Case Report
Successful Treatment of Paraneoplastic Cholestasis in Relapsed/Refractory Hodgkin Lymphoma With Bridging Therapy and Checkpoint Blockade

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Introduction

Paraneoplastic cholestasis (PC) is a rare manifestation of Hodgkin lymphoma (HL). It is comprised of 2 distinct pathologic entities: vanishing bile duct syndrome (VBDS) and idiopathic cholestasis (IC) without ductopenia. There are less than 20 published cases of IC in HL, with none reported in relapsed HL. Treatment of PC is challenging as many chemotherapeutic agents are metabolized by the liver. There is no literature available regarding the treatment of IC in relapsed HL. Here, we present the first report of successful treatment of a patient with IC in the setting of relapsed HL post autologous stem cell support (ASCT) with bridging therapy (cyclophosphamide, methylprednisolone) and sequential nivolumab.

A 37-year-old Caucasian woman with relapsed/refractory HL presented with gradual onset yellowing of eyes and skin, fatigue, and cola-colored urine for 2 months. She developed extreme fatigue and lost 10 pounds during this period but denied abdominal pain, fever, nausea, or vomiting. She had initially been diagnosed with mixed cellularity classical HL 4 years previously, when she presented with painless cervical lymphadenopathy and intense pruritus while 20 weeks pregnant. She had no laboratory evidence of liver involvement at diagnosis; staging scans could not be performed owing to her gravid state. She received 3 cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) followed by successful delivery of a healthy baby girl at 32 weeks gestation. Thereafter, she completed 3 additional cycles of ABVD and achieved a complete metabolic response. Six months later, she developed intense pruritus. Positron emission tomography (PET) scan showed recurrent right cervical and mediastinal lymphadenopathy; biopsy confirmed relapsed HL. She underwent salvage therapy with 2 cycles of ICE (ifosfamide, carboplatin, and etoposide) followed by high-dose chemotherapy-ASCT (HDC-ASCT) with CBV (cyclophosphamide, carmustine, and etoposide) conditioning regimen and attained a complete metabolic response on day +100 post-HDC-ASCT. Her disease relapsed 21 months later, with PET scan showing enlarging thoracic and cervical lymphadenopathy; biopsy confirmed classical HL. She initiated therapy with 20 mg lenalidomide on a clinical trial; restaging PET after 3 cycles showed stable disease. She had been on lenalidomide for an additional 3 months when she developed progressively worsening cholestatic jaundice.

The patient was admitted twice at an outside hospital with suspected drug-induced liver injury; all medications, including lenalidomide, aspirin, oral contraceptives, and fluoxetine were discontinued, albeit with no improvement. Antimitochondrial antibody, antinuclear antibody, anti-smooth muscle antibody, anti-liver-kidney-smooth muscle antibody, hepatitis A, B, and C, cytomegalovirus, and Epstein-Barr virus workups were negative. Ceruloplasmin, thyroid-stimulating hormone, and alpha-1 antitrypsin levels were normal. Ferritin was elevated at 1682 ng/mL; however, serum iron levels were normal. Liver biopsy showed intracellular and intracanalicular cholestasis with mild intracellular iron deposition and no evidence of lymphoma (Figure 1).

At this point, she was referred to our clinic. Physical examination showed icteric sclera and skin with multiple scratch marks over the extremities. Eastern Cooperative Oncology Group performance status was 2. Complete blood count was normal. Liver function tests showed total bilirubin of 28.3 mg/dL, direct bilirubin of 25 mg/dL, alanine transaminase 131 IU/L, aspartate transaminase 126 IU/L, alkaline phosphatase 733 IU/L, and international normalized ratio of 1.31. PET scan showed worsening adenopathy in the neck, thoracic cavity, and retroperitoneum with unchanged involvement of the spleen; however, no portal or intra-hepatic disease was noted (Figure 2A). A diagnosis of paraneoplastic IC was considered. The patient was admitted for urgent chemotherapy and received 3 doses of intravenous cyclophosphamide 100 mg/m2 and intravenous methylprednisolone 125 mg once a day. Serum bilirubin decreased from its peak of 28 mg/dL to 12.6 mg/dL within 72 hours of initiation of therapy, but then started climbing back up to 18 mg/dL. Three days after receiving the bridging therapy, based on programmed death-ligand 1 positivity in her most recent biopsy, the patient initiated single-agent nivolumab 3 mg/kg every 2 weeks, which she tolerated well. Bilirubin gradually declined to 1.2 mg/dL by the fifth cycle, and the patient improved clinically (Figure 3). Imaging studies confirmed a partial remission after 4 cycles of nivolumab (Figure 2B). Two years later, the patient continues to respond to nivolumab, and she has deferred an allogenic stem cell transplant (allo-SCT).

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Discussion

Liver involvement is noted in up to 3% to 13% of patients with HL.1 Causes of cholestasis in HL include direct hepatic infiltration, extrinsic compression of the bile duct by a lymph node, and PC. PC is a rare manifestation of HL. Clinical presentation includes nausea, anorexia, weight loss, pruritis, and jaundice. Although clinically indistinguishable, based on histology, PC is divided into VBDS and IC. VBDS is characterized by loss of bile ducts in more than 50% of the portal tracts in an

Disclosure

F.J. Hernandez-Ilizaliturri has served on the advisory boards for Millennium Pharmaceuticals, Pharmacyclics, Celgene, Amgen, Genentech, and Seattle Genetics. The remaining authors have stated that they have no conflicts of interest.

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