Association between Direct Acting Agents used for chronic hepatitis C virus infection and the occurrence of acute leukaemia – A disproportionality analysis

BACKGROUND AND AIMS A recent single-center study reported a significant increase in acute myeloid leukaemia (AML) cases, including mixed-phenotype acute leukaemia (MPAL), after exposure to direct acting agents (DAA). We investigated whether DAA use increased the risk of AML in patients with chronic hepatitis C virus (HCV) infection. METHODS We conducted a disproportionality analysis of the WHO Pharmacovigilance database Vigibase up to 2020. Queries focused on all DAAs, subclasses, combinations or each DAA separately as well as interferon and ribavirin as negative controls. The primary outcome was AML. Secondary outcomes were AML without MPAL, MPAL, acute lymphoid leukemia (ALL) and acute leukemia (AL, high-level term encompassing AML, ALL, MPAL and unspecified acute leukemia [UAL]). The information component (IC0.25) and proportional reporting ratio (PRR0.25) were computed to assess a potential pharmacovigilance signal. RESULTS We identified 49 notifications reporting any AL occurrence after anti-HCV treatments from June 1997 to December 2020: 23 (47%) involved a DAA, 24 (49%) interferon and 12 (24%) ribavirin. The DAAs sofosbuvir and ledipasvir were suspected in 74% (n=17) and 39% (n=9) of cases. The events reported were AML (n=22), ALL (n=11), AML and ALL (n=1) and UAL (n=15) and no MPAL. DAA, interferon or ribavirin were not significantly associated with AML, ALL or AL. CONCLUSION This study did not find any association between DAA exposure and the occurrence of AML. Nevertheless, vigilance should remain, particularly for MPAL, which may not have been well captured in our study because of its rareness and high risk of misclassification.