Chemotherapy-Associated Thrombotic Microangiopathy

Abstract

Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma exchange, immunosuppression, and complement inhibition has improved morbidity and mortality for primary TMAs, the management of secondary TMAs, particularly drug-induced TMA, remains less clear. TMA related to cancer drugs disrupts the antineoplastic treatment course, increasing the risk of cancer progression. Chemotherapeutic agents such as mitomycin-C, gemcitabine, and platinum-based drugs as well as targeted therapies such as antiangiogenesis agents and proteasome inhibitors have been implicated in oncotherapy-associated TMA. Among TMA subtypes, drug-induced TMA is less well-understood. Treatment generally involves withdrawal of the offending agent and supportive care targeting blood pressure and proteinuria reduction. Immunosuppression and therapeutic plasma exchange have not shown clear benefit. The terminal complement inhibitor, eculizumab, has shown promising results in some cases of chemotherapy-associated TMA including in re-exposure. However, the data are limited, and unlike in primary atypical hemolytic uremic syndrome, the role of complement in the pathogenesis of drug-induced TMA is unclear. Larger multicenter studies and unified definitions are needed to elucidate the extent of the problem and potential treatment strategies.

Frequency and characteristics of chemotherapy‐associated thrombotic microangiopathy: Analysis from a large pharmacovigilance database

“…Of all the drug classes that we examined, carfilzomib had the highest IC 025 , and each of the PIs (carfilzomib, bortezomib, and ixazomib) had a positive IC 025 . TMA has been reported with gemcitabine and mitomycin in case series, 1,3 and these two drugs had the 2nd and 3rd highest IC 025 among studied drugs, respectively. While most of the VEGFi/TKIs, all the platinums, and most of the other chemotherapies had a positive IC 025 , only two of eight ICPIs with reported TMA in the VigiBase had positive IC 025 .…”

“…3 Despite the known association between gemcitabine and TMA, reports of TMA following gemcitabine are largely limited to case series. Patients with gemcitabine-associated TMA often have progressive kidney dysfunction 3 ; thus, understanding characteristics and outcomes of TMA in patients receiving this drug is critical. Time to anti-neoplastic drug-associated TMA is highly variable in case series.…”

“…We then searched for anti-neoplastic therapies that have been associated with TMA in the literature. 1,3 These consisted of 38 distinct anti-neoplastic therapies, which were further classified as gemcitabine/mitomycin, PIs, platinum-based chemotherapies, VEGFi/TKIs, ICPIs, and others (bleomycin, docetaxel, doxorubicin, and pentostatin) (Supplemental Methods; Supplemental Table 1).…”

“…Gemcitabine and mitomycin were examined together as these are the most commonly reported conventional chemotherapies associated with TMA. 3 The search also included combinations of any of these pre-specified medications. The query was run on de-duplicated data, whereby suspected duplicates were identified, flagged, and then removed.…”

Complement-Mediated Thrombotic Microangiopathy and Spontaneous Splenic Rupture Associated With Cytomegalovirus Infection

“…She has no other known risk factors for complement-mediated TMA, such as HIV, autoimmune disease, malignancy, organ transplant, irradiation, or drug exposure (eg, tacrolimus). 1,2,8,11,12 Complement-mediated TMA is described in association with various mutations in genes of complement factors or with autoantibodies against complement regulators. Around 60% of patients with complement-mediated TMA have an identified complement abnormality.…”