• 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 Chan, Amy Pui Pui Ng, Heidi Ka Ying Lo, Krystal Chi Kei Lee, Wing Chung Chang, William Chi Wai Wong, ChanEsther Wai YinEWY0000-0002-7602-9470Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR.Laboratory of Data Discovery for Health (D24H), , WongIan Chi KeiICK0000-0001-8242-0014Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR.Laboratory of Data Discovery for Health (D24H), Hon, Yi Chai, and Francisco Tsz Tsun Lai.
• Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR.
• PLoS Med. 2024 Dec 1; 21 (12): e1004457e1004457.

BackgroundClozapine 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 FindingsWe 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 2 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 to 75th percentile: 4.45 to 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 subgroups 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.ConclusionsAbsolute rate difference in HM incidence associated with clozapine is small despite a 2-fold elevated rate. Given the rarity of HM and existing blood monitoring requirements, more restrictive indication for clozapine or special warnings may not be necessary.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.

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