Rare but elevated incidence of hematological malignancy after clozapine use in schizophrenia: a population cohort study

Yuqi Hu, Le Gao, Lingyue Zhou, Wenlong Liu, Cuiling Wei, Boyan Liu, Qi Sun, Wenxin Tian, Rachel Yui Ki Chu, Song Song, Franco Wing Tak Cheng, Joe Kwun Nam Cham, Amy Pui Pui Ng, Heidi Ka Ying Lo, Krystal Chi Kei Lee, Wing Chung Chang, William Chi Wai Wong, Esther Wai Yin Chan, Ian Chi Kei Wong, Yi ChaiFrancisco Tsz Tsun Lai

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Clozapine is widely regarded as a highly efficacious psychotropic drug that is largely underused worldwide. Recent disproportionality analyses and nationwide case-control studies suggested a potential association between clozapine use and hematological malignancy (HM). Nevertheless, the absolute rate difference is not well-established due to the absence of analytic cohort studies. The clinical significance of such a potential risk remains unclear.

METHODS AND FINDINGS: We extracted data from a territory-wide public healthcare database from January 2001 to August 2022 in Hong Kong to conduct a retrospective cohort study of anonymized patients aged 18+ years with a diagnosis of schizophrenia who used clozapine or olanzapine (drug comparator with highly similar chemical structure and pharmacological mechanisms) for 90+ days, with at least two prior other antipsychotic use records within both groups. Weighted by inverse probability of treatment (IPTW) based on propensity scores, Poisson regression was used to estimate the incidence rate ratio (IRR) of HM between clozapine and olanzapine users. The absolute rate difference was also estimated. In total, 9,965 patients with a median follow-up period of 6.99 years (25th – 75th percentile: 4.45-10.32 years) were included, among which 834 were clozapine users. After IPTW, the demographic and clinical characteristics of clozapine users were comparable to those of olanzapine users. Clozapine users had a significant weighted IRR of 2.22 (95% confidence interval (CI) [1.52, 3.34]; p<0.001) for HM compared to olanzapine users. The absolute rate difference was estimated at 57.40 (95% CI [33.24, 81.55]) per 100,000 person-years. Findings were consistent across sub-groups by age and sex. Sensitivity analyses all supported the robustness of the results and showed good specificity to HM but no other cancers. The main limitation of this observational study is the potential residual confounding effects that could have arisen from the lack of randomization in clozapine or olanzapine use.

CONCLUSION: Absolute rate difference in HM incidence associated with clozapine is small despite a twofold elevated rate. Given the rarity of HM and existing blood monitoring requirements, more restrictive indication for clozapine or special warnings may not be necessary.
Original languageEnglish
Article numbere1004457
Number of pages15
JournalPLoS Medicine
Volume21
Issue number12
Early online date5 Dec 2024
DOIs
Publication statusPublished - 5 Dec 2024

Bibliographical note

Copyright © 2024 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Access Statement

Data underlying the results presented in this article cannot be shared publicly because the raw data is confidential and not allowed for sharing in accordance with the prevailing policies of the Hospital Authority of Hong Kong. The data may be requested from Hong Kong Hospital Authority’s Central Panel on Administrative Assessment of External Data Requests (https://www3.ha.org.hk/data/Provision/Submission). The R statistical programming codes are publicly available at https://doi.org/10.5281/zenodo.13871037

Fingerprint

Dive into the research topics of 'Rare but elevated incidence of hematological malignancy after clozapine use in schizophrenia: a population cohort study'. Together they form a unique fingerprint.

Cite this