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Predictors and outcomes of steroid-refractory
immune checkpoint inhibitor hepatitis.
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Earlier Immunosuppressant Spurs Faster Resolution of Steroid-Refractory ICI Hepatitis
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
Adding the immunosuppressant CellCept or Imuran to steroids led to faster resolution of steroid-refractory immune checkpoint inhibitor (ICI) hepatitis in a 103-person multicenter retrospective study [1]. Alanine aminotransferase (ALT) slope in the week after steroids began predicted steroid-refractory disease in this group with melanoma.
Researchers from Boston's Brigham and Women's Hospital noted that ICIs transformed cancer therapy. But immune-related adverse events complicate ICI use, including ICI hepatitis in 10% of patients [2]. About 1% to 2% of ICI-treated people endure grade 3 liver injury, indicated by liver enzymes more than 5 times the upper limit of normal.
This multicenter retrospective study focused on all melanoma patients treated in the Mass General Brigham hospital system between January 2010 and June 2020 in whom grade 3 or higher ICI hepatitis developed. The researchers defined steroid-refractory hepatitis as hepatitis requiring additional immunosuppressive therapy because of an inadequate biochemical response after 48 hours of at least 1 mg/kg prednisone equivalents. The primary outcome was time to a normal ALT (below 50 U/L).
In this Boston hospital system, 1913 people with melanoma received ICI therapy, of whom 257 had ALT above 200 U/L during the study period. Grade 3-4 hepatitis developed in 103 people (5.4% of 1913), and steroid-refractory ICI hepatitis arose in 37 people (36% of 103). Thirty-five of those steroid-refractory patients received additional treatment with mycophenolate mofetil (CellCept) and 2 got azathioprine (Imuran). The 103 people with grade 3-4 hepatitis averaged 56.4 years in age and had a median follow-up of 584 days.
People with steroid-refractory versus responsive ICI hepatitis had more severe hepatitis indicated by (1) higher peak ALT (627 vs 399 U/L, P < 0.001), (2) longer time to peak ALT (median 9 vs 0 days, P < 0.001), and (3) almost 4-fold greater likelihood of grade 4 ICI hepatitis (46% vs 12%, RR 3.8, 95% confidence interval [CI] 1.8 to 7.9, P < 0.001).
Time to ALT improvement was significantly longer in people with steroid-refractory hepatitis, reflected in a longer time to ALT below 100 U/L (median 26 vs 14 days, P < 0.001) and a longer time to a normal ALT (median 45 vs 23 days, P = 0.017). Cox regression analysis adjusted for liver metastases, preexisting liver disease, and combination ipilimumab/nivolumab therapy determined that steroid-refractory individuals took more time to reach an ALT below 100 U/L (hazard ratio [HR] 0.38, 95% CI 0.25 to 0.59, P < 0.001) and to reach a normal ALT (HR 0.65, 95% CI 0.42 to 0.98, P = 0.042).
After steroid therapy began, people with steroid-refractory versus responsive hepatitis had a significantly higher ALT on day 3 (415 vs 264 U/L, P = 0.004) and day 7 (302 vs 114 U/L, P < 0.001). Through the first 7 days after steroids began, people with refractory hepatitis had a 30-U/L smaller daily improvement in ALT (-9.2 vs -39.1 U/L).
The Brigham team figured that the ALT slope in the first 7 days of steroid treatment can predict emergence of steroid-refractory hepatitis with good discrimination (AUC 0.850 for ROC curve). They set prediction rule cutoffs for high risk and low risk by picking cutoffs closest to 90% sensitivity and 90% specificity:
High risk: greater than 51.9% predicted probability of refractory disease: day 7 ALT/day 0 ALT = 0.71 (sensitivity 91.9%)
Low risk: less than 17.7% predicted probability of refractory disease: day 7 ALT/day 0 ALT = 0.35 (specificity 89.2%)
In their population of 103 people with grade 3-4 hepatitis, that would leave 35 people in the intermediate-risk range (17.7% to 51.9%).
Next the researchers determined that receiving additional treatment with CellCept or Imuran earlier got patients to an ALT below 100 U/L faster (median 20 vs 46 days, P < 0.001) and to a normal ALT faster (28 vs 68 days, P < 0.001). Cox regression analysis adjusted for the three variables noted above determined that people receiving early CellCept or Imuran had more than a 4-fold greater chance of reaching an ALT below 100 U/L faster (HR 4.60, 95% CI 1.88 to 11.25, P < 0.001) and almost a 4-fold greater chance of reaching ALT normalization faster (HR 3.76, 95% CI 1.60 to 8.84, P = 0.002). Each additional day before starting an immunosuppressant lowered chances of reaching an ALT below 100 U/L by 5% (HR 0.95, 95% CI 0.91 to 0.99, P = 0.008) and lowered chances of reaching a normal ALT by 7% (HR 0.93, 95% CI 0.89 to 0.98, P = 0.004).
The Brigham and Women's researchers summarized their main three findings like this:
-"Steroid-refractory ICI hepatitis in melanoma patients is more severe and takes longer to resolve than steroid-responsive ICI hepatitis."
- "The slope of ALT from 0 to 7 days after steroid treatment can predict development of steroid-refractory disease with good discrimination."
- "Earlier addition of CellCept or Imuran in steroid-refractory patients is associated with faster hepatitis resolution."
The investigators noted that their analysis is limited in its focus only on people with melanoma, almost all of whom are white. They hope for external validation of these findings.
References
1. Li M, Sack J, Rahma OE, Grover S, Zucker SD. Predictors and outcomes of steroid-refractory immune checkpoint inhibitor hepatitis. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 115.
2. Suzman DL, Pelosof L, Rosenberg A, Avigan MI. Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int. 2018;38:976-987. doi: 10.1111/liv.13746. https://onlinelibrary.wiley.com/doi/full/10.1111/liv.13746
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