Florence Daviet1, Franck Rouby2,3,4, Pascale Poullin5, Julie Moussi-Francès1, Marion Sallée1,6, Stéphane Burtey1,6, Julien Mancini7, Florence Duffaud8, Renaud Sabatier9, Bertrand Pourroy10, Aurélie Grandvuillemin11, Steven Grange12, Véronique Frémeaux-Bacchi13, Paul Coppo14, Joëlle Micallef2,3,4, Noémie Jourde-Chiche1,6. 1. Department of Nephrology, Aix-Marseille University, AP-HM Hôpital de la Conception, Marseille, France. 2. Department of Clinical Pharmacology and Pharmacovigilance, Regional Centre of Pharmacovigilance, Aix-Marseille University, AP-HM Hôpital de la Timone, Marseille, France. 3. Department of Clinical Pharmacology and Pharmacovigilance, Aix-Marseille University, AP-HM Hôpital de la Timone, Marseille, France. 4. INSERM UMR_S 1106, INS, Inst Neurosciences Systems, Aix Marseille University, Marseille, France. 5. Department of Apheresis, Regional Reference Center for Thrombotic Microangiopathy, Aix-Marseille University, AP-HM Hôpital de la Conception, Marseille, France. 6. Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France. 7. Department of Public Health, Aix-Marseille University, AP-HM Hôpital de la Timone, Marseille, France. 8. Department of Clinical Oncology, Aix-Marseille University, AP-HM Hôpital de la Timone, Marseille, France. 9. Department of Clinical Oncology, Institut Paoli Calmettes, Laboratory of Molecular Oncology, Aix-Marseille University, CRCM INSERM UMR 1068, Marseille, France. 10. Department of Parmacy, OncoPharma Unit, Aix-Marseille University, AP-HM Hôpital de la Timone, Marseille, France. 11. Regional Center of Pharmacovigilance, Dijon University Hospital, Dijon, France. 12. Medical intensive care unit, Regional Center for Thrombotic Microangiopathy, Hôpital Charles Nicolle, Rouen University Hospital, Rouen, France. 13. Laboratory of Immunology, AP-HP Hôpital Européen Georges Pompidou, Paris, France. 14. Department of Hematology, French Reference Center for Thrombotic Microangiopathy (www.cnr-mat.fr), Paris 6 University, Paris, France.
Abstract
AIMS: Gemcitabine has been associated with thrombotic microangiopathy (TMA). We conducted a national retrospective study of gemcitabine-associated TMA (G-TMA). METHODS: From 1998 to 2015, all cases of G-TMA reported to the French Pharmacovigilance Network and the French TMA Reference Center, and cases explored for complement alternative pathway abnormalities, were analysed. RESULTS: G-TMA was diagnosed in 120 patients (median age 61.5 years), after a median of 210 days of treatment, and a cumulative dose of 12 941 mg m-2 . Gemcitabine indications were: pancreatic (52.9%), pulmonary (12.6%) and breast (7.6%) cancers, metastatic in 34.2% of cases. Main symptoms were oedema (56.7%) and new-onset or exacerbated hypertension (62.2%). Most patients presented with haemolytic anaemia (95.6%) and thrombocytopenia (74.6%). Acute kidney injury was reported in 97.4% and dialysis was required in 27.8% of patients. Treatment consisted of: plasma exchange (PE; 39.8%), fresh frozen plasma (21.4%), corticosteroids (15.3%) and eculizumab (5.1%). A complete remission of TMA was obtained in 42.1% of patients and haematological remission in 23.1%, while 34.7% did not improve. The survival status was known for 52 patients, with 29 deaths (54.7%). Patients treated with PE, despite a more severe acute kidney injury, requiring dialysis more frequently, displayed comparable rates of remission, but with more adverse events. No abnormality in complement alternative pathway was documented in patients explored. CONCLUSION: This large cohort confirms the severity of G-TMA, associated with severe renal failure and death. Oedema and hypertension could be monitored in patients treated with gemcitabine to detect early TMA. The benefit of PE or eculizumab deserves further investigation.
AIMS: Gemcitabine has been associated with thrombotic microangiopathy (TMA). We conducted a national retrospective study of gemcitabine-associated TMA (G-TMA). METHODS: From 1998 to 2015, all cases of G-TMA reported to the French Pharmacovigilance Network and the French TMA Reference Center, and cases explored for complement alternative pathway abnormalities, were analysed. RESULTS:G-TMA was diagnosed in 120 patients (median age 61.5 years), after a median of 210 days of treatment, and a cumulative dose of 12 941 mg m-2 . Gemcitabine indications were: pancreatic (52.9%), pulmonary (12.6%) and breast (7.6%) cancers, metastatic in 34.2% of cases. Main symptoms were oedema (56.7%) and new-onset or exacerbated hypertension (62.2%). Most patients presented with haemolytic anaemia (95.6%) and thrombocytopenia (74.6%). Acute kidney injury was reported in 97.4% and dialysis was required in 27.8% of patients. Treatment consisted of: plasma exchange (PE; 39.8%), fresh frozen plasma (21.4%), corticosteroids (15.3%) and eculizumab (5.1%). A complete remission of TMA was obtained in 42.1% of patients and haematological remission in 23.1%, while 34.7% did not improve. The survival status was known for 52 patients, with 29 deaths (54.7%). Patients treated with PE, despite a more severe acute kidney injury, requiring dialysis more frequently, displayed comparable rates of remission, but with more adverse events. No abnormality in complement alternative pathway was documented in patients explored. CONCLUSION: This large cohort confirms the severity of G-TMA, associated with severe renal failure and death. Oedema and hypertension could be monitored in patients treated with gemcitabine to detect early TMA. The benefit of PE or eculizumab deserves further investigation.
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