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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: chretien-b@chu-caen.fr
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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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References

Alonso, S., Su, M., Jones, J. W., Ganguly, S., Kane, M. A., Jones, R. J., & Ghiaur, G. (2015). Human bone marrow niche chemoprotection mediated by cytochrome P450 enzymes. Oncotarget, 6, 14905–14912.CrossRefGoogle ScholarPubMed
Bachmann, C. J., Aagaard, L., Bernardo, M., Brandt, L., Cartabia, M., Clavenna, A., … Taylor, D. (2017). International trends in clozapine use: A study in 17 countries. Acta Psychiatrica Scandinavica, 136, 37–51.CrossRefGoogle ScholarPubMed
Bate, A., Lindquist, M., & Edwards, I. R. (2008). The application of knowledge discovery in databases to post-marketing drug safety: Example of the WHO database. Fundamental & Clinical Pharmacology, 22, 127–140.CrossRefGoogle ScholarPubMed
Bellamri, M., Le Hegarat, L., Vernhet, L., Baffet, G., Turesky, R. J., & Langouët, S. (2016). Human T lymphocytes bioactivate heterocyclic aromatic amines by forming DNA adducts. Environmental and Molecular Mutagenesis, 57, 656–667.CrossRefGoogle Scholar
Chavant, F., Favrelière, S., Lafay-Chebassier, C., Plazanet, C., & Pérault-Pochat, M.-C. (2011). Memory disorders associated with consumption of drugs: Updating through a case/noncase study in the French PharmacoVigilance Database. British Journal of Clinical Pharmacology, 72, 898–904.CrossRefGoogle ScholarPubMed
de Silveira, A. S. A., Rocha, D. M. L. V., de Attux, C. R. F., Daltio, C. S., da Silva, L. A., Elkis, H., … Bressan, R. A. (2015). Patterns of clozapine and other antipsychotics prescriptions in patients with treatment-resistant schizophrenia in community mental health centers in São Paulo, Brazil. Archives of Clinical Psychiatry (São Paulo), 42, 165–170.CrossRefGoogle Scholar
Egberts, A. C. G., Meyboom, R. H. B., & van Puijenbroek, E. P. (2002). Use of measures of disproportionality in pharmacovigilance. Drug Safety, 25, 453–458.CrossRefGoogle ScholarPubMed
Evans, S. J. W., Waller, P. C., & Davis, S. (2001). Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiology and Drug Safety, 10, 483–486.CrossRefGoogle ScholarPubMed
Faillie, J.-L. (2019). Case-non-case studies: Principle, methods, bias and interpretation. Therapie, 74, 225–232.CrossRefGoogle ScholarPubMed
Garbe, E., & Suissa, S. (2014). Pharmacoepidemiology. In Ahrens, W. & Pigeot, I. (Eds.), Handbook of epidemiology (pp. 1875–1925). New York, NY: Springer New York.CrossRefGoogle Scholar
Gardner, I., Zahid, N., MacCrimmon, D., & Uetrecht, J. P. (1998). A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes. Molecular Pharmacology, 53, 991–998.Google ScholarPubMed
Hallek, M., Shanafelt, T. D., & Eichhorst, B. (2018). Chronic lymphocytic leukaemia. Lancet (London, England), 391, 1524–1537.CrossRefGoogle ScholarPubMed
Höglund, M., Sandin, F., & Simonsson, B. (2015). Epidemiology of chronic myeloid leukaemia: An update. Annals of Hematology, 94(Suppl 2), S241–S247.CrossRefGoogle ScholarPubMed
Jegouzo, A., Gressier, B., Frimat, B., Brunet, C., Dine, T., Luyckx, M., … Cazin, J. C. (1999). Comparative oxidation of loxapine and clozapine by human neutrophils. Fundamental & Clinical Pharmacology, 13, 113–119.CrossRefGoogle ScholarPubMed
Ji, J., Sundquist, K., Ning, Y., Kendler, K. S., Sundquist, J., & Chen, X. (2013). Incidence of cancer in patients with schizophrenia and their first-degree relatives: A population-based study in Sweden. Schizophrenia Bulletin, 39, 527–536.CrossRefGoogle ScholarPubMed
Juliusson, G., Antunovic, P., Derolf, A., Lehmann, S., Möllgård, L., Stockelberg, D., … Höglund, M. (2009). Age and acute myeloid leukemia: Real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood, 113, 4179–4187.CrossRefGoogle ScholarPubMed
Koeffler, H. P., Ranyard, J., & Pertcheck, M. (1985). Myeloperoxidase: Its structure and expression during myeloid differentiation. Blood, 65, 484–491.CrossRefGoogle ScholarPubMed
Leung, J. G., Barreto, J. N., & Thompson, C. A. (2018). Lymphoma following clozapine exposure: More information needed. Schizophrenia Research, 199, 420–421.CrossRefGoogle ScholarPubMed
Li, R., Ma, X., Wang, G., Yang, J., & Wang, C. (2016). Why sex differences in schizophrenia? Journal of Translational Neuroscience, 1, 37–42.Google Scholar
Meltzer, M. (2016). Lymphoma developing during clozapine therapy. The Australian and New Zealand Journal of Psychiatry, 50, 498–499.CrossRefGoogle ScholarPubMed
Messias, E., Chen, C.-Y., & Eaton, W. W. (2007). Epidemiology of schizophrenia: Review of findings and myths. The Psychiatric Clinics of North America, 30, 323–338.CrossRefGoogle ScholarPubMed
Montastruc, J.-L., Sommet, A., Bagheri, H., & Lapeyre-Mestre, M. (2011). Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. British Journal of Clinical Pharmacology, 72, 905–908.CrossRefGoogle Scholar
Ng, W., Kennar, R., & Uetrecht, J. (2014). Effect of clozapine and olanzapine on neutrophil kinetics: Implications for drug-induced agranulocytosis. Chemical Research in Toxicology, 27, 1104–1108.CrossRefGoogle ScholarPubMed
Nielsen, J., & Boysen, A. (2010). Clozapine treatment associated with increased risk of acute myeloid leukemia (AML). Schizophrenia Research, 123, 270–272.CrossRefGoogle Scholar
Novak, M., & Zhang, Y. (2012). Chapter three – antitumor drugs and nitrenium ions. In Williams, I. H. and Williams, N. H. (Eds.), Advances in physical organic chemistry (Vol. 46, pp. 121–164). Cambridge, MA: Academic Press.Google Scholar
Opgen-Rhein, C., & Dettling, M. (2008). Clozapine-induced agranulocytosis and its genetic determinants. Pharmacogenomics, 9, 1101–1111.CrossRefGoogle ScholarPubMed
Ostrousky, O., Meged, S., Loewenthal, R., Valevski, A., Weizman, A., Carp, H., & Gazit, E. (2003). NQO2 gene is associated with clozapine-induced agranulocytosis. Tissue Antigens, 62, 483–491.CrossRefGoogle ScholarPubMed
Pereira, A., & Dean, B. (2006). Clozapine bioactivation induces dose-dependent, drug-specific toxicity of human bone marrow stromal cells: A potential in vitro system for the study of agranulocytosis. Biochemical Pharmacology, 72, 783–793.CrossRefGoogle Scholar
Rajagopal, S. (2005). Clozapine, agranulocytosis, and benign ethnic neutropenia. Postgraduate Medical Journal, 81, 545–546.CrossRefGoogle ScholarPubMed
Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophrenia in adults. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie, 62, 604–616.CrossRefGoogle ScholarPubMed
Schaus, J. M., & Bymaster, F. P. (1998). Chapter 1 – dopaminergic approaches to antipsychotic agents. In Bristol, J. A. (Ed.), Annual reports in medicinal chemistry (Vol. 33, pp. 1–10). Cambridge, MA: Academic Press.Google Scholar
Sharrar, R. G., & Dieck, G. S. (2013). Monitoring product safety in the postmarketing environment. Therapeutic Advances in Drug Safety, 4, 211–219.CrossRefGoogle ScholarPubMed
Sikora, A., Adamus, J., & Marcinek, A. (2007). Disproportionation of clozapine radical: A link between one-electron oxidation of clozapine and formation of its nitrenium cation. Chemical Research in Toxicology, 20, 1093–1098.CrossRefGoogle ScholarPubMed
Singh, R., Arlt, V. M., Henderson, C. J., Phillips, D. H., Farmer, P. B., & Gamboa da Costa, G. (2010). Detection and quantitation of N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine adducts in DNA using online column-switching liquid chromatography tandem mass spectrometry. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 878, 2155–2162.CrossRefGoogle Scholar
Smith, A., Crouch, S., Lax, S., Li, J., Painter, D., Howell, D., … Roman, E. (2015). Lymphoma incidence, survival and prevalence 2004–2014: Sub-type analyses from the UK's haematological malignancy research network. British Journal of Cancer, 112, 1575–1584.CrossRefGoogle ScholarPubMed
Snodgrass, R., Nguyen, L. T., Guo, M., Vaska, M., Naugler, C., & Rashid-Kolvear, F. (2018). Incidence of acute lymphocytic leukemia in Calgary, Alberta, Canada: A retrospective cohort study. BMC Research Notes, 11, 1–4.CrossRefGoogle ScholarPubMed
Taylor, D. M. (2004). Prescribing of clozapine and olanzapine: Dosage, polypharmacy and patient ethnicity. Psychiatric Bulletin, 28, 241–243.CrossRefGoogle Scholar
Uetrecht, J., Zahid, N., Tehim, A., Mim Fu, J., & Rakhit, S. (1997). Structural features associated with reactive metabolite formation in clozapine analogues. Chemico-Biological Interactions, 104, 117–129.CrossRefGoogle ScholarPubMed
van der Weide, K., Loovers, H., Pondman, K., Bogers, J., van der Straaten, T., Langemeijer, E., … van der Weide, J. (2017). Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population. The Pharmacogenomics Journal, 17, 471–478.CrossRefGoogle Scholar
Williams, D. P., Pirmohamed, M., Naisbitt, D. J., Uetrecht, J. P., & Park, B. K. (2000). Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine. Molecular Pharmacology, 58, 207–216.CrossRefGoogle ScholarPubMed
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