Percutaneous Hepatic Perfusion Melphalan Induced Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease) in a Patient with Metastatic Uveal Melanoma

Abstract

Introduction

Percutaneous hepatic perfusion using the HEPZATO KIT^™ (Delcath Systems, Inc., Queensbury, NY) is a US Food and Drug Administration approved treatment for liver metastases from uveal melanoma. We discuss the development of sinusoidal obstruction syndrome/veno-occlusive disease after treatment using percutaneous hepatic perfusion.

Case Presentation

The patient is a 49-year-old male with a history of hepatic metastatic uveal melanoma. Despite several rounds of trans-arterial chemoembolization, the patient had progression of liver disease and was then treated with percutaneous hepatic perfusion. Several weeks later, the patient was found to have liver injury and was diagnosed with biopsy-proven sinusoidal obstruction syndrome. He was treated with defibrotide and symptoms resolved, but passed away several months later due to progression in metastatic disease.

Conclusion

To our knowledge, this represents the first case of sinusoidal obstruction syndrome after melphalan administration for percutaneous hepatic perfusion. Rapid progression of disease versus sinusoidal obstruction disease must be considered in patients who present with signs of liver injury/failure after this procedure as prompt diagnosis and treatment are crucial.

Introduction

Though rare, uveal melanoma (UM) is the most common intraocular malignancy in adults. Approximately half of patients with UM develop metastatic disease (metastatic UM [mUM]), with about 90% of cases metastatic to the liver. Since most patients eventually succumb due to liver failure from metastases, the National Comprehensive Cancer Network recommends various liver-directed therapies, including percutaneous hepatic perfusion (PHP), to prolong survival [1].

PHP was approved by the US Food and Drug Administration (FDA) in August 2023 for the treatment of mUM in patients with unresectable hepatic tumors affecting less than 50% of the liver [2]. PHP uses a hepatic delivery system designed to saturate the liver with melphalan. Early results show promising response rates and a favorable benefit-risk profile [1]. Using veno-veno bypass, blood flows from the hepatic veins into the inferior vena cava isolated by a double-balloon catheter, allowing flow through filtration cartridges extracting melphalan before returning blood to the patient (Fig. 1).

Fig. 1.

Digital subtraction angiography (a) and angiography on bone windows (b) demonstrate inflation of the double-balloon catheter (white arrowheads) isolating the hepatic venous drainage (white arrow) allowing flow through filtration cartridges before returning the blood systemically.

Melphalan is an alkylating agent historically used in the treatment of hematological malignancies such as multiple myeloma [3]. Myelosuppression, hypersensitivity reactions, gastrointestinal toxicities, secondary malignancies, embryo-fetal toxicities, and infertility are reported melphalan side effects following PHP [2]. van Iersel et al. [4] have described additional toxicities of melphalan use in isolated hepatic perfusion, including development of veno-occlusive disease (VOD) in 4 patients, although none were diagnosed by a pathological basis. Alkylating agents have been implicated in the development of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) when used to induce myelosuppression [5]. To our knowledge, this represents the first reported case of biopsy-proven SOS/VOD due to melphalan use in PHP.

Case Presentation

A 49-year-old man underwent proton beam radiation for a left choroidal melanoma in April 2018. Gene expression profiling revealed Castle Class 1A, PRAME negative. His HLA-A*02:01 status was negative. Imaging detected a 2.1-cm segment 6 metastasis in November 2022, which was surgically resected in January 2023. A repeat MRI in May 2023 demonstrated additional right lobe metastases. He underwent immunoembolization [6] of the right hepatic lobe in May 2023. Substantial tumor progression was seen angiographically during repeat treatment in June 2023 necessitating treatment with 1,3-bis (2-chloroethyl)-1-nitroso-urea chemoembolization [7]. He received six lobar chemoembolization treatments from July 2023 to February 2024 with repeat MR imaging after every two procedures. Imaging in February 2024 (Fig. 2) noted progression of hepatic metastases, and the decision was made to proceed with PHP in April and May 2024. The procedures were performed in accordance with the manufacturer’s guidance with administration of 220 mg of melphalan during each procedure. There were no immediate procedural complications, and he was discharged the day after each PHP procedure.

Fig. 2.

Contrast-enhanced MRI of the abdomen pre-PHP. Axial (a) and coronal (b) imaging showing hypointense hepatic metastatic disease (red arrows) throughout the liver, but predominantly in the right hepatic lobe.

Post-procedure day (PPD) 7 after the second PHP, he presented with fever to 103.5 F and nausea. Pertinent laboratory values included WBC 11.2 k/μL and mildly elevated liver function tests (LFTs). He was treated with intravenous antibiotics and discharged the next day in stable condition. He was readmitted with fever to 103.0 F, abdominal fullness, severe lower extremity edema, weight gain, and nausea on PPD 11. On this admission, he had a leukocytosis of 15.1 k/μL and elevated LFTs with a total bilirubin 2.7 mg/dL, AST 329 U/L, ALT 222 U/L, and ALP 269 U/L. MRI demonstrated heterogeneous hepatic enhancement and decreased size of hepatic metastatic disease (Figs. 3; 4). He underwent a transjugular liver biopsy on PPD 16 demonstrating a portosystemic gradient of 9 mm Hg, central sinusoidal dilation, hemorrhage, and necrosis, consistent with SOS/VOD (Fig. 5). He received treatment with a 14-day course of defibrotide and was discharged on PPD 33. On discharge, he had normal LFTs except for an elevated ALP to 639 U/L. He remained well without symptoms related to SOS/VOD for 2 months. Imaging in August 2024 showed disease progression, and he was started on ipilimumab and nivolumab but passed away 5 weeks later.

Fig. 3.

Contrast-enhanced axial MRI of the abdomen demonstrates heterogeneous enhancement (white arrows) of the liver parenchyma which may be seen in hepatic SOS/VOD [8].

Fig. 4.

Contrast-enhanced MRI of the abdomen post-PHP. Axial (a) and coronal (b) MRI images showing markedly decreased size of hepatic metastatic disease (red arrows). Of note, there is new gallbladder wall thickening (open white arrow), which is likely related to reactive edema from hepatitis. There is heterogeneous enhancement of the liver parenchyma (white arrow) which may be seen in SOS/VOD.

Fig. 5.

a H&E stain shows central hepatocellular necrosis and hemorrhage. It is difficult to see terminal hepatic venules. b PAS-D stain shows central hepatocellular necrosis with ceroid-laden macrophages and outline of terminal hepatic venules. c Trichrome stain shows central hepatocellular young collagen and outline of the terminal hepatic venules. H&E, hematoxylin and eosin; PAS-D, periodic acid-Schiff-diastase.

Discussion

SOS/VOD is a potentially life-threatening complication which acutely presents with symptoms of post-sinusoidal portal hypertension, including weight gain, ascites, tender hepatomegaly, and jaundice [5]. SOS/VOD is most commonly observed in bone marrow transplant patients because of preconditioning prior to transplantation with intravenous chemotherapy, which includes melphalan, although SOS/VOD has been observed in patients receiving immunotherapy or antibody drug conjugates [9–11]. SOS/VOD has also been observed in patients outside of the post-hematopoietic cell transplant population in treatment of solid organ tumors [12]. The proposed pathophysiology of SOS/VOD involves damage of the sinusoidal endothelial cells leading to the egress of red blood cells, leukocytes, and cellular debris into the space of Disse [9, 11]. This buildup causes dissection of the endothelial lining leading to sloughing and outflow obstruction [5, 9, 11]. Subacute and chronic SOS/VOD may present with nonspecific symptoms, including fatigue and abdominal swelling [5]. Laboratory values are typically consistent with hepatocellular pattern of enzyme elevation.

Because untreated SOS/VOD can be life threatening, with a mortality rate of over 80%, therapy must be initiated as soon as possible [9]. Treatment is guided by diagnostic criteria and severity scoring assessment, such as the European Society for Blood and Marrow Transplantation diagnostic and severity criteria [11, 13]. Based on clinical symptoms and laboratory values for patients 21 days post-stem cell transplantation, these gold standard criteria allow for the early diagnosis of SOS/VOD to initiate treatment without the need for tissue diagnosis. In certain patients, liver biopsy and concurrent measurement of hepatic venous pressure may be performed to confirm SOS/VOD [4].

Treatment of SOS/VOD involves either preventative therapy or curative therapy. Pharmacological measures, including the use of unfractionated heparin and ursodeoxycholic acid, used to prevent SOS/VOD are controversial, and prior meta-analyses have shown no overall significant benefit to prophylactic treatment [9]. Primary treatment of SOS/VOD involves management of symptoms which includes treatment of fluid balance and electrolyte abnormalities using diuretics, percutaneous fluid drainage, and, rarely, hemodialysis and/or transjugular intrahepatic portosystemic shunt placement. The only proven treatment for SOS/VOD is defibrotide, which is an oligonucleotide, and is approved for treatment of SOS/VOD in the post-hematopoietic cell transplant population [9, 11]. While the mechanism of action is uncertain, defibrotide likely exerts protection of endothelial cells via anti-ischemic and local antithrombotic effects. Prior studies have shown improved complete response rates in patients treated with defibrotide compared with historical controls leading to its European and FDA approval for SOS/VOD treatment [9, 14].

Since patients who receive PHP for mUM have baseline liver dominant metastases, rapid progression of disease versus SOS/VOD must be considered in patients who present with signs of liver injury/failure post-PHP. Early diagnosis and treatment are crucial as mortality is high for patients with SOS/VOD.

Statement of Ethics

This study protocol was reviewed, and the need for approval was waived by the Jefferson Institutional Review Board. Written informed consent was obtained for participation in this study by the patient’s next of kin. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000547005).

Conflict of Interest Statement

R.D.A., M.O., and D.J.E. are consultants for Delcath Systems, Inc.

Funding Sources

This study was not supported by any funding.

Author Contributions

S.S.L., C.F.G., and D.J.E. all contributed to the writing of the manuscript. M.O., R.D.A., and C.C.L. all contributed to the review and editing of the manuscript.

Funding Statement

This study was not supported by any funding.

Data Availability Statement

The patient(s) data that support the findings of this study are not publicly available due to HIPAA, but are available from the Jefferson Institutional Review Board upon reasonable request.