Disproportionate reporting of hepatic injury with acute leukemia therapies.

Abstract

e18509 Background: Therapies to treat relapsed/refractory acute leukemia are associated with hepatotoxicity. Cholestatic and hepatocellular injury are adverse drug reactions (ADRs) seen in clinical trials. This pharmacovigilance study uses the FDA Adverse Event Reporting System (FAERS) to evaluate signaling for hepatic ADRs across therapies. Methods: FAERS is a voluntarily reported database to monitor ADRs. Reports for suspected therapies associated with cholestasis, hepatitis, jaundice, graft-versus-host disease (GvHD), and sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were evaluated. The OpenVigil system was used for common therapies- including antibody therapies, tyrosine kinase inhibitors (TKI), hypomethylating agents, and targeted agents. The Reporting Odds Ratio (ROR) was used to determine if these reports were significant. 95% confidence intervals (CI) and p-values were calculated to assess the significance between each drug and ADR. P-values were significant (≤ 0.05), unless stated otherwise. ROR=(positive reports with drug/negative reports with drug)/(positive reports without drug/negative reports without drug). An ROR >1 is considered a potential signal for an ADR. Results: (Table 1) Gilteritinib showed disproportionate reporting for cholestasis (ROR 4.19, 95% CI 2.43-7.22) and hepatitis (ROR 4.54, 95% CI 2.89-7.12). Blinatumomab showed disproportionate reporting for cholestasis (ROR 2.63, 95% CI 1.75-3.96). Imatinib showed signals across all outcomes: cholestasis (ROR 1.41, 95% CI 1.08-1.86), hepatitis (ROR 1.67, 95% CI 1.35-2.08), and jaundice (ROR 2.49, 95% CI 2.09-2.95). Enasidenib showed disproportionate reporting for jaundice (ROR 2.45, 95% CI 1.32-4.57). Dasatinib showed reduced signals across all outcomes: cholestasis (ROR 0.52, 95% CI 0.32-0.83), hepatitis (ROR 0.56, 95% CI 0.38-0.84), and jaundice (ROR 0.66, 95% CI 0.46-0.94). Ponatinib, azacitidine, and midostaurin had insufficient reports for evaluation. There were no reports of GvHD or SOS/VOD. Conclusions: Hepatotoxicity associated with leukemia therapy showed agent-specific differences, notably with gilterinib and imatinib across multiple domains. In contrast, dasatinib and venetoclax had potentially favorable safety profiles. The lack of SOS/VOD and hepatic GvHD signals in FAERS may reflect underreporting and the exclusion of known causes, like gemtuzumab ozogamicin. These findings support further investigation of hepatotoxicity in these patients. ADR signals. Drug Total ADRs ROR, CI (cholestasis) ROR, CI (hepatitis) ROR, CI (jaundice) Blinatumomab 9609 2.63 (1.75-3.96) - - Imatinib 40399 1.41 (1.08-1.86) 1.67 (1.35-2.08) 2.49 (2.09-2.95) Dasatinib 35913 0.52 (0.32-0.83) 0.56 (0.38-0.84) 0.66 (0.46-0.94) Venetoclax 55871 - 0.61 (0.45-0.83) 0.74 (0.56-0.96) Gilteritinib 3420 4.19 (2.43-7.22) 4.54 (2.89-7.12) - Enasidenib 3115 - - 2.45 (1.32-4.57)