Case Report,  Clin Oncol Case Rep Vol: 7 Issue: 1

Ipilimumab and Nivolumab-Induced Pancreatitis and Hepatitis in Malignant Melanoma

Xu Sharon^1*, Hsin Jerline¹ , Liang Yu² , Ngo Peter^3,4 , Xing Yan³

¹Department of Pharmacy, City of Hope, Duarte, CA, USA

²Department of Pathology, City of Hope, Duarte, CA, USA

³Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA, USA

⁴Department of Hematology and Medical Oncology, Harbor-UCLA, Torrance, CA, USA

*Corresponding Author: Xu Sharon, Department of Pharmacy
City of Hope, Duarte, CA, USA,
E-mail: shxu@coh.org

Received: January 24, 2024; Manuscript No: COCR-24-125784
Editor Assigned: January 27, 2024; PreQC Id: COCR-24-125784 (PQ)
Reviewed: February 05, 2024; QC No: COCR-24-125784 (Q)
Revised: February 08, 2024; Manuscript No: COCR-24-125784 (R)
Published: February 16, 2024; DOI: 10.4173/cocr.7(1).332

Citation: Xu S, Jerline H, Yu L, Peter N, Yan X, (2024) Ipilimumab and Nivolumab-Induced Pancreatitis and Hepatitis in Malignant Melanoma Clin Oncol Case Rep 7:1

Abstract

Keywords: Checkpoint inhibitors; Pancreatitis; Hepatotoxicity; Nivolumab; Ipilimumab; irAE

Introduction

Programmed Death-1 (PD-1)/ligand-1 (PD-L1) and Cytotoxic T-Cell Lymphocyte-4 (CTLA-4) inhibitors are used in combination to treat malignant melanoma [3]. Nivolumab is a human Immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits Programmed Cell Death-1 (PD-1) activity by binding to the PD-1 receptor [1]. This interaction promotes tumor-killing effects of T cells. Ipilimumab binds to CTLA-4, an antibody that helps to boost the immune response and increase the function and growth of T cells. The combination has been effective in melanoma treatment, but results in increased irAE including diarrhea and colitis [3-6]. Almost every organ can be affected by irAE. Hepatitis can be seen as high as 13%-30% in combination therapy [7] . Asymptomatic pancreatitis can occur in 8%-27% of patients on combination therapy.

We report a unique case of acute hepatitis and pancreatitis following the use of ipilimumab and nivolumab combination therapy for a patient with malignant melanoma.

Case Presentation

A 39-year-old female with malignant melanoma of the right upper extremity was first diagnosed in 2020. She was lost to follow up until 2.5 years later when she underwent right axillary lymph node excision, received one dose of adjuvant nivolumab, experienced a seizure approximately two months after, and was found to have new brain metastases (Figure 1). She underwent a right frontal craniotomy and received one week of radiation to the brain lesion. A month after the brain metastases diagnosis, she began Cycle 1 of combination ipilimumab 3 mg/ kg and nivolumab 1 mg/kg every 3 weeks. She received Cycle 2 three weeks later.

Approximately two weeks after the second dose of ipilimumab and nivolumab (Day 37 after first dose of nivolumab), the patient presented to an outside hospital for complaints of generalized abdominal pain to the right upper quadrant lasting 5 days, weakness, and fever. Her lipase was elevated at 1454 U/L, total bilirubin 5.7 mg/dL, AST 1007 U/L and ALT 1416 U/L; her hepatitis panel was nonreactive. Imaging, including US, CT, and MRCP, were completed. Patient was transferred to our facility on Day 40 for further care where GI was consulted. Imaging US, CT, and MRCP all showed a non-dilated, normal biliary system. Surgical gallbladder was excluded as nonspecific gallbladder findings could be explained in context of hepatitis. Choledocholithiasis was very low on the differential given lack of corresponding imaging findings. Based on the diagnosis of exclusion, there was high suspicion for immunotherapy-induced hepatitis and pancreatitis.

As her total bilirubin continued to rise, treatment was started on Day 41 with IV fluid and electrolyte repletion, methylprednisolone IV 1 mg/kg daily, and N-Acetyl Cysteine (NAC). Her labs on Day 42 continued to elevate, with total bilirubin 15.2 mg/dL, direct bilirubin 8.8 mg/dL, AST of 1315 U/L, ALT of 1839 U/L, lipase 536 U/L, and amylase 403 U/L. Phytonadione was started for an elevated INR at 1.9. She was additionally started on diphenhydramine for significant maculopapular rash on her lower chest, abdomen, flanks, back and arms (Figure 2).

On her third and final day of NAC, her labs were at total bilirubin 14.4 mg/dL, direct bilirubin 8.4 mg/dL, AST 662 U/L, ALT 1494 U/L, lipase 359 U/L, amylase 272 U/L, and INR 1.9. The day after discontinuing NAC her liver enzymes increased. Her steroids were increased from methylprednisolone IV 1 mg/kg daily to 1.5 mg/kg/day IV divided into two doses daily on Day 45. Minimal response was seen and mycophenolate 1000 mg twice daily was added on Day 47. A liver biopsy on Day 49 showed moderate to severe active hepatitis with bridging necrosis and cholestasis, findings compatible with checkpoint inhibitor-induced liver injury.

On Day 52, mycophenolate was tapered down to 500 mg twice daily for neutropenia. Her LFTs began to trend down, and steroids were tapered starting Day 60 to prednisone 80 mg daily. Due to persistent pancytopenia mycophenolate was discontinued, and the patient started on tacrolimus 2 mg by mouth every 12 hours with tacrolimus trough goal of 6 ng/mL to 10 ng/mL drawn three times a week (Figure 3).

The patient’s hospital stay was complicated by pulmonary aspergillus pneumonia found on bronchoscopy on Day 67 with a several days history of fever, chills, and cough associated with neutropenia. The patient initiated amphotericin B liposome 3 mg/kg on Day 66 and switched to isavuconazonium on Day 72. She started a slow prednisone taper on Day 71 and continued to have improved total bilirubin 3.9 mg/dL and LFTs (ALT 60 U/L; AST 18 U/L) towards the date of discharge. The patient was discharged home on Day 77 with tacrolimus 3 mg by mouth twice daily and a prednisone taper. Her tacrolimus was tapered off completely on Day 197. Post-treatment PET CT scan continued to show no evidence of FDG-avid metastases. Ultimately, the patient initiated next-line therapy with dabrafenib and trametinib (Table 1).

Table 1: Liver and pancreatic function laboratory values during hospital admission.

Discussion

Immunotherapy is an effective therapy option for patients with melanoma because the disease has high immunogenicity [1]. Cancer cells suppress T-cell mediated cytotoxicity mechanisms through checkpoint inhibition which can be overcome with the use of immune checkpoint inhibitors.

Patients receiving combination therapy with nivolumab and ipilimumab experience a higher percentage of Treatment-Related Adverse Events (TRAEs) compared to that of monotherapy. The CheckMate 067 trial reported grade 3 or 4 TRAEs in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group [7]. Immunotherapy-induced hepatotoxicity is a diagnosis of exclusion. The timing of liver injury to immunotherapy treatment is a useful indicator, as hepatotoxicity onset is usually 8 weeks to 12 weeks after initiation of treatment [4-5]. Immunotherapy-associated pancreatic injury can be asymptomatic or symptomatic, with diagnosis of acute pancreatitis depending on identification of at least 2 of the following features: (1) severe epigastric pain often radiating to the back; (2) elevated serum lipase/amylase levels (at least three times the upper normal limit); and (3) characteristic findings of acute pancreatitis on abdominal imaging [6]. In a study by Friedman et al, 119 patients treated with nivolumab and ipilimumab therapy showed 20% of these patients manifested grade ≥ 3 amylase elevations, 6.3% had grade ≥ 3 lipase elevations, 20% had increased levels of both enzymes, and 1.7% developed immune-related pancreatitis [8].

Treatment of irAE is largely limited to steroids because of the inflammatory nature of the reactions [4-6]. A previous case presentation reported a 62-year-old male diagnosed with squamous cell carcinoma of lung metastatic to vertebrae on nivolumab immunotherapy who presented with severe abdominal pain and nausea and vomiting was initiated on corticosteroids and had complete resolution of symptoms [9]. Less guidance is available in the setting of steroid-refractory immunotherapy induced adverse effects. Second line therapy with mycophenolate mofetil may be considered in steroid refractory cases, and infliximab in steroid-resistant colitis and pneumonitis (without liver injury) and ATG can be trialed (acts to deplete CD4 lymphocytes) [10]. A subsequent trial of tacrolimus or sirolimus after poor response to second line therapy in irAE hepatitis can be considered. Tomsitz et al describes a case of immunotherapy-induced hepatitis requiring 5 years of treatment with tacrolimus and failure in dose tapering.

Conclusion

We describe the first case of a steroid-refractory, immunotherapy-induced hepatitis and pancreatitis in a malignant melanoma patient successfully treated with mycophenolate and transitioned to tacrolimus upon discharge. The patient’s tacrolimus was successfully tapered, and she has been in remission for 16 months so far without further therapy for her malignant melanoma.

Declarations of interest

None. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Funding

This research did not receive funding.

Abbreviations

(CT) Computed Tomography, (CTLA-4) Cytotoxic T-cell Lymphocyte-4, (IgG4) Immunoglobulin G4, (irAE) Immune-related Adverse Effects, (MRCP) Magnetic Resonance Cholangiopancreatography, (NAC) N-Acetyl Cysteine, (PD-1) Programmed Death-1, (PD-L1) Programmed Death Ligand-1, (TRAEs) Treatment-Related Adverse Events and (US) ultrasound.

References

1. Checkpoint inhibitors to treat cancer.National Cancer Institute.
2. Liu Y, Zhang H, Zhou L, Li W, Yang L, et al (2021). Immunotherapy-associated pancreatic adverse events: current understanding of their mechanism, diagnosis, and management. Front Oncol 11: 627612. [Google Scholar]  [Cross Ref]
3. Ralli M, Botticelli A, Visconti IC, Angeletti D, Fiore M, et al. (2020). Immunotherapy in the treatment of metastatic melanoma: current knowledge and future directions. J immunol res [Google Scholar]  [Cross Ref]
4. Grover S, Rahma OE, Hashemi N, and Lim RM. Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management. Am Soc Clin Oncol Educ Book 38:13-19 [Google Scholar]  [Cross Ref]
5. Mathew Thomas V, Bindal P, Ann Alexander S, & McDonald K, et al. (2020). Nivolumab-induced hepatitis: a rare side effect of an immune check point inhibitor. J Oncol Pharm Pract 26 : 459-461. [Google Scholar]  [Cross Ref]
6. Hsu C, Marshall JL, & He AR. (2020). Workup and management of immune‐mediated hepatobiliary pancreatic toxicities that develop during immune checkpoint inhibitor treatment. oncologist 25: 105-111. [Google Scholar]  [Cross Ref]
7. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, et al. (2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. lancet oncol 16: 375-384. [Google Scholar]  [Cross Ref]
8. Friedman CF, Clark V, Raikhel AV, Barz T, Shoushtari AN, et al. (2017). Thinking critically about classifying adverse events: incidence of pancreatitis in patients treated with nivolumab+ ipilimumab. JNCI: J Natl Cancer Inst 109 : djw260 [Google Scholar]  [Cross Ref]
9. Bhatia U, Bajaj S, Gandhi D, & Bajaj D. (2021). Nivolumab Induced Acute Pancreatitis and Hyper-bilirubinemia. Int J Oncol Res 4 : 32. [Google Scholar]  [Cross Ref]
10. Tomsitz D, Ruf T, Zierold S, French LE, & Heinzerling L, et al. (2023). Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors. Cancers 15:2538. [Google Scholar]  [Cross Ref]