Sinusoidal Occlusion Syndrome Following Exposure to Gemtuzumab: Unsuccessful Treatment with Defibrotide

Abstract

Purpose: Sinusoidal occlusion syndrome (SOS) is a rare, life-threatening disorder characterized by abdominal distention, weight gain, tender hepatomegaly, ascites, and elevated aspartate aminotransferase (AST) and creatinine (Cr) concentrations. Ultrasonography (US) demonstrates patent portal and hepatic venous circulations. SOS arises most commonly in the setting of bone marrow transplantation (BMT). Gemtuzumab, an anti-CD33 monoclonal antibody, is a new agent for the management of relapsed acute myeloid leukemia (AML). Abnormal liver tests occur in 1/3 of gemtuzumab-treated patients, but only 1–2% have documented SOS. A 24 year-old man, diagnosed with AML 13 months after receiving chemotherapy for a mediastinal germ cell malignancy failed to respond to initial protocol chemotherapy with amonafide, cytarabine and mitoxantrone. Salvage chemotherapy with gemtuzumab was initiated in standard dose and schedule. Five days after first exposure to gemtuzumab the patient began gaining weight, and by day 9 his weight gain was 4 kg. His abdomen was distended and uncomfortable, and he required oxygen for dyspnea. Laboratory studies were as follows: AST 6733 IU/L (normal range [NR]: 10–60), alkaline phosphatase 162 IU/L (NR: 30–135), prothrombin time 17.7 s (NR: 11.1–13), total bilirubin 1.9 mg% (NR: 0.2–1.2) and Cr 5.9 mg% (NR: 0.4–1.4). US scan confirmed the presence of splenomegaly and ascites; the hepatic and portal vein branches were patent. However, the direction of flow in the latter was reversed. Both the vena cava and hepatic artery were patent. Relevant acute viral, metabolic and immune forms of liver disease were excluded on the basis of appropriate serologic studies. Given the symptom complex, compassionate approval was sought for use of the non FDA-approved drug, defibrotide. However, despite this intervention, continuous veno-veno hemodialysis, and further antimicrobial therapy, the patient developed acute liver failure and died 26 days after first gemtuzumab exposure. This man's clinical, laboratory and US findings met diagnostic criteria for SOS. While experience with SOS in the BMT setting is well recorded, other etiologies are rarely recorded. This patient's clinical course was virtually diagnostic of gemtuzumab-induced SOS. Although use of defibrotide has been reported to improve 1/3 of patients having SOS in the BMT setting, experience among patients with SOS after gemtuzumab therapy is very limited.