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

PLoS Med. 2024 Dec 5;21(12):e1004457. doi: 10.1371/journal.pmed.1004457. eCollection 2024 Dec.

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 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.

Conclusions: Absolute 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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antipsychotic Agents* / adverse effects
  • Antipsychotic Agents* / therapeutic use
  • Clozapine* / adverse effects
  • Clozapine* / therapeutic use
  • Cohort Studies
  • Female
  • Hematologic Neoplasms* / chemically induced
  • Hematologic Neoplasms* / drug therapy
  • Hematologic Neoplasms* / epidemiology
  • Hong Kong / epidemiology
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Olanzapine* / adverse effects
  • Olanzapine* / therapeutic use
  • Retrospective Studies
  • Schizophrenia* / drug therapy
  • Schizophrenia* / epidemiology
  • Young Adult

Substances

  • Clozapine
  • Antipsychotic Agents
  • Olanzapine

Grants and funding

This work is partially funded by the Laboratory of Data Discovery for Health (D24H) under AIR@InnoHK (ICKW and FTTL) administered by the Innovation and Technology Commission. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.