Background and Aims

Hematological immune related adverse events (irAE) are rare, affecting 0.5% of patients on anti-PD(L)1, mainly represented by neutropenia, hemolytic anemia or immune thrombocytopenia. Warm type autoimmune hemolytic anemia (AIHA) is the most described presentation, while cold agglutinin disease (CAD) seems much rarer.

Methods

We report the case of a patient with CAD occurring during treatment with anti-PD-1 and review the literature.

Results

A 72-year-old patient with metastatic lung cancer developed grade 3 seronegative immune-induced cholangitis after 37 nivolumab infusions. Since liver tests rapidly normalized under ursodeoxycholic acid, without corticosteroid therapy, she was rechallenged with nivolumab. Ten infusions later, she complained about dyspnea and asthenia, and developed de novo cold-induced livedo. Biology revealed deep hemolytic anemia with hemoglobin 4.2 g/dl, positive Coombs test (IgG and C3d) and cold agglutinins, together with eosinophilia (2.98 G/L) and mild cholestasis. Comprehensive etiological workout was negative. She recovered after nivolumab discontinuation and high dose steroids (2 mg/kg).

Apart from our case, only seven ICI-induced CAD were reported: four women and three men, with a median age of 64 years, all occurring under anti-PD(L)-1 (3 under pembrolizumab, two nivolumab and two atezolizumab). The median time to onset was 15 days with grade ≥ 3 for 6/7 and one death. Coombs was positive in 6/7 cases. None of the cases described any other associated irAE. Four cases were steroid-refractory and required rituximab.

Conclusions

ICI-induced CAD is a rare and serious irAE. A late onset is possible and steriod sensitivity seems to be greater than in non-ICI-related CAD.

Background and Aims

Immune checkpoint inhibitors (ICI) changed the landscape of cancer therapy. Liver toxicity is occurring in up to 25% of patients under ICI. International guidelines recommend pausing immunotherapy and administering corticotherapy, regardless of the hepatitis phenotype. Our study aimed at describing the phenotypes and evolution of ICI-induced hepatitis.

Methods

We conducted an observational study CHILI (CHeckpoint Inhibitors Liver Injury) in patients with ICI-mediated hepatitis through Montpellier «ToxImmun» multidisciplinary meeting between December 2018 and February 2022. Data regarding cancer, hepatitis treatments, and ICI rechallenge were collected. The hepatitis phenotype was defined by the ratio of serum ALT and ALP [R value = (ALT/ULN)/(ALP/ULN)], and categorized as cholestatic (R≤2), hepatocellular (R≥5), or mixed (2<R<5).

Results

From 479 patients discussed, ICI-hepatitis accounted for 12.3% of cases. 59 patients were included (54% men, median age 65). PD-1-inhibitor was the most prescribed ICI class (89.8%), alone (63.5%), or with CTLA-4-inhibitor (30.5%). Hepatitis phenotype was cholestatic in 44%, hepatocellular in 30.5% and mixed in 25.4%. Hepatitis were predominantly grade 3, according to CTCAE (69.5%). No case of severe acute hepatitis was reported. Liver biopsy was performed in 39%. Biliary stenosis occurred in 6 patients (23.1%). An extra-hepatic irAE was reported in 45.9%. Most patients were treated with corticosteroids (76.3%) and ursodeoxycholic acid (UDCA, 35.6%). ICI was resumed in 50.8%, while 63.3% received the same ICI and 96.6 % received a single ICI. The rate of recurrence after ICI rechallenge was 31%.

Conclusions

Future studies should consider adapting the treatment to the hepatitis phenotype, and question the place of UCDA in the case of cholestatic pattern.