(P-070) Risk of Thrombotic Microangiopathy with Tyrosine Kinase Inhibitors: A Disproportionality Analysis from Vigibase and AERS Databases

Background: Thrombotic microangiopathies (TMAs) are highly diverse disorders, found in adults and children. They have multiple etiologies and may be hereditary or acquired. Drug-associated TMA can be an acute, immune-mediated disorder or the result of gradual, dose-dependent toxicity. Despite their diversity, TMA syndromes are united by common, defining clinical and pathological features which involve vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall. Malignancies of many types with systemic microvascular involvement may cause TMA.

Objectives: To quantify disproportionate reporting (Disp-Rep) for the risk of drug-associated TMA for 29 clinically approved tyrosine kinase inhibitors (TKIs) in 2 groups: 1) Anti-angiogenic (AA) TKIs; 2) Non-anti-angiogenic (NAA) TKIs.

Methods: We used the AERS and VigiBase databases, with data up to September 2020 for analysis. Cases were identified using MedDRA (v23.0) and a grouping of 4 Preferred Terms (PT): thrombotic microangiopathy, thrombotic thrombocytopenic purpura, haemolytic uremic syndrome, and microangiopathic haemolytic anaemia. Empirical Bayes Geometric Means (EBGM) with 90%CI were calculated to quantify Disp-Rep. We considered Dis-Rep as confirmed if the lower bound, EB05, was > 2. We studied 3 groups of drugs: 1) Positive control group (non-TKIs associated with TMA: quinine and bortezomib) and two groups of TKIs: 2) AA TKIs & 3) NAA TKIs. Drugs were identified by non-proprietary name.

Results: We retrieved 634 TMA cases in AERS and 501 in VigiBase. In AERS; Disp-Rep with EBGM [90%CI, EB05-EB95] was confirmed for the positive control group: Quinine 14.3 [12.5-16.4], and bortezomib 2.7 [2.3-3.1]. Disp-Rep was confirmed for only 1 of 14 AA TKIs: Sunitinib 3.8 [3.3-4.4]. No Dis-Rep (EB05 < 2) was found for the rest of AA TKIs: Acalabrutinib, axitinib, cabozantinib, dacomitinib, lenvatinib, neratinib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, tivozanib and vandetanib. No Dis-Rep was found for any of NAA TKIs: Afatinib, bosutinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, nilotinib, osimertinib and vemurafenib. The analysis in VigiBase database yielded similar results.

Conclusions: Sunitinib (AA TKI) was the only drug among the 29 different TKIs studied with Disp-Rep in both databases. Our results however, should be interpreted with caution as disproportionality analyses are hypothesis generating rather than hypothesis testing.