Novel treatment of Yttrium-90 radioembolization-induced liver disease (REILD) with defibrotide in a pediatric liver transplant recipient

Novel treatment of Yttrium-90 radioembolization-induced liver disease (REILD) with defibrotide in a pediatric liver transplant recipient | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 5 May 2025 V1 Latest version Share on Novel treatment of Yttrium-90 radioembolization-induced liver disease (REILD) with defibrotide in a pediatric liver transplant recipient Authors : Elise Kang [email protected] , Mercedes Martinez , Diane George , Sidney Brejt , Michael Lee , Darrel Yamashiro , Amanda Cantor , Urvi Kapoor , Steven Lobritto , Joshua Weintraub , and Pooja Reddy Spector Authors Info & Affiliations https://doi.org/10.22541/au.174644503.32180962/v1 473 views 190 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Radioembolization with yttrium-90 (Y-90) microspheres is primarily used in liver tumor patients with suboptimal response to chemotherapy. Radioembolization-induced liver disease (REILD) is a potentially fatal complication of Y-90 radioembolization (Y-90 RE). The clinical presentation of REILD mimics sinusoidal obstructive syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), sharing features including hyperbilirubinemia, coagulopathy, and ascites. While SOS/VOD in pediatric bone marrow transplant recipients is commonly treated with defibrotide, no standardized guidelines exist for the treatment of REILD. We present a case of a pediatric liver transplant recipient who developed REILD after Y-90 RE and was successfully treated with defibrotide. Novel treatment of Yttrium-90 radioembolization-induced liver disease (REILD) with defibrotide in a pediatric liver transplant recipient Elise Kang 1 , Mercedes Martinez 1 , Diane George 2 , Sidney Z Brejt 3 , Michael Lee 4 , Darrell J. Yamashiro 2,4 , Amanda Cantor 1 , Urvi Kapoor 2 , Steven Lobritto 1 , Joshua Weintraub 3 , Pooja Reddy Spector 1 1. Columbia University Irving Medical Center, Department of Pediatrics, New York, USA. 2. Columbia University Irving Medical Center, Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, New York, USA. 3. Columbia University Irving Medical Center, Division of Interventional Radiology, Columbia University Irving Medical Center, New York, USA. 4. Columbia University Irving Medical Center, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, USA. Corresponding author: Elise Kang, MD MS [email protected] Word Count: Abstract: 99, Main Text: 1000 2 Figures (Image 1, Image 2) Short running title : Defibrotide for radioembolization induced liver disease Keywords : Yttrium-90, radioembolization, radioembolization induced liver disease, sinusoidal obstructive syndrome, vaso-occlusive disease, Defibrotide Y-90 Yttrium-90 REILD Radioembolization-induced liver disease SOS Sinusoidal obstructive syndrome BMT Bone Marrow Transplant VOD Veno-occlusive disease AFP Alpha-fetoprotein C5VD cisplatin, 5-Fluorouracil, vincristine, and doxorubicin NOS Not otherwise specified HSCT Hematopoietic stem cell transplantation This case report will be presented at the Annual Meeting of the Society of Pediatric Liver Transplantation (SPLIT) on May 1, 2025 in Washington, DC. Abstract Radioembolization with yttrium-90 (Y-90) microspheres is primarily used in liver tumor patients with suboptimal response to chemotherapy. Radioembolization-induced liver disease (REILD) is a potentially fatal complication of Y-90 radioembolization (Y-90 RE). The clinical presentation of REILD mimics sinusoidal obstructive syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), sharing features including hyperbilirubinemia, coagulopathy, and ascites. While SOS/VOD in pediatric bone marrow transplant recipients is commonly treated with defibrotide, no standardized guidelines exist for the treatment of REILD. We present a case of a pediatric liver transplant recipient who developed REILD after Y-90 RE and was successfully treated with defibrotide. Introduction Radioembolization (RE) with yttrium-90 (Y-90) labeled microspheres is a relatively novel treatment modality for pediatric liver malignancies with poor response to systemic chemotherapy 1,2 . While the hepatic arterial system primarily supplies liver tumors, the portal vein supplies mainly liver parenchyma. Y-90 RE allows for targeted therapy with relative sparing of liver parenchyma. Microsphere deposition in non-tumorous parenchyma can also result in radioembolization-induced liver disease (REILD). Symptomatic REILD is a debilitating, potentially lethal condition 3 with a similar clinical and histopathological presentation to sinusoidal obstructive syndrome (SOS), previously known as hepatic veno-occlusive disease (VOD), seen in bone marrow transplant (BMT) recipients 4 . We present a case of a pediatric liver transplant patient who developed REILD after Y-90 RE and successfully treated with defibrotide. Case Description A 3-year-old male presented with non-metastatic PRETEXT-III presumed hepatoblastoma with portal vein thrombosis and alpha-fetoprotein (AFP) hepatocellular neoplasm not otherwise specified (NOS). Tumor was unresectable after four cycles of chemotherapy with cisplatin, 5-Fluorouracil, vincristine, and doxorubicin (C5VD) the team decided to proceed with liver transplantation. Unfortunately, AFP continued to uptrend, leading to two extra cycles of chemotherapy and chemoembolization before receiving a whole deceased donor liver transplant five months after initial diagnosis followed by adjuvant chemotherapy (Image 1) . Resected tissue demonstrated hepatocellular neoplasm NOS, consistent with a hybrid hepatoblastoma and hepatocellular carcinoma (Image 2A, 2B). Post liver transplant, he received two additional cycles of C5VD. The AFP, however, failed to normalize, and he subsequently received three cycles of carboplatin and etoposide. Rising AFP ( Image 1) and histology ( Image 2C, 2D) of four resected perihepatic nodules eleven months post-transplant supported the diagnosis of recurrent disease. He resumed chemotherapy with cisplatin and Vorinostat. An MRI demonstrating multifocal perihepatic nodules 15 months post-transplant supported diagnosis of second recurrence. Given disease extent, the decision was made to pursue Y-90 RE. After initial mapping procedure with an MAA Tc-99m arteriogram, 30mCi of local radiation was administered into the right hepatic artery. Six weeks later, he received additional Y-90 to the left hepatic artery with 6.13mCi of radiation. Eight weeks after the last Y-90 treatment, his liver enzymes rose: AST-655 ALT-299, Tbili-1.2/Dbili-0.6, INR-2.0. Imaging showed new-onset ascites and ascitic fluid analysis was consistent with portal hypertension without evidence of malignancy. Liver biopsy demonstrated diffuse sinusoidal congestion consistent with SOS/VOD ( Image 2E) and patchy sinusoidal fibrosis (Image 2F) . Given a similar pathophysiology to SOS/VOD after BMT, defibrotide (6.25 mg/kg/dose every 6 hours) was administered for a shortened course of 18 days due to bleeding risk, with resolution of symptoms. Bilirubin peaked at Tbili-2.7/Dbili-1.2. Labs at discharge: INR-1.1 AST-57 ALT-32 and Tbili-1.5/Dbili-0.6. Now, nine months after Y-90, he has no recurrence of ascites, minimal transaminitis, and INR <2. Discussion While treatment of liver tumors has advanced over the past decades, treatment options are limited for chemo-refractory, unresectable tumors. For select patients with liver tumors, Y-90 RE may be used for primary therapy, downstaging of lesions, a bridge to resection or liver transplantation or as palliative treatment for tumor burden control 2,5 . Although Y-90 is generally well tolerated, REILD is a potentially fatal, rare complication 6 . To our knowledge, we present the first case of a pediatric patient developing Y-90 likely secondary to REILD 7-12 and the first case of Y-90-induced REILD treated with defibrotide. As liver tumors predominantly rely on hepatic arterial blood supply while native liver relies mainly on portal vein flow, Y-90 RE provides targeted therapy with injection of microspheres containing radioactive isotope Y-90 into the hepatic artery, getting delivered directly to tumoral tissue with limited exposure to normal hepatic parenchyma. Despite such reduced radiation exposure, REILD still occurs in 0-5.4% of patients undergoing Y-90 with a mortality of 0-5% 3,14,15 . REILD shares features with SOS/VOD, a life-threatening complication that occurs in approximately 13% of patients undergoing hematopoietic stem cell transplantation 16,17 . In BMT patients, SOS/VOD may occur due to the conditioning regimen and subsequent immune mediated injury of sinusoidal endothelial cells. Sloughing of damaged endothelial cells may cause sinusoidal obstruction and hepatic congestion leading to hepatocellular damage. Similarly, in REILD, radiation is thought to induce sinusoidal endothelial damage, which induces a hypercoagulable state in the central veins and hepatic sinusoids. Congestion in peri-portal areas ultimately leads to loss of centrilobular hepatocytes, leading to SOS/VOD 18 . In 2016, Defibrotide was approved by the FDA 19 as a drug for treating severe SOS/VOD after HSCT 20,21 . Defibrotide is a mixture of single-stranded polydeoxyribonucleotides, derived from porcine DNA, with antithrombotic, anti-inflammatory, and profibrinolytic properties that mitigate endothelial damage 22 . In patients with SOS/VOD with multi-organ failure, defibrotide has been shown to have significant survival benefits and response rates with tolerable side effects 20 . Given the overlapping pathology of SOS/VOD after HSCT and REILD after Y90 RE, the potential use of defibrotide has been proposed but not reported for patients with severe REILD 23 . Risk of REILD may vary depending on prior exposure to chemotherapy, liver function reserve, and the amount of radiation exposure 15 . Our patient had extensive exposure to chemotherapy, likely placing him at higher risk for REILD. Strategies to minimize radiation include modifying radiation dosage depending on remnant liver volume and health of the liver, selective catheterization, and waiting at least six weeks between treatments. With a questionnaire-based study, Powerski et al. suggested administering prophylactic steroids for one week after RE to minimize REILD 24 . Gil-Alzugaray et al. demonstrated reduced REILD by administering ursodeoxycholic acid for 2 months and methylprednisolone 8mg daily for 1 month followed by a taper after Y90 15 . However, this protocol also modified the amount of radiation, making it difficult to ascertain if medications or reduced radiation minimized REILD risk. Within a few days of our patient developing symptoms of REILD, prompt histopathological diagnosis was made. Per multidisciplinary discussion, we decided to administer defibrotide given its success in BMT patients. Given the similar pathophysiology of REILD and hepatic SOS/VOD after HSCT, we propose that defibrotide may be a potential endothelial-sparing agent to treat REILD after Y90 as demonstrated by the success in this case. Future prospective studies are needed to evaluate defibrotide’s safety and efficacy for REILD treatment. Conflict of Interest There are no conflicts of interests to declare. Acknowledgements We would like to acknowledge and thank our patient and his family who graciously agreed to sharing his case. References 1. Salem R, Gordon AC, Mouli S, et al. Y90 Radioembolization Significantly Prolongs Time to Progression Compared With Chemoembolization in Patients With Hepatocellular Carcinoma. Gastroenterology 2016;151(6):1155-1163.e2. (In eng). DOI: 10.1053/j.gastro.2016.08.029.2. Salem R, Johnson GE, Kim E, et al. Yttrium-90 Radioembolization for the Treatment of Solitary, Unresectable HCC: The LEGACY Study. Hepatology 2021;74(5):2342-2352. (In eng). DOI: 10.1002/hep.31819.3. Braat MN, van Erpecum KJ, Zonnenberg BA, van den Bosch MA, Lam MG. Radioembolization-induced liver disease: a systematic review. Eur J Gastroenterol Hepatol 2017;29(2):144-152. (In eng). DOI: 10.1097/meg.0000000000000772.4. Guha C, Kavanagh BD. Hepatic radiation toxicity: avoidance and amelioration. Semin Radiat Oncol 2011;21(4):256-63. (In eng). DOI: 10.1016/j.semradonc.2011.05.003.5. Gabr A, Kulik L, Mouli S, et al. Liver Transplantation Following Yttrium-90 Radioembolization: 15-Year Experience in 207-Patient Cohort. Hepatology 2021;73(3):998-1010. (In eng). 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A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993;45(2):259-94. (In eng). DOI: 10.2165/00003495-199345020-00007.23. Sangro B, Martínez-Urbistondo D, Bester L, et al. Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review. Hepatology 2017;66(3):969-982. (In eng). DOI: 10.1002/hep.29207.24. Powerski MJ, Scheurig-Münkler C, Banzer J, Schnapauff D, Hamm B, Gebauer B. Clinical practice in radioembolization of hepatic malignancies: a survey among interventional centers in Europe. Eur J Radiol 2012;81(7):e804-11. (In eng). DOI: 10.1016/j.ejrad.2012.04.004. Image 1 Image 2: Histopathology from Liver Explant and from Recurrence of Hepatic Malignancy LEGENDS Image 1A: Timeline of Alpha Fetoprotein Trends Before and After Orthotopic Liver Transplantation. Abbreviations: AFP (alpha fetoprotein), OLT (orthotopic liver transplantation), C5VD (cisplatin, 5-flourouracil, vincristine, doxorubicin), Y-90 (yttrium-90) Image 2. 2A: Liver Explant, hepatocellular neoplasm not otherwise specified (NOS). Malignant hepatocellular neoplasm with high grade, pleomorphic nuclei (H&E stain, 100X). 2B: Liver explant, hepatocellular neoplasm NOS. Prominent pseudoacini, a morphologic feature of hepatocellular carcinoma (H&E stain, 400X). 2C: Peritoneal nodule. Hepatoblastoma (left) and hepatocellular carcinoma (right) with patchy necrosis (H&E stain, 100X). 2D: Peritoneal nodule. Hepatoblastoma with markedly pleomorphic nuclei, scattered mitotic figures and patchy necrosis (H&E stain, 200X). 2E : Sinusoidal congestion and dilatation of vaso-occlusive disease (H&E stain, 100X). 2F: Trichrome stain highlighting patchy sinusoidal fibrosis (Trichrome stain, 90X). Information & Authors Information Version history V1 Version 1 05 May 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords hepatoblastoma liver pathology pediatric oncology radiation therapy transplantation tumors veno-occlusive disease Authors Affiliations Elise Kang [email protected] Columbia University Department of Pediatrics View all articles by this author Mercedes Martinez Columbia University Department of Pediatrics View all articles by this author Diane George Columbia University Department of Pediatrics View all articles by this author Sidney Brejt New York-Presbyterian/Columbia University Irving Medical Center View all articles by this author Michael Lee Columbia University Department of Pathology and Cell Biology View all articles by this author Darrel Yamashiro Columbia University Department of Pediatrics View all articles by this author Amanda Cantor Columbia University Department of Pediatrics View all articles by this author Urvi Kapoor Columbia University Department of Pediatrics View all articles by this author Steven Lobritto Columbia University Department of Pediatrics View all articles by this author Joshua Weintraub New York-Presbyterian/Columbia University Irving Medical Center View all articles by this author Pooja Reddy Spector Columbia University Department of Pediatrics View all articles by this author Metrics & Citations Metrics Article Usage 473 views 190 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Elise Kang, Mercedes Martinez, Diane George, et al. Novel treatment of Yttrium-90 radioembolization-induced liver disease (REILD) with defibrotide in a pediatric liver transplant recipient. Authorea . 05 May 2025. DOI: https://doi.org/10.22541/au.174644503.32180962/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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