Monitor liver tests every 2-3 days
Monitor liver tests every 2-3 days
for 15 days
Taper over 6-8 weeks*
Resume ICI when LFTs grade 1 or normal**
Taper over 10-12 weeks*
Resume ICI when LFTs normal**
Liver tests worsening within 7 days
+ histological confirmation of immune-mediated hepatitis
and/or bilirubin ≥2.5 mg/dl or INR ≥1.5
1. Start steroids 0.5 mg/kg/d or 1 mg/kg/d if severe
2. Add UDCA 500 mg bid if cholestasis
Increase steroids to 1 or 2 mg/kg/d depending on previous dose
If no improvement within 7 days at 2 mg/kg/d,
add 1 steroids pulse of 500 mg
(repeat 3 times according to liver test evolution)
YES
NO
IMPROVEMENT YES
NO
Review
IMPROVEMENT YES
NO
Monitor liver tests every 2-3 days
for 15 days
Taper over 6-8 weeks*
Resume ICI when LFTs grade 1 or normal**
Taper over 10-12 weeks*
Resume ICI when LFTs normal**
Taper over 10-12 weeks*
Resume ICI when LFTs normal **
Permanently discontinue ICI
1. Start steroids 0.5 mg/kg/d or 1 mg/kg/d if severe
2. Add UDCA 500 mg bid if cholestasis
Add MMF 1 g bid
Discuss ATG/plasmapheresis in expert liver centre
Stop MMF
Add tacrolimus (trough level 5-7 ng/ml)
Increase steroids to 1 or 2 mg/kg/d depending on previous dose
If no improvement within 7 days at 2 mg/kg/d,
add 1 steroids pulse of 500 mg
(repeat 3 times according to liver test evolution)
YES
NO
IMPROVEMENT YES
NO
IMPROVEMENT YES
NO
IMPROVEMENT YES
NO
Fig. 5. Proposal for the management of patients who experience ICI-related grade >
−3 hepatitis. *Steroid tapering proposal see Table S2. **Wait until MMF and
steroid discontinuation. Resume anti-PD-1 or anti-PD-L1 alone; permanently discontinue anti-CTLA-4; if UDCA administered resume ICI under UDCA. CTLA-4,
cytotoxic T lymphocyte-associated protein 4; ICI, immune checkpoint inhibitor; LFTs, liver function tests; MMF, mycophenolate mofetil; PD-1, programmed

27. Est-il possible de réintroduire un traitement par ICI
après toxicité hépatique ?

28. Recommandations de l’ESMO
Sévérité Traitement Immunothérapie
Grade 1
ASAT ou ALAT >LSN-3xLSN
Pas de traitement Continuer l’immunothérapie
Grade 2
ASAT ou ALAT >3-5xLSN Si ASAT ou ALAT élevées au deuxième contrôle
Introduire predniso(lo)ne 1mg/kg/jour
Suspendre l’immunothérapie
Reprise si grade £ 1
Grade 3
ASAT ou ALAT >5-20xLSN ASAT ou ALAT < 400 et bilirubine
totale/INR/diminution de l’albumine introduire
prednisolone 1mg/kg/jour
ASAT o uALAT > 400 ou augmentation de la
bilirubine/INR/diminution de l’albumine :
(methyl)prednisolone 2mg/kg/jour i.v.
Suspendre l’immunothérapie
Reprise si grade £ 1 avec accord
de l’hépatologue
Grade 4
ASAT ou ALAT >20xLSN
(methyl)prednisolone 2mg/kg/jour i.v. Arrêter définitivement
Haanen, Ann of Oncology 2018

29. this was caused by the prolonged activity of the anti-PD-1 drug
during the introduction of the anti-CTLA-4 antibody.125
Although
the half-life of nivolumab is 17–25 days, PD-1 remains on
different immunosuppressive molecular and cellular mech
nisms. Therefore, strategies to induce vascular normalisation (i
combining ICIs and antiangiogenic agents) may enhance t
Table 3. Re-challenge with ICIs after resolved immune-mediated hepatitis.
Study Patients retreated
with ICI after liver
toxicity
ICI first therapy Grade of
first liver
toxicity
>
−3
ICI re-challenge Time between toxicity
and reintroduction
Days (median, range)
Liver toxicity
recurrence
Othe
irAEs
Ziemer 2016 2 Anti-PD-1 2 Anti-PD-1 103 and 38 0 0
Spankuch 2017 1 Anti-CTLA-4 + anti-PD-1 1 Anti-PD-1 n.a. 0 0
Spain 2017 2 Anti-CTLA-4 + anti-PD-1 2 Anti-CTLA-4 + anti-PD-1 n.a. 1 (grade 4) 1
Pollack 2018 29 Anti-CTLA-4 + anti-PD-1 19 Anti-PD-1 58 (14-395) 5 n.a.
De Martin 2018 3 Anti-CTLA-4 + anti-PD-1 3 Anti-PD-1 n.a. 1 0
Gauci 2018 5 Anti-CTLA4 or Anti-PD-1 NA Anti-CTLA-4 or Anti-PD-1 n.a. 0 0
Riveiro-Barciela 2019 1 Anti-PD-1 0 Anti-CTLA-4 n.a. 1 (grade 4) 0
Simonaggio 2019 5 Anti-PD-1 or Anti-PDL-1 3 0
Cheung 2019 4 Anti-CTLA-4 + anti-PD-1 2 Anti-PD-1 n.a. 0 0
Riveiro-Barciela 2020 6 Anti-PD-1 or Anti-PD-L1
or Anti-CTLA-4 (2)
0 Anti-PD-1 n.a. 0 0
Total 58 29 (50%) 11 (19%)
CTLA-4, cytotoxic T lymphocyte-associated protein 4; ICI, immune checkpoint inhibitors; irAEs, immune-related adverse events; n.a., not available; PD-1, programmed c
death 1; PD-L1, programmed cell death 1 ligand 1.
Review
Réintroduction d’une ICI après hépatite
immuno-médiée
Études de réintroduction de l’immunothérapie après hépatite immuno-mediée
Patients re-traités avec
immunothérapie après
une toxicité hépatique
Immunothérapie
de première ligne
Grade
premier
Toxicité ³ 3
Immunothérapie
réintroduction
Intervalle de temps
entre la toxicité et la
réintroduction jours
Récidive de la
toxicité hépatique
Etude
De Martin, JHEP Reports 2021

30. Discussion multidisciplinaire
RCP ImmunoTox
17h30 salle A808 (4e étage)
1er et 3e Mercredi du Mois
Une RCP dédiée aux toxicités induites par immunothérapie.
Inscrire vos cas en envoyant un email à: RCP.iTOX@gustaveroussy.fr
Oncologist, Immunologist, Pharmacologist, Organ specialists..

31. Le choix du traitment
• 76-year-old patient with an ovarian
cancer ! grade 2 hepatitis on
Nivolumab improved by
corticosteroids.
• Introduction of Ipilimumab due to
cancer progression ! no response
to 2mg/kg/day of steroids + 1.5
g/day of MMF.
• Development of fulminant hepatitis.
• Resolution with plasma exchange.
0
2
4
6
8
10
12
14
0
20
40
60
80
100
120
Prothrombin time (%) Total bilirubin (mg/dL)
PLASMA EXCHANGE
HE
Figure
HE: hepatic encephalopathy
Riveiro-Barcela, J Hepatol 2018

32. Place d’un traitement en prophylaxie
Ziemer, J Hepatol 2016
Methylprednisolone, starting dose 1 mg/kg body weight (50 mg/d),
5 mg/d at the time of restart pembrolizumab
Ursodeoxycholic acid 2 x 500 mg
Budesonide 3 x 3 mg
(dose reduced to 2 x 3 mg on day 188)
1000
1200
1400
1600
1800 ALT
AST
GGT
embro
pembro
pembro
pembro
ot
given
A
B
Ursodeoxycholicacid 2 x 500 mg
N-acetylcysteine 3 x 1200 mg
(dose reduced to 3 x 600 mg on day 90)
Budesonide 3 x3 mg (dose reduced to 2 x 3 mg onday162)
Methylprednisolone, starting dose
1 mg/kg body weight (72 mg/d),
stopped at the time of restart nivolumab
0
50
100
150
200
250
300
350
400
1 14 28 30 35 38 41 44 45 46 49 50 53 56 66 69 73 83 90 105 119 133 147 161 175 189 203
U/L
Day
1
st
cycle
nivo
2
nd
cycle
nivo
3
rd
cycle
not
given
Restart
nivo
ALT
AST
GGT
Letter to the Editor
• 73-year-old patient with metastatic
melanoma ! grade 3 hepatitis after
2 cycle of Nivolumab.
• No hepatitis recurrence after
immunotherapy reintroduction on
budesonide prophylaxis.
Evolution of AST, ALT and GGT

33. Mme G.C. , 63 ans mélanome métastatique
Mars 2017 Juin 2017 Décembre 2017 Mars 2018 Mai 2018
Hépatite aigue
immuno-mediée
Grade 4.
Corticoïdes
1mg/kg/jour.
Amélioration.
NIVO + IPI PEMBRO
Corticoïdes
20mg/jour
PEMBRO
Entérocolite
Immuno-mediée
Corticoïdes
20>40>60
mg/jour.
Amélioration.
Récidive de
l’entérocolite
à l’arrêt de
corticoïdes
Anti-TNFα 2
injections !
Bonne réponse.
ICI
irAEs

34. Conclusion
• Le diagnostic de toxicité hépatique des immune checkpoint inhibitors
nécessite l’exclusion de toute autre cause d’hépatite aigue.
• La sévérité de l’atteinte hépatique peut être surestimée par la classification
de la sévérité des effets indésirables (CTCAE). Une expertise hépatologique
est souhaitable.
• L’examen histologique confirme le diagnostic et permet d’évaluer la
sévérité de l’atteinte hépatique. Une biopsie hépatique est conseillée en
cas de toxicité hépatique sévère.

35. • La mise en place d’un traitement par corticoïdes pour la toxicité de
l’immunothérapie ne doit pas être systématique mais doit être évaluée en
fonction de sa sévérité.
• La réintroduction du traitement anticancéreux est possible après
amélioration du bilan hépatique (toxicité de grade £ 1). Elle doit être
validée par une réunion multidisciplinaire en tenant compte du rapport
bénéfice-risque.
Conclusion

36. Acknowledgments
Centre Hépato-Biliaire
Paul Brousse
Institut
Gustave Roussy