Navigating Transaminitis Following Onasemnogene abeparvovec (Zolgensma): Insights into Risk Factors and Management Strategies


Clinical Management

Poster Number: S99


Natalie Kukulka, MD, Children's National Hospital, Sarah Wright, DO, MS, Children's National Hospital

Viral-vector mediated gene therapy causes both early (humoral) and late (T-cell mediated) immune responses. Diligent monitoring of T-cell mediated transaminitis is required in patients with SMA post-Zolgensma given the risk of liver failure or death. Consensus guidelines recommend increased oral or intravenous steroids for treatment of transaminitis, which leads to higher overall steroid exposure and prolonged steroid use. Small case reports have identified that older patients (>8 months) and heavier patients are at increased risk of transaminitis. Our objective was to confirm these findings in our patient cohort, and to identify additional factors that may predict transaminitis necessitating subsequent prolonged steroid use following gene therapy. We conducted a retrospective chart review analyzing patient demographics, SMN2 copy number, baseline AAV9 titer (<1_25 or =1:25), and sequential therapies in patients treated with Zolgensma (n=10). Pre- and post-gene therapy safety lab values were trended in 2-week increments up to 10 weeks post-therapy. A total of 40% of patients (n=4) received an extended course (>1 month) of steroid treatment; 30% of patients (n=3) required intravenous steroids for persistent transaminitis (ALT >3x ULN) despite titration of oral steroids. Older age (mean: 17.75 months, median: 22 months) and higher initial weight (mean: 8.98 kg) emerged as potential risk factors for post-gene therapy transaminitis. SMN2 copy count, AAV9 titer elevation (=1:25), and sequential therapy did not show an increased risk. Similarly, laboratory trends did not reveal any early markers predictive of developing transaminitis. Our findings confirm prior reports that the largest risk of liver injury is in older and heavier pediatric patients, but no other risk factors were identified. These findings offer insights for informing discussions regarding vigilant post-therapy monitoring and management of transaminitis, along with reviewing the risks of prolonged steroid use including adrenal insufficiency.