Drug-Induced Thrombotic Microangiopathy due to Cumulative Toxicity of Ixazomib

Abstract

Drug-induced thrombotic microangiopathies (DTMAs) are increasingly being recognized as an important category of thrombotic microangiopathies (TMAs). Cancer therapeutic agents including proteasome inhibitors (PIs) are among the most common medications reported to cause DTMA. PIs could cause DTMA either by an immune mechanism or dose-dependent/cumulative toxicity. Eleven cases of DTMA have been reported with bortezomib and carfilzomib. To the best of our knowledge, only one case of DTMA has been reported with ixazomib due to an immune-mediated mechanism. Here, we report the first case of ixazomib-induced DTMA due to cumulative toxicity rather than immune-mediated mechanism. In this article, we discuss the precipitating factors for cumulative toxicity of ixazomib, resulting in DTMA, diagnostic workup, and management of DTMA. We also discuss clinical reasoning based analysis of DTMA versus cancer-associated TMA as well as DTMA versus cyclic thrombocytopenia seen in PI use.

Thrombotic Microangiopathy Syndromes—Common Ground and Distinct Frontiers

“…Ultimately these are the two principal mechanisms of toxicity. 55,56 The direct toxicity route results in damage to endothelium leading to CM-TMA. The immune-mediated toxicity leads to TMA presentations driven by antibodies to drugprotein complexes.…”

“…The immune-mediated toxicity leads to TMA presentations driven by antibodies to drugprotein complexes. 55 Gemcitabine, for example, causes direct endothelial cell toxicity, which results in TMA caused by complement dysfunction. 57 Both tyrosine kinase inhibitors (TKIs) and VEGF inhibitors (VEGFis) have been reported to cause TMA.…”

An Update in Drug-Induced Thrombotic Microangiopathy

“…The majority of reports have implicated bortezomib and cafilzomib (3,40). Recent reports also support a causal association of ixazomib with DITMA (41)(42)(43). Some authors report successful treatment of carfilzomib-induced TMA with eculizumab (44,45).…”

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

“…Some natural compounds known to exhibit pleiotropic activities were reported to also inhibit NF-κB, e.g., curcumin [ 28 , 29 ] and caffeic acid phenethyl ester (CAPE) [ 30 ]. CAPE inhibited the activation of NF-κB in cells with an IC 50 between 10 and 20 µM, for which the Michael reaction acceptor and the catechol motif in the structure were required [ 31 ].…”