Eculizumab in gemcitabine-induced thrombotic microangiopathy: experience of the French thrombotic microangiopathies reference centre

Abstract

Background Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA). Methods This study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016. Results Twelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4–44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2–22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0–10) before treatment vs 0 (range 0–1) after one injection, P < 0.001). Two patients recovered completely renal function (17%), and 8 achieved a partial remission (67%). Compared to a control group of G-TMA without use of eculizumab, renal outcome was more favourable. At the end of the follow up, median eGFR was 45 vs 33 ml/min/1.73m2 respectively in the eculizumab group and in the control group. Conclusions These results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery.

Gemcitabine-induced thrombotic microangiopathy treated with eculizumab: a case report

“…The exact pathophysiology of gemcitabine-induced TMA is not well established. In a recent retrospective study, deposits of C5b9 in kidney biopsies suggest an at least partial role of complement activation, which may result from a direct endothelial toxicity of the drug ( 4 ). This could also explain why treatment with eculizumab is potentially successful in this setting.…”

“…Aside from permanent discontinuation of gemcitabine and supportive care, the optimal treatment is not known ( 4 ). The use of eculizumab in gemcitabine-induced TMA is limited probably due to several factors.…”

Drug-induced thrombotic microangiopathy: An updated review of causative drugs, pathophysiology, and management

“…In particular, eculizumab proved its efficacy in three out of 9 (33.3%) patients who resolved the IFN-related TMA without further complications, and in four out of six patients who needed dialysis treatment at DITMA onset and discontinued dialysis after a mean of 2 months of eculizumab treatment ( Allinovi et al, 2021 ). Moreover ( Grall et al, 2021 ), reported a significantly better kidney response (83% vs. 64% of complete/partial recovery) and kidney outcome (eGFR 45 vs. 33 ml/min/1.73) in 13 patients with gemcitabine-induced TMA treated with anti-complement therapy. However, conflicting results were reported by previous articles gemcitabine-induced TMA treated with C5-inhibitor ( Al Ustwani et al, 2014 ; Daviet et al, 2019 ).…”

“…Other Authors ( Duineveld and Wetzels, 2019 )do not suggest the use of eculizumab in secondary DITMA cases, relying on data indicating that renal outcome was not significantly altered by the use of the complement inhibitor. Several case report and little case series suggested the effectiveness of C5-inhibitor in DITMA in terms of normalization of hematological parameters and, in some cases, partial or complete recovery of kidney function ( Allinovi et al, 2017 ; Cavero et al, 2017 ; Caravaca-Fontan and Praga, 2019 ; Grall et al, 2021 ). In particular, eculizumab proved its efficacy in three out of 9 (33.3%) patients who resolved the IFN-related TMA without further complications, and in four out of six patients who needed dialysis treatment at DITMA onset and discontinued dialysis after a mean of 2 months of eculizumab treatment ( Allinovi et al, 2021 ).…”

Thrombotic microangiopathy (TMA) in adult patients with solid tumors: a challenging complication in the era of emerging anticancer therapies

“…However, if antibody-mediated TMA is suspected, a trial with plasmapheresis could be useful. There are emerging case reports and small retrospective cohorts of successful outcomes with complement inhibition with eculizumab, a monoclonal antibody against complement factor C5 [ 57 , 58 ] and rituximab [ 59 ] for the management of gemcitabine-induced TMA. However, none of these latter therapies can be formally recommended, since there are no prospective randomized trials evaluating their efficacy and safety in this setting.…”