Introduction

Axatilimab is a humanized monoclonal antibody to the colony stimulating factor-1 receptor that is used to treat patients with chronic graft-versus-host disease who have active disease despite having received at least two previous systemic therapies. Axatilimab therapy is often accompanied by transient serum enzyme elevations, but it has not been linked to instances of clinically apparent liver injury with jaundice.

Background

Axatilimab (axe” a til’ i mab) is a humanized monoclonal IgG4 antibody directed against the colony stimulating factor-1 receptor (CSF-1R) which is used to treat adults with active, refractory chronic graft-vs-host disease (GvHD). Axatilimab binds to CSF-1R on monocytes and macrophages, blocking their activation and induction of proinflammatory cytokines and fibrogenic genes. This monoclonal antibody was shown to decrease disease activity in an animal model of GvHD. In human trials, axatilimab induced clinical responses in over 70% of patients with chronic GvHD who had received at least 2 previous systemic lines of therapy. Axatilimab was approved for use in the United States in 2024, the fourth agent approved for treatment of chronic GvHD, others being ibrutinib, belumosudil, and rituximab. Current indications for axatilimab are treatment of chronic GvHD despite at least previous systemic therapies in adults and pediatric patients weighing 40 kg or more. Axatilimab is available under the brand name Niktimvo in single dose vials of 50 mg in 1 mL. The recommended dose is 0.3 mg/kg body weight (maximal 35 mg) given as an intravenous infusion over 30 minutes every 2 weeks. Adverse effects can include infusion reactions for which premedication with an antihistamine and antipyretics is recommended in patients who experienced a previous infusion reaction to axatilimab. Other common adverse events include fatigue, musculoskeletal pain, headache, dizziness, nausea, diarrhea, cough, fever, dyspnea, and increased risk of bacterial, fungal and viral infections. Laboratory abnormalities can include elevations in liver enzymes, creatine kinase, amylase, lipase, and calcium, and decreases in hemoglobin and serum phosphate. Uncommon but potentially serious side effects include severe hypersensitivity reactions (angioedema or anaphylaxis), severe infections, and embryo-fetal toxicity.

Hepatotoxicity

In preregistration controlled trials, elevations in serum aminotransferase levels arose in 12.7% of patients treated with 0.3 mg/kg and in higher rates with higher doses, 21.5% at 1 mg/kg and 40% at 3 mg/kg. Elevations in aminotransferase levels above 5 times the ULN occurred in only 1.3% of patients and all of the elevations were transient and none required drug discontinuation or was accompanied by jaundice. Since its approval, there have been no case reports of liver injury with jaundice linked to axatilimab therapy but clinical experience with the drug has been limited. Furthermore, patients with chronic GvHD frequently have elevations in serum enzymes because of graft-vs-host injury to the liver. Reactivation of hepatitis B as well as immune-mediated hepatitis can occur with use of immunosuppressive monoclonal antibodies such as infliximab and adalimumab, but instances have not been reported with axatilimab.

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

Mechanism of Injury

Serum ALT elevations may be a direct result of inhibition of CSF-1R because elevations occur in many enzyme levels including alkaline phosphatase, GGT, creatine phosphatase, amylase and lipase, but rarely result in organ injury. These transient laboratory abnormalities may be explained by Kupffer cells depletion and reduced clearance function following CSF-1R blockade. Graft-vs-host disease commonly affects the liver, and liver test abnormalities during axatilimab therapy may be due to the underlying disease rather than the drug therapy. For this reason, patients should be assessed for the presence of liver involvement before starting therapy for chronic GvHD.

Outcome and Management

It is appropriate to monitor patients with chronic GvHD for liver test abnormalities before starting and at intervals during therapy. The serum aminotransferase elevations that were reported during axatilimab therapy were generally transient, mild and asymptomatic and did not require dose modification or delay in therapy. Elevations above 5 times the upper limit of normal should lead to clinical assessment of the possible causes and more careful monitoring and suspension of further infusions, at least until levels return to normal or near normal levels or until the underlying cause is identified. There is no evidence of cross sensitivity to hepatic reactions among the various monoclonal antibodies or small molecule therapies for GvHD.

Drug Class: Monoclonal Antibodies

Other Drugs for GvHD: Belumosudil, Ibrutinib, Ruxolitinib