P2508 - Implementation of an Enhanced "Step-Up" Approach Towards Early Tocilizumab for Management of Immune Checkpoint Inhibitor-Mediated Hepatotoxicity: A Case Study in Revisiting Paradigms of Treatment

Monday, October 23, 2023

10:30 AM – 4:15 PM PT

Location: Exhibit Hall

Has Audio

Presenting Author(s)

Hao Chi Zhang, MD

University of Texas MD Anderson Cancer Center
Houston, TX

Hao Chi Zhang, MD, Ethan Miller, MD, Pavlos Msaouel, MD, Lan Wang, MD
University of Texas MD Anderson Cancer Center, Houston, TX

Introduction: Society guidelines have endorsed routine use of high-dose systemic corticosteroids to treat immune checkpoint inhibitor-mediated hepatotoxicity (IMH), with an additional steroid taper across 4-6 weeks after induction. Observations reveal that up to half of IMH cases do not require steroids. Emerging experience also showcases tocilizumab (TCZ) as a steroid-sparing strategy for IMH for refractory cases, a method still being studied. We describe a case of an enhanced "step-up" approach to reduce steroid exposure and utilize TCZ to ultimately manage IMH.

Case Description/Methods: A 50-year-old man with a history of clear cell renal cell carcinoma treated with left nephrectomy and with 2 cycles of ipilimumab/nivolumab, obesity, and Gilbert syndrome, was evaluated for high-grade liver enzyme elevations. He had no prior established liver disease, was taking supplemental turmeric, black seed oil, and multivitamins, and consumed 3 cans of beer/month. His baseline labs were: ALT 38, AST 22, and alkaline phosphatase (ALP) 103. After the second cycle of immunotherapy, his ALT rose to 3266, AST to 1955, and ALP to 209. Serologic work-up for liver disease was unrevealing. Liver biopsy showed portal/lobular mononuclear inflammation with interface activity, zone 3 necrosis, hepatocyte dropout, and mixed steatosis (5%); diagnosis was compatible with IMH. Abdomen MRI/MRCP showed periportal edema without obstruction and no biliary ductal dilation. After 10 days of observation, his ALT improved to 579, but soon rose to 1210. After starting induction IV methylprednisolone (MP) 93.75 mg followed by 60 mg/d and then prednisone, ALT improved to 368, but it subsequently rose again to 976. After IV MP 100 mg/d, he suffered from hyperglycemia. So, IV TCZ 800 mg was given, followed by a rapid steroid taper of prednisone across 23 days. He achieved steroid-free biochemical remission 33 days after TCZ, with ALT 39, AST 28, and ALP of 101.

Discussion: This patient exhibited 3 behaviors of IMH during the same episode: 1) natural improvement of liver enzymes (estimated 33-50% of IMH cases); 2) ongoing toxicity necessitating steroids; 3) development of steroid-resistance prompting escalation to TCZ. Steroids were implemented only when necessary. Prompt identification of steroid-resistance allowed for escalation to early TCZ, without requiring mycophenolate mofetil. Knowing that TCZ can be used to ultimately rescue relapsed/refractory IMH enabled a shorter steroid tapering schedule, mitigating the associated adverse events.

Figure: Chronological trends of liver biochemical labs during the clinical course and with respect to management phases. This patient exhibited 3 distinct behaviors that have been observed with immune-mediated hepatotoxicity. In the first phase, observation alone without immunosuppression revealed that the liver was capable of spontaneous improvement, during which the patient was spared of steroid use, and significant improvement in ALT and AST occurred. When further natural improvement was not possible, this prompted the utilization of steroids to induce remission; this second phase is most familiar to clinicians as the mainstay of management for this toxicity. Despite initial response to intravenous steroids, oral steroids were not adequate, as evidenced by the resurgent ALT and AST levels, which represents the third phase. This third phase is the first cue to escalate the immunosuppression regimen. Because tocilizumab allows for decoupling of steroids, tocilizumab was administered followed by an accelerated steroid taper to compress the steroid exposure. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; Ipi, ipilimumab; Nivo, nivolumab; d, day; IV, intravenous; MP, methylprednisolone; pred., prednisone; TCZ, tocilizumab.

Laboratory parameters	Baseline (59 d before presentation)	Initial presentation	Liver enzyme nadir with observation alone (10 d after presentation)	1 d before TCZ (28 d after presentation)	Day of TCZ	1 d after TCZ	19 d after TCZ	33 d after TCZ (61 d after initial presentation)
ALT (N £ 35 U/L)	38	3266	579	760	614	466	74	39
AST (N £ 40 U/L)	22	1955	267	175	132	68	35	28
ALP (N = 40-129 U/L)	103	209	168	183	160	126	105	101
Direct bilirubin (N £ 0.3 mg/dL)	0.3	1.3	1.5	0.8	0.6	1.1	0.7	0.4
INR (N = 0.89-1.10)	-	1.47	1.06	1.13	1.17	1.22	0.96	1.01

Disclosures:

Hao Chi Zhang indicated no relevant financial relationships.

Ethan Miller indicated no relevant financial relationships.

Pavlos Msaouel: BMS – Grant/Research Support. Mirati Therapeutics – Advisory board. Takeda – Grant/Research Support.

Lan Wang indicated no relevant financial relationships.

Hao Chi Zhang, MD, Ethan Miller, MD, Pavlos Msaouel, MD, Lan Wang, MD. P2508 - Implementation of an Enhanced "Step-Up" Approach Towards Early Tocilizumab for Management of Immune Checkpoint Inhibitor-Mediated Hepatotoxicity: A Case Study in Revisiting Paradigms of Treatment, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.