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Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma

Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab... Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 8870334, 5 pages https://doi.org/10.1155/2021/8870334 Case Report Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma 1 2 Lindsey Teal and Jeffrey Yorio The University of Texas at Austin Dell Medical School, Austin, Texas, USA Texas Oncology, Austin, Texas, USA Correspondence should be addressed to Jeffrey Yorio; jeff.yorio@usoncology.com Received 28 April 2020; Revised 1 March 2021; Accepted 11 March 2021; Published 30 March 2021 Academic Editor: Ossama W. Tawfik Copyright © 2021 Lindsey Teal and Jeffrey Yorio. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP. FDA-approved standard of care for metastatic uveal mela- 1. Introduction noma [8]. Melanoma incidence continues to rise, and unresectable met- Immune checkpoints mediate immune response and pre- astatic melanoma is associated with high mortality [1]. Uveal vent tissue damage [5]. Immune checkpoint receptors, such melanoma is a rare subtype of melanoma that progresses to as PD-1 and CTLA-4, serve as an “off switch” for T-cell func- metastatic disease in over 50% of patients [2]. Approximately tions in tissues, such as destroying other cells [6]. Tumor cells 20-30% of patients will die of systematic metastases within 5 take advantage of this by upregulating ligands for PD-1, years of being diagnosed [3]. The development of immune thereby blocking the antitumor response. Anti-PD-1 inhibi- checkpoint inhibitors, particularly those targeting cytotoxic tors block this PD-1 pathway and serve as an “on switch” T-lymphocyte-associated antigen 4 (CTLA-4) and pro- to allow for the antitumor response to take place and cause tumor regression. grammed cell death-1 (PD-1), has dramatically improved long-term prognosis for patients with advanced cutaneous Anti-PD-1 inhibitors, such as nivolumab, serve as an melanomas [4–7]. However, responses in advanced uveal ideal treatment option for uveal melanoma due to their low melanoma have been very limited, so there remains no side effect profile. However, anti-PD-1 inhibitors have been 2 Case Reports in Oncological Medicine involving the entire liver rather than progression of metasta- known to induce relatively mild immune-related adverse events (irAEs) such as fatigue, pruritis, and arthritis [9, 10]. tic disease which would have shown more heterogeneous Serious adverse events occur in <10% of patients taking nivo- FDG avidity corresponding to the sites of tumor activity lumab and include interstitial pneumonitis, hepatitis, hypo- (Figure 2). thyroidism, diarrhea/colitis, adrenal insufficiency, and The patient was admitted to the hospital, and further lab pituitary insufficiency [9, 11, 12]. The incidence of grade 3 workup including anti-nuclear antibodies, anti-smooth mus- or 4 immune-related hepatitis is only seen in about 1% of cle antibodies, anti-liver kidney antibodies, anti- patients, while fulminant hepatic failure has only rarely been mitochondrial antibodies, and IgG levels was all unremark- able. The patient was started on high-dose intravenous Solu- reported [9, 13]. Chemosaturation with percutaneous hepatic perfusion medrol and liver function tests (LFTs), and symptoms (PHP) is a therapy that delivers chemotherapy in high doses initially improved during his first few hospital days. How- directly to the liver with the goal of targeting hepatic metas- ever, on the fourth hospital day (day 26 in Figure 1), his con- tases [14, 15]. One phase III randomized trial in patients pri- dition dramatically declined. His LFTs rose rapidly to the marily with uveal melanoma with liver metastases thousands, resulting in fulminant liver failure. He then devel- demonstrated a significant improvement in progression- oped acute renal failure, anion gap metabolic acidosis, and free survival (PFS) from 1.6 months to 5.4 months when hyperkalemia. The patient was placed on a bicarbonate drip, compared to the best available care. Further clinical trials and efforts were made to reverse his acidosis to stabilize him; are being done in the United States, but it is currently used however, his condition continued to decline and LFTs con- tinued to worsen (AST: 7,708 U/L, ALT: 3,131 U/L, alkaline as a treatment for uveal melanoma in other countries [16]. Early animal studies have shown high rates of bone marrow phosphatase: 817 U/L, and total bilirubin: 11.9 mg/dL). depression, but studies have not measured the effect it may Mycophenolate mofetil 1,000 mg IV was administered with have when given with immunotherapy [15]. no improvement. The patient was not a liver transplant can- We present the case of a patient with metastatic uveal didate because of his metastatic cancer diagnosis. The fulmi- nant hepatic failure was irreversible and led to death melanoma treated with PHP followed by nivolumab who developed fulminant hepatic failure. secondary to cardiorespiratory arrest. 2. Case Presentation 3. Discussion A 46-year-old man with no significant past medical history presented with blurry vision and was ultimately diagnosed To our knowledge, this is the first reported case of fulminant with choroidal melanoma of the right eye. He underwent pla- hepatic failure secondary to nivolumab in a patient with prior que brachytherapy and was followed with surveillance imag- PHP treatment. Immune-related hepatitis from PD-1 inhib- ing. Fifteen months after his original diagnosis, MRI itors is usually mild-to-moderate and self-limited, but in less abdomen revealed multiple hepatic lesions. A CT-guided than 1.0% of the patients, the hepatitis is considered severe liver biopsy of one of the lesions was performed, and pathol- [17]. This is a result of impaired self-tolerance from the loss ogy confirmed metastatic uveal melanoma. Initial staging of T-cell inhibition and can lead to autoimmune-related showed only liver metastases. The patient travelled to the inflammation in normal, noncancerous tissues. These United Kingdom and received four cycles of chemosatura- adverse events can usually be treated by modulating the tion with PHP using high-dose melphalan over a 6-month immune system with steroids or other immunosuppressing period. Repeat imaging initially showed a partial response agents, but in some cases, such as this one, it can be fatal. to this treatment in the liver. After 6 months, the patient Mild-to-moderate hepatitis usually occurs between 6 and started to complain of rib pain and back pain. A PET/CT 14 weeks after starting treatment; however, the patient in our scan revealed diffuse bony metastases. He was treated with case developed hepatitis in under 4 weeks after starting treat- palliative radiation prior to initiation of nivolumab at ment [18]. One study found that liver toxicity was most com- 3 mg/kg every two weeks. monly seen after 2 to 6 cycles of nivolumab, which aligns Shortly after the first cycle of nivolumab, he began having with our case [17]. However, there is no established timeline mild right upper quadrant pain, low-grade fevers, diaphore- for fulminant liver failure, as it is rare and has only been sis, and fatigue. Two weeks later, he was given a second dose reported a handful of times in the literature. One case of ful- of nivolumab. Then, one week after that, his right upper minant hepatic failure due to nivolumab was reported in quadrant abdominal pain worsened, and he was found to October 2018 [19]. However, this patient was also taking a have an aspartate aminotransferase (AST) level of 310 U/L, CTLA-4 inhibitor, ipilimumab, concurrently. The combina- alanine aminotransferase (ALT) of 187 U/L, alkaline phos- tion of CTLA-4 and PD-1 blockade is known to cause a phatase of 713 U/L, and total bilirubin of 3.8 mg/dL higher incidence of hepatitis than single-drug immunother- (Figure 1). Clinical exam revealed marked hepatomegaly. apy, with the incidence being 6.9% and 1%, respectively Given his extensive liver metastases, there was an initial ques- [20]. Another patient taking nivolumab after carboplatin tion about progression of his disease versus an autoimmune and gemcitabine suffered from fulminant hepatic failure hepatitis, so a PET/CT scan was performed revealing an [21]. In 2018, a patient with malignant melanoma underwent enlarged liver along with diffusely homogenous uptake in 17 cycles of nivolumab before developing grade 4 ALT eleva- the liver. This suggested a diffuse inflammatory process tion [22]. After steroids, his ALT did not recover to normal Case Reports in Oncological Medicine 3 >2000 ⁎ ⁎ ⁎ Day 1 Day 14 Day 19 Day 20 Day 22 Day 23 Day 24 Day 25 Day 26 AST ALT Alkaline phosphatase Figure 1: Liver function tests before, during, and after 2 cycles of nivolumab. The dates are numbered starting with the first day of the first st cycle of nivolumab. AST: aspartate aminotransferase; ALT: alanine aminotransferase; day 1∗: start of the 1 cycle of nivolumab; day 14∗: start nd st of the 2 cycle of nivolumab; day 22∗:1 dose of corticosteroids. The graph shows the rapid increase in liver function tests after the patient began taking nivolumab and the minor response after being treated with corticosteroids. It also depicts the timeline until the patient perspired. (a) (b) Figure 2: PET/CT scan of the abdomen. (a) One month prior to the first cycle of nivolumab: multiple intrahepatic lesions. (b) Day 22 after the first cycle of nivolumab: significant hepatomegaly due to hepatitis, significant increased metabolic activity of the entire liver, and new abdominal ascites. The PET/CT scan of the patient abdomen depicts the changes in the patient’s liver before and after starting nivolumab. The second picture shows the large size of the liver when the patient developed autoimmune hepatitis. U/L 4 Case Reports in Oncological Medicine range, even after 5 months. Fulminant hepatic failure has also Consent been seen with the PD-1 inhibitor, pembrolizumab [23]. Consent for publication was unable to be obtained from fam- In this case, the patient had been previously exposed to ily members after multiple attempts. No identifiers have been PHP to treat liver metastases from uveal melanoma. As dis- used. cussed above, in phase 3 randomized controlled trials (RCTs), PHP has been shown to be efficacious when com- pared to chemotherapy, but it can also lead to adverse events. Conflicts of Interest One RCT found the rate of grade 3 or 4 hepatic dysfunction, The authors declare that they have no conflicts of interest. diagnosed by hyperbilirubinemia, to be 14.3% [16]. There were also 5.7% of patients in the RCT that discontinued treat- ment because of hepatic toxicity, diagnosed by hyperbilirubi- Authors’ Contributions nemia (5.7%), increase in ALT (2.9%), and increase in AST All authors contributed to the collection of data and writing (2.9%) [16]. One retrospective review of 14 patients who of the manuscript. All authors read and approved the final underwent PHP found 1 patient who had hepatic failure that manuscript. resulted in death [24]. There is limited knowledge regarding concurrent immunotherapy and PHP treatment, as patients undergo- References ing immunotherapy have been excluded from PHP RCTs [1] N. H. Matthews, W. Q. Li, A. A. Qureshi, M. A. Weinstock, [16]. However, there is a case report of a man who began and E. Cho, “Epidemiology of melanoma,” Exon Publications, immunotherapy with ipilimumab 10 weeks after PHP, vol. 30, pp. 3–22, 2017. resulting in gallbladder toxicity [25]. In our case, the [2] A. D. Singh, M. E. Turell, and A. K. Topham, “Uveal mela- patient had normal LFTs after receiving PHP and before noma: trends in incidence, treatment, and survival,” Ophthal- starting nivolumab. It was not until he received two doses mology, vol. 118, no. 9, pp. 1881–1885, 2011. of nivolumab that his LFTs began to quickly escalate. [3] E. Kujala, T. Mäkitie, and T. Kivelä, “Very long-term prognosis Given his prior PHP treatments, he may have been at of patients with malignant uveal melanoma,” Investigative increased risk for immune-related hepatitis from Ophthalmology & Visual Science, vol. 44, no. 11, pp. 4651– nivolumab. 4659, 2003. [4] K. M. Komatsubara and R. D. Carvajal, “Immunotherapy for the treatment of uveal melanoma: current status and emerging 4. Conclusion therapies,” Current Oncology Reports, vol. 19, no. 7, p. 45, 2017. [5] D. M. Pardoll, “The blockade of immune checkpoints in can- In conclusion, since fulminant hepatic failure from nivolu- cer immunotherapy,” Nature Reviews. Cancer, vol. 12, no. 4, mab alone is rare and PHP is also known to cause hepatic pp. 252–264, 2012. toxicity and hepatic failure, we believe that PHP preceding [6] V. A. Boussiotis, P. Chatterjee, and L. Li, “Biochemical signal- nivolumab contributed to fulminant hepatic failure. Health- ing of PD-1 on T cells and its functional implications,” Cancer care providers should use caution in starting immunotherapy Journal (Sudbury, Mass), vol. 20, no. 4, pp. 265–271, 2014. for patients who have previously received PHP therapy. [7] F. S. Hodi, V. Chiarion-Sileni, R. Gonzalez et al., “Nivolumab Careful monitoring of liver function tests and early interven- plus ipilimumab or nivolumab alone versus ipilimumab alone tion for hepatic deterioration should be implemented in all in advanced melanoma (CheckMate 067): 4-year outcomes of patients receiving immunotherapy. a multicentre, randomised, phase 3 trial,” The Lancet Oncol- ogy, vol. 19, no. 11, pp. 1480–1492, 2018. [8] J. Yang, D. K. Manson, B. P. Marr, and R. D. Carvajal, “Treat- Abbreviations ment of uveal melanoma: where are we now?,” Therapeutic Advances in Medical Oncology, vol. 10, article ALT: Alanine aminotransferase 1758834018757175, 2018. AST: Aspartate aminotransferase [9] C. Robert, G. V. Long, B. Brady et al., “Nivolumab in previ- CTLA-4: Cytotoxic T-lymphocyte-associated protein 4 ously untreated melanoma without BRAF mutation,” The LFT: Liver function test New England Journal of Medicine, vol. 372, no. 4, pp. 320– PD-1: Programmed death 1 receptor 330, 2015. PD-L1: Programmed death 1 receptor ligand [10] J. Naidoo, D. B. Page, B. T. Li et al., “Toxicities of the anti-PD-1 PHP: Percutaneous hepatic perfusion and anti-PD-L1 immune checkpoint antibodies,” Annals of RCT: Randomized controlled trial. Oncology, vol. 26, no. 12, pp. 2375–2391, 2015. [11] S. L. Topalian, F. S. Hodi, J. R. Brahmer et al., “Safety, activity, and immune correlates of anti–PD-1 antibody in cancer,” The Data Availability New England Journal of Medicine, vol. 366, no. 26, pp. 2443– 2454, 2012. The datasets generated and/or analyzed during the current [12] F. Gelsomino, G. Vitale, A. D’errico, C. Bertuzzi, P. Andreone, study are not publicly available due to individual privacy and A. Ardizzoni, “Nivolumab-induced cholangitic liver dis- but are available from the corresponding author on reason- ease: a novel form of serious liver injury,” Annals of Oncology, able request. vol. 28, no. 3, pp. 671-672, 2016. Case Reports in Oncological Medicine 5 [13] L. Spain, S. Diem, and J. Larkin, “Management of toxicities of immune checkpoint inhibitors,” Cancer Treatment Reviews, vol. 44, pp. 51–60, 2016. [14] E. M. de Leede, M. C. Burgmans, T. S. Meijer et al., “Prospec- tive clinical and pharmacological evaluation of the Delcath system’s second-generation (GEN2) hemofiltration system in patients undergoing percutaneous hepatic perfusion with mel- phalan,” Cardiovascular and Interventional Radiology, vol. 40, no. 8, pp. 1196–1205, 2017. [15] F. M. Moeslein, E. G. McAndrew, W. M. Appling et al., “Eval- uation of Delcath systems’ generation 2 (GEN 2) melphalan hemofiltration system in a porcine model of percutaneous hepatic perfusion,” Cardiovascular and Interventional Radiol- ogy, vol. 37, no. 3, pp. 763–769, 2014. [16] M. S. Hughes, J. Zager, M. Faries et al., “Results of a random- ized controlled multicenter phase III trial of percutaneous hepatic perfusion compared with best available care for patients with melanoma liver metastases,” Annals of Surgical Oncology, vol. 23, no. 4, pp. 1309–1319, 2016. [17] O. Abdel-Rahman, H. ElHalawani, and M. Fouad, “Risk of ele- vated transaminases in cancer patients treated with immune checkpoint inhibitors: a meta-analysis,” Expert Opinion on Drug Safety, vol. 14, no. 10, pp. 1507–1518, 2015. [18] J. S. Weber, K. C. Kähler, and A. Hauschild, “Management of immune-related adverse events and kinetics of response with ipilimumab,” Journal of Clinical Oncology, vol. 30, no. 21, pp. 2691–2697, 2012. [19] P. Bhave, A. Buckle, S. Sandhu, and S. Sood, “Mortality due to immunotherapy related hepatitis,” Journal of Hepatology, vol. 69, no. 4, pp. 976–978, 2018. [20] N. Fujiwara, S. L. Friedman, N. Goossens, and Y. Hoshida, “Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine,” Journal of Hepatology, vol. 68, no. 3, pp. 526–549, 2018. [21] S. Sarmen and S. Tara, “Acute liver failure from anti-PD-1 antibody nivolumab in a patient with metastatic lung squa- mous cell carcinoma,” Austin Oncology, vol. 1, no. 2, p. 1006, [22] T. Matsubara, T. Nishida, Y. Higaki et al., “Nivolumab induces sustained liver injury in a patient with malignant melanoma,” Internal Medicine, vol. 57, no. 12, pp. 1789–1792, 2018. [23] Z. Wu, L. Lai, M. Li, L. Zhang, and W. Zhang, “Acute liver fail- ure caused by pembrolizumab in a patient with pulmonary metastatic liver cancer: a case report,” Medicine, vol. 96, no. 51, p. e9431, 2017. [24] B. A. Boone, S. Perkins, R. Bandi et al., “Hepatic artery infusion of melphalan in patients with liver metastases from ocular melanoma,” Journal of Surgical Oncology, vol. 117, no. 5, pp. 940–946, 2018. [25] A. F. Idris, M. J. Martin, I. R. Davidson, G. J. O’Sullivan, A. A. Jamaludin, and P. P. Donnellan, “Ocular melanoma liver metastases treated by percutaneous hepatic perfusion with melphalan followed by ipilimumab: a case report,” Journal of Clinical Oncology, vol. 31, no. 15, article e20008, 2017. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma

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Copyright © 2021 Lindsey Teal and Jeffrey Yorio. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 8870334, 5 pages https://doi.org/10.1155/2021/8870334 Case Report Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma 1 2 Lindsey Teal and Jeffrey Yorio The University of Texas at Austin Dell Medical School, Austin, Texas, USA Texas Oncology, Austin, Texas, USA Correspondence should be addressed to Jeffrey Yorio; jeff.yorio@usoncology.com Received 28 April 2020; Revised 1 March 2021; Accepted 11 March 2021; Published 30 March 2021 Academic Editor: Ossama W. Tawfik Copyright © 2021 Lindsey Teal and Jeffrey Yorio. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP. FDA-approved standard of care for metastatic uveal mela- 1. Introduction noma [8]. Melanoma incidence continues to rise, and unresectable met- Immune checkpoints mediate immune response and pre- astatic melanoma is associated with high mortality [1]. Uveal vent tissue damage [5]. Immune checkpoint receptors, such melanoma is a rare subtype of melanoma that progresses to as PD-1 and CTLA-4, serve as an “off switch” for T-cell func- metastatic disease in over 50% of patients [2]. Approximately tions in tissues, such as destroying other cells [6]. Tumor cells 20-30% of patients will die of systematic metastases within 5 take advantage of this by upregulating ligands for PD-1, years of being diagnosed [3]. The development of immune thereby blocking the antitumor response. Anti-PD-1 inhibi- checkpoint inhibitors, particularly those targeting cytotoxic tors block this PD-1 pathway and serve as an “on switch” T-lymphocyte-associated antigen 4 (CTLA-4) and pro- to allow for the antitumor response to take place and cause tumor regression. grammed cell death-1 (PD-1), has dramatically improved long-term prognosis for patients with advanced cutaneous Anti-PD-1 inhibitors, such as nivolumab, serve as an melanomas [4–7]. However, responses in advanced uveal ideal treatment option for uveal melanoma due to their low melanoma have been very limited, so there remains no side effect profile. However, anti-PD-1 inhibitors have been 2 Case Reports in Oncological Medicine involving the entire liver rather than progression of metasta- known to induce relatively mild immune-related adverse events (irAEs) such as fatigue, pruritis, and arthritis [9, 10]. tic disease which would have shown more heterogeneous Serious adverse events occur in <10% of patients taking nivo- FDG avidity corresponding to the sites of tumor activity lumab and include interstitial pneumonitis, hepatitis, hypo- (Figure 2). thyroidism, diarrhea/colitis, adrenal insufficiency, and The patient was admitted to the hospital, and further lab pituitary insufficiency [9, 11, 12]. The incidence of grade 3 workup including anti-nuclear antibodies, anti-smooth mus- or 4 immune-related hepatitis is only seen in about 1% of cle antibodies, anti-liver kidney antibodies, anti- patients, while fulminant hepatic failure has only rarely been mitochondrial antibodies, and IgG levels was all unremark- able. The patient was started on high-dose intravenous Solu- reported [9, 13]. Chemosaturation with percutaneous hepatic perfusion medrol and liver function tests (LFTs), and symptoms (PHP) is a therapy that delivers chemotherapy in high doses initially improved during his first few hospital days. How- directly to the liver with the goal of targeting hepatic metas- ever, on the fourth hospital day (day 26 in Figure 1), his con- tases [14, 15]. One phase III randomized trial in patients pri- dition dramatically declined. His LFTs rose rapidly to the marily with uveal melanoma with liver metastases thousands, resulting in fulminant liver failure. He then devel- demonstrated a significant improvement in progression- oped acute renal failure, anion gap metabolic acidosis, and free survival (PFS) from 1.6 months to 5.4 months when hyperkalemia. The patient was placed on a bicarbonate drip, compared to the best available care. Further clinical trials and efforts were made to reverse his acidosis to stabilize him; are being done in the United States, but it is currently used however, his condition continued to decline and LFTs con- tinued to worsen (AST: 7,708 U/L, ALT: 3,131 U/L, alkaline as a treatment for uveal melanoma in other countries [16]. Early animal studies have shown high rates of bone marrow phosphatase: 817 U/L, and total bilirubin: 11.9 mg/dL). depression, but studies have not measured the effect it may Mycophenolate mofetil 1,000 mg IV was administered with have when given with immunotherapy [15]. no improvement. The patient was not a liver transplant can- We present the case of a patient with metastatic uveal didate because of his metastatic cancer diagnosis. The fulmi- nant hepatic failure was irreversible and led to death melanoma treated with PHP followed by nivolumab who developed fulminant hepatic failure. secondary to cardiorespiratory arrest. 2. Case Presentation 3. Discussion A 46-year-old man with no significant past medical history presented with blurry vision and was ultimately diagnosed To our knowledge, this is the first reported case of fulminant with choroidal melanoma of the right eye. He underwent pla- hepatic failure secondary to nivolumab in a patient with prior que brachytherapy and was followed with surveillance imag- PHP treatment. Immune-related hepatitis from PD-1 inhib- ing. Fifteen months after his original diagnosis, MRI itors is usually mild-to-moderate and self-limited, but in less abdomen revealed multiple hepatic lesions. A CT-guided than 1.0% of the patients, the hepatitis is considered severe liver biopsy of one of the lesions was performed, and pathol- [17]. This is a result of impaired self-tolerance from the loss ogy confirmed metastatic uveal melanoma. Initial staging of T-cell inhibition and can lead to autoimmune-related showed only liver metastases. The patient travelled to the inflammation in normal, noncancerous tissues. These United Kingdom and received four cycles of chemosatura- adverse events can usually be treated by modulating the tion with PHP using high-dose melphalan over a 6-month immune system with steroids or other immunosuppressing period. Repeat imaging initially showed a partial response agents, but in some cases, such as this one, it can be fatal. to this treatment in the liver. After 6 months, the patient Mild-to-moderate hepatitis usually occurs between 6 and started to complain of rib pain and back pain. A PET/CT 14 weeks after starting treatment; however, the patient in our scan revealed diffuse bony metastases. He was treated with case developed hepatitis in under 4 weeks after starting treat- palliative radiation prior to initiation of nivolumab at ment [18]. One study found that liver toxicity was most com- 3 mg/kg every two weeks. monly seen after 2 to 6 cycles of nivolumab, which aligns Shortly after the first cycle of nivolumab, he began having with our case [17]. However, there is no established timeline mild right upper quadrant pain, low-grade fevers, diaphore- for fulminant liver failure, as it is rare and has only been sis, and fatigue. Two weeks later, he was given a second dose reported a handful of times in the literature. One case of ful- of nivolumab. Then, one week after that, his right upper minant hepatic failure due to nivolumab was reported in quadrant abdominal pain worsened, and he was found to October 2018 [19]. However, this patient was also taking a have an aspartate aminotransferase (AST) level of 310 U/L, CTLA-4 inhibitor, ipilimumab, concurrently. The combina- alanine aminotransferase (ALT) of 187 U/L, alkaline phos- tion of CTLA-4 and PD-1 blockade is known to cause a phatase of 713 U/L, and total bilirubin of 3.8 mg/dL higher incidence of hepatitis than single-drug immunother- (Figure 1). Clinical exam revealed marked hepatomegaly. apy, with the incidence being 6.9% and 1%, respectively Given his extensive liver metastases, there was an initial ques- [20]. Another patient taking nivolumab after carboplatin tion about progression of his disease versus an autoimmune and gemcitabine suffered from fulminant hepatic failure hepatitis, so a PET/CT scan was performed revealing an [21]. In 2018, a patient with malignant melanoma underwent enlarged liver along with diffusely homogenous uptake in 17 cycles of nivolumab before developing grade 4 ALT eleva- the liver. This suggested a diffuse inflammatory process tion [22]. After steroids, his ALT did not recover to normal Case Reports in Oncological Medicine 3 >2000 ⁎ ⁎ ⁎ Day 1 Day 14 Day 19 Day 20 Day 22 Day 23 Day 24 Day 25 Day 26 AST ALT Alkaline phosphatase Figure 1: Liver function tests before, during, and after 2 cycles of nivolumab. The dates are numbered starting with the first day of the first st cycle of nivolumab. AST: aspartate aminotransferase; ALT: alanine aminotransferase; day 1∗: start of the 1 cycle of nivolumab; day 14∗: start nd st of the 2 cycle of nivolumab; day 22∗:1 dose of corticosteroids. The graph shows the rapid increase in liver function tests after the patient began taking nivolumab and the minor response after being treated with corticosteroids. It also depicts the timeline until the patient perspired. (a) (b) Figure 2: PET/CT scan of the abdomen. (a) One month prior to the first cycle of nivolumab: multiple intrahepatic lesions. (b) Day 22 after the first cycle of nivolumab: significant hepatomegaly due to hepatitis, significant increased metabolic activity of the entire liver, and new abdominal ascites. The PET/CT scan of the patient abdomen depicts the changes in the patient’s liver before and after starting nivolumab. The second picture shows the large size of the liver when the patient developed autoimmune hepatitis. U/L 4 Case Reports in Oncological Medicine range, even after 5 months. Fulminant hepatic failure has also Consent been seen with the PD-1 inhibitor, pembrolizumab [23]. Consent for publication was unable to be obtained from fam- In this case, the patient had been previously exposed to ily members after multiple attempts. No identifiers have been PHP to treat liver metastases from uveal melanoma. As dis- used. cussed above, in phase 3 randomized controlled trials (RCTs), PHP has been shown to be efficacious when com- pared to chemotherapy, but it can also lead to adverse events. Conflicts of Interest One RCT found the rate of grade 3 or 4 hepatic dysfunction, The authors declare that they have no conflicts of interest. diagnosed by hyperbilirubinemia, to be 14.3% [16]. There were also 5.7% of patients in the RCT that discontinued treat- ment because of hepatic toxicity, diagnosed by hyperbilirubi- Authors’ Contributions nemia (5.7%), increase in ALT (2.9%), and increase in AST All authors contributed to the collection of data and writing (2.9%) [16]. One retrospective review of 14 patients who of the manuscript. All authors read and approved the final underwent PHP found 1 patient who had hepatic failure that manuscript. resulted in death [24]. There is limited knowledge regarding concurrent immunotherapy and PHP treatment, as patients undergo- References ing immunotherapy have been excluded from PHP RCTs [1] N. H. Matthews, W. Q. Li, A. A. Qureshi, M. A. Weinstock, [16]. However, there is a case report of a man who began and E. Cho, “Epidemiology of melanoma,” Exon Publications, immunotherapy with ipilimumab 10 weeks after PHP, vol. 30, pp. 3–22, 2017. resulting in gallbladder toxicity [25]. In our case, the [2] A. D. Singh, M. E. Turell, and A. K. Topham, “Uveal mela- patient had normal LFTs after receiving PHP and before noma: trends in incidence, treatment, and survival,” Ophthal- starting nivolumab. It was not until he received two doses mology, vol. 118, no. 9, pp. 1881–1885, 2011. of nivolumab that his LFTs began to quickly escalate. [3] E. Kujala, T. Mäkitie, and T. Kivelä, “Very long-term prognosis Given his prior PHP treatments, he may have been at of patients with malignant uveal melanoma,” Investigative increased risk for immune-related hepatitis from Ophthalmology & Visual Science, vol. 44, no. 11, pp. 4651– nivolumab. 4659, 2003. [4] K. M. Komatsubara and R. D. Carvajal, “Immunotherapy for the treatment of uveal melanoma: current status and emerging 4. 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Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: Mar 30, 2021

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