Introduction

Emapalumab is a human monoclonal antibody to interferon gamma which acts to block its binding to cell surface receptors and activation of inflammatory signals. Emapalumab is used to treat the severe inflammatory condition of hemophagocytic lymphohistiocytosis (HLH) in which serum gamma interferon levels are elevated. Emapalumab therapy is associated with mild and transient serum enzyme elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury.

Background

Emapalumab (em" a pal' ue mab) is a recombinant, human IgG1 monoclonal antibody to gamma interferon, which inhibits its binding to cell surface interferon receptors and the subsequent activation of intracellular proinflammatory signaling pathways. Gamma interferon levels are known to be elevated in patients with hemophagocytic lymphohistiocytosis (HLH), a life-threatening inflammatory syndrome marked by fever, enlargement of liver and spleen, macrophage update of red blood cells (hemophagocytosis) in bone marrow, spleen and lymph nodes, low natural killer cell activity and high levels of serum ferritin, triglycerides and multiple cytokines. HLH has primary genetic causes but can also arise secondarily as a complication of viral infections, cancer, severe rheumatic diseases and immunosuppression after transplantation. In clinical trials, emapalumab was found to reduce hemolysis and the need for blood transfusions with subsequent improvement in symptoms and quality of life in children and adults with recurrent HLH. Emapalumab was approved for use in HLH in the United States in 2018. Emapalumab is available as a solution in single dose vials of 10 mg in 2 mL or 50 mg in 10 mL (5 mg/mL) under the commercial name Gamifant. The recommended starting dose is 1 mg/kg as an intravenous infusion twice per week. Doses can be modified based upon clinical and laboratory results and therapy continued until hematopoietic cell transplantation, or unacceptable toxicity or until it is no longer thought to be needed. Premedication with dexamethasone is recommended as is prophylaxis for herpes zoster, Pneumocystis jirovecii and fungal infections. Side effects can include infusion site reactions, infections, fever and hypertension. Uncommon severe complications include severe infusion reactions and severe infections, including reactivation of tuberculosis, herpes zoster, pneumocystis jirovecii and fungal infections. Generally, however, the symptoms and complications of the underlying HLH overshadow the adverse effects of inhibition of gamma interferon.

Hepatotoxicity

In clinical trials of emapalumab in patients with HLH, serum enzymes were usually elevated before therapy as a part of the underlying the hyperinflammatory condition. In the small number of patients treated, there was little evidence of hepatotoxicity, serum enzyme elevations generally being transient and rising only slightly above baseline elevated levels. There have been no reports of clinically apparent liver injury with jaundice attributed to emapalumab therapy in patients with HLH. Because in blocks interferon gamma signaling, it may cause reactivation of microbial organisms that are ordinarily modulated by interferon gamma-induced cytokines or intracellular proteins. Reactivation of tuberculosis, pneumocystis jirovecii, herpes zoster and fungal infections but not hepatitis B or C are listed as potential complications of therapy. In preregistration clinical trials, there were no reports of reactivation of hepatitis B and none have been published since the introduction of emapalumab therapy into clinical practice.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which emapalumab might cause liver injury is unknown. Emapalumab is a monoclonal antibody and, like other proteins, is metabolized into amino acids and is unlikely to have intrinsic toxicity.

Outcome and Management

Emapalumab therapy has been linked to instances of mild, transient serum enzyme elevations during therapy, typically arising a few weeks after an initial or an early infusion of the monoclonal antibody. These elevations are typically mild and self-limiting and rarely require dose modification. Neverthelss, routine pre-screening as well as on-therapy monitoring of renal, electrolyte and hepatic function is recommended. In patients who develop persistent marked elevations of serum ALT or alkaline phosphatase or who develop jaundice and symptoms, therapy should be interrupted at least until levels return to or near baseline values. Restarting emapalumab should be done with caution and continued monitoring.

Drug Class: Hematologic Agents, Monoclonal Antibodies