Big data support clozapine’s safety: Rare incidence of blood cancer

An analytic cohort study in Hong Kong has shown that clozapine is associated with a rare but two-fold increased rate of haematological malignancy. Special warnings or more restrictive indications for its use may not be necessary.

Clozapine is the only drug approved by the US FDA for treatment-resistant schizophrenia. Recent case-control studies in Finland and the US suggested a potential association between its use and haematological malignancy. Nevertheless, the absolute rate difference is not well established due to the absence of analytic cohort studies. The clinical significance of this potential risk remains unclear. [Prim Care Companion CNS Disord 2024;26:23f03702; Lancet Psychiatry 2022;9:353-362; J Clin Psychiatry 2024;85:23m15149; PLoS Med 2024;21:e1004457]

Therefore, researchers from the University of Hong Kong (HKU) conducted an analytic cohort study using data from the Hospital Authority’s Clinical Management System. The study included adult patients with schizophrenia who had a record of using clozapine (n=834) or olanzapine (n=9,131) for ≥90 days between January 2001 and August 2022, and were followed up for a median of 6.99 years. [PLoS Med 2024;21:e1004457]

“To the best of our knowledge, this is the world’s first analytic cohort study on this association to estimate absolute rate differences,” noted the researchers.

Clozapine users had a significant weighted incidence rate ratio (IRR) of 2.22 (95 percent confidence interval [CI], 1.52–3.34; p<0.001) for haematological malignancy compared with olanzapine users, suggesting that there was a slight association.

Notably, the absolute risk of haematological malignancy was very low. In the cohort of 10,000 patients followed over a period of about 7 years, only 39 patients developed haematological malignancy, including nine from the clozapine group and 30 from the olanzapine group. After statistical adjustment, the rate difference was small, with <50 additional cases of haematological malignancy per 100,000 person-years of clozapine vs olanzapine use (95 percent CI, 33.24–81.55).

There was no evidence of heterogeneity across gender or age subgroups. Sensitivity analyses supported the robustness of the results and showed good specificity to haematological malignancy but not other cancer types.

“Our study provides reliable evidence for patients and healthcare professionals, supporting the safety of clozapine,” commented Professor Francisco Tsz-Tsun Lai of the Department of Pharmacology and Pharmacy and the Department of Family Medicine, HKU. “Given the rarity of haematological malignancy and existing comprehensive blood monitoring requirements, special warnings or more restrictive indications for clozapine use may not be necessary.”

“One of the key strengths of this study is the cohort design with a range of important confounding factors properly adjusted, including prior antipsychotic use, underlying mental illnesses, and history of immunological diseases observed at e baseline,” said the researchers.

“Additionally, the comprehensive medical records, based on a consistent coding system and practices, confer great strengths, such as good generalizability and representativeness of the findings,” added Lai. “This allows us to leverage big data to address clinically meaningful healthcare issues more efficiently than researchers in many other countries, highlighting the unique strengths of Hong Kong’s healthcare big data and its potential applications in drug safety monitoring.”