Patients with hemophilia A who have received valoctocogene roxaparvovec gene therapy need to be managed carefully to minimize their risk of hepatotoxicity, according to new guidelines published in Blood Advances. The authors, an interdisciplinary group of 13 hepatology and hemophilia experts, suggest that a pretreatment assessment and ongoing monitoring of liver health after gene therapy administration may prevent short and potentially long-term hepatic sequelae.
“We published a practical guidance, written by a board of hepatologists and hemophilia clinicians involved in tertiary care at Italian-based centers that are enabled to deliver gene therapy for hemophilia,” said Vincenzo La Mura, MD, PhD, lead study author and associate professor in the Department of Pathophysiology and Transplantation at the Università degli Studi di Milano in Italy.
Valoctocogene roxaparvovec was approved by the U.S. Food and Drug Administration (FDA) in 2023 as an intravenous, single-dose treatment for adults with severe hemophilia A. The therapy is an adeno-associated virus (AAV) vector-based gene therapy specifically indicated for the treatment of adults with severe hemophilia A who have congenital factor VIII deficiency with factor VIII activity and who do not have antibodies to AAV serotype 5 (AAV5) detected by an FDA-approved test. The vector is delivered into the liver’s hepatocytes, and the hypothesis is that immune responses to the AAV gene transfer increase the risk of hepatotoxicity, including an increase in serum levels of alanine aminotransferase (ALT), which is usually transient and asymptomatic.
“Valoctocogene roxaparvovec gene therapy represents a highly innovative therapy for severe hemophilia A,” Dr. La Mura said. “The high success rate of the therapy may be counterbalanced by the risk of liver-related adverse events (AEs). A close collaboration between hemophilia treaters and hepatologists may improve the benefit/risk ratio of this therapy and patient care.”
To develop the guidelines, the team of experts convened in person to discuss the assessment of liver health to determine patient eligibility for gene therapy for hemophilia A and monitoring of liver health after gene therapy. “In these initial stages of gene therapy [for patients with hemophilia A] in clinical practice, careful selection should be made to exclude patients with compromised liver health or with risk factors of hepatocellular carcinoma so as to avoid any potential additional liver damage and maximize treatment efficacy,” the guideline authors wrote.
The detailed guidelines include recommendations on tests and evaluations to determine liver health before gene therapy, including blood tests to identify current or past hepatic infections and liver imaging. Long-term monitoring following the delivery of the gene therapy should include laboratory testing via blood sample analyses and liver ultrasound. “Long-term monitoring and data collection are necessary to determine whether gene therapy has any long-term hepatotoxic effects,” the authors concluded.
Upon receipt of valoctocogene roxaparvovec, patients need to be managed for liver function. In general, when patients with good liver health are selected for treatment and closely monitored thereafter, ALT elevations — in agreement with the experience from clinical trials — can be swiftly treated and are expected to resolve without long-term hepatic consequences.
Valoctocogene roxaparvovec is contraindicated in those patients with hemophilia A who also have acute or uncontrolled liver infections, autoimmune hepatitis, or cirrhosis. Before using gene therapy in patients with liver steatosis or other liver disorders, the risk of liver damage should be considered using a highly individualized approach, according to the authors. Because treatment is not recommended in patients with abnormal liver enzymes, including ALT at any level above the upper limit of normal, pretreatment assessment of liver health should include laboratory tests, abdominal ultrasound, and liver stiffness measurements by transient elastography. Baseline liver conditions and careful clinical management to minimize risks of hepatotoxicity are needed to determine if a patient is eligible for the gene therapy.
Dr. La Mura and his coauthors noted that, according to the literature on patients with hemophilia A treated with valoctocogene roxaparvovec, the most common AE is elevated ALT levels, yet there have been no documented cases of liver dysfunction.
“New pathogenic studies are necessary to better understand the mechanisms causing aminotransferase increase after infusion,” Dr. La Mura said. “This would warrant a better selection of candidates and a targeted approach to face this frequent AE. Independent follow-up studies are mandatory to definitively draw the safety profile of valoctocogene roxaparvovec in the long-term.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
La Mura V, Cardinale V, De Cristofaro R Prof, et al. Liver-related aspects of valoctocogene roxaparvovec gene therapy for hemophilia A: expert guidance for clinical practice [published online ahead of print, 2024 September 3]. Blood Adv. doi: 10.1182/bloodadvances.2024013750.
