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Haematologic malignancies associated with clozapine v. all other antipsychotic agents: a pharmacovigilance study in VigiBase®

Published online by Cambridge University Press:  10 February 2020

Basile Chrétien Open the ORCID record for Basile Chrétien [Opens in a new window] ,
Véronique Lelong-Boulouard ,
Sylvain Chantepie ,
Marion Sassier ,
Mickael Bertho ,
Perrine Brazo ,
Xavier Humbert ,
Joachim Alexandre ,
Sophie Fedrizzi  and
Charles Dolladille
Basile Chrétien*
Affiliation:
Department of Pharmacology, Caen University Hospital, Caen, F-14000, France Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, France
Véronique Lelong-Boulouard
Affiliation:
Department of Pharmacology, Caen University Hospital, Caen, F-14000, France Normandie Univ, UNICAEN, UFR Santé, INSERM UMR 1075, COMETE-MOBILITES “Vieillissement, Pathologie, Santé”, 14000Caen, France
Sylvain Chantepie
Affiliation:
Department of Clinical Haematology, Caen University Hospital, Caen, F-14000, France
Marion Sassier
Affiliation:
Department of Pharmacology, Caen University Hospital, Caen, F-14000, France Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, France
Mickael Bertho
Affiliation:
Department of Pharmacology, Caen University Hospital, Caen, F-14000, France Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, France
Perrine Brazo
Affiliation:
Department of Psychiatry, Esquirol Center, Caen University Hospital, Caen, F-14000, France Normandie Univ, UNICAEN, EA7466, Imagerie et Stratégies Thérapeutiques de la Schizophrénie (ISTS), 14000Caen, France
Xavier Humbert
Affiliation:
Department of Pharmacology, Caen University Hospital, Caen, F-14000, France Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, France General Practice Department, Normandie Univ, UNICAEN, 14000Caen, France Normandie Univ, UNICAEN, EA4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, 14000Caen, France
Joachim Alexandre
Affiliation:
Department of Pharmacology, Caen University Hospital, Caen, F-14000, France Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, France Normandie Univ, UNICAEN, EA4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, 14000Caen, France
Sophie Fedrizzi
Affiliation:
Department of Pharmacology, Caen University Hospital, Caen, F-14000, France Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, France Normandie Univ, UNICAEN, EA4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, 14000Caen, France
Charles Dolladille
Affiliation:
Department of Pharmacology, Caen University Hospital, Caen, F-14000, France Normandie Univ, UNICAEN, EA4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, 14000Caen, France
*
Author for correspondence: Basile Chrétien, E-mail: [email protected]
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Abstract

Background

Clozapine is mainly used in patients with treatment-resistant schizophrenia and may lead to potentially severe haematologic adverse events, such as agranulocytosis. Whether clozapine might be associated with haematologic malignancies is unknown. We aimed to assess the association between haematologic malignancies and clozapine using Vigibase®, the WHO pharmacovigilance database.

Methods

We performed a disproportionality analysis to compute reporting odds-ratio adjusted for age, sex and concurrent reporting of antineoplastic/immunomodulating agents (aROR) for clozapine and structurally related drugs (loxapine, olanzapine and quetiapine) compared with other antipsychotic drugs. Cases were malignant lymphoma and leukaemia reports. Non-cases were all other reports including at least one antipsychotic report.

Results

Of the 140 226 clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was significantly associated with malignant lymphoma (aROR 9.14, 95% CI 7.75–10.77) and leukaemia (aROR 3.54, 95% CI 2.97–4.22). Patients suffering from those haematologic malignancies were significantly younger in the clozapine treatment group than patients treated with other medicines (p < 0.001). The median time to onset (available for 212 cases) was 5.1 years (IQR 2.2–9.9) for malignant lymphoma and 2.5 years (IQR 0.6–7.4) for leukaemia. The aROR by quartile of dose of clozapine in patients with haematologic malignancies suggested a dose-dependent association.

Conclusions

Clozapine was significantly associated with a pharmacovigilance signal of haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors of haematologic malignancies. Clozapine should be used at the lowest effective posology.

Keywords

Clozapinehaematologic malignanciesleukaemialymphomapharmacovigilancesafety
Type
Original Articles
Information
Psychological Medicine , Volume 51 , Issue 9 , July 2021 , pp. 1459 - 1466
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Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

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