Clozapine use tied to haematological malignancy risk in schizophrenia patients

The use of clozapine appears to slightly increase the risk of haematological malignancy (HM) among patients with schizophrenia compared with olanzapine use, suggests a study.

The “[a]bsolute rate difference in HM incidence associated with clozapine is small despite a twofold elevated rate,” the investigators said. “Given the rarity of HM and existing blood monitoring requirements, more restrictive indication for clozapine or special warnings may not be necessary.”

In this retrospective cohort study, data were extracted from a territory-wide public healthcare database from January 2001 to August 2022 in Hong Kong. A total of 9,965 adult patients with a diagnosis of schizophrenia who used clozapine or olanzapine for ≥90 days, with at least two prior other antipsychotic use records within both groups, were included.

The investigators used Poisson regression, weighted by inverse probability of treatment (IPTW) based on propensity scores, to measure the incidence rate ratio (IRR) of HM between users of clozapine and olanzapine. They also estimated the absolute rate difference. The median follow-up was 6.99 years.

Of the patients, 834 were clozapine users. After IPTW, the demographic and clinical characteristics were similar between clozapine and olanzapine users. [PLoS Med 2024;21:e1004457]

Compared with olanzapine users, those on clozapine had a significant weighted IRR for HM of 2.22 (95 percent confidence interval [CI], 1.52–3.34; p<0.001), with an absolute rate difference of 57.40 (95 percent CI, 33.24–81.55) per 100,000 person-years. 

These results persisted across subgroups by age and sex. Sensitivity analyses confirmed the strength of the findings and demonstrated good specificity to HM, but not to other types of cancer.

Causal association

“The strong association observed in this and the previous two case-control studies, as well as its good coherence with previous evidence on the haematological abnormalities associated with clozapine, constitute a strong case that this association is likely causal,” the investigators said. [PLoS Med 2014;11:e1001760]

“We believe the effects of blood abnormalities being induced by the prolonged use of clozapine may accumulate over the duration of use and potentially increase the risk of malignancy through a range of potential mechanisms,” they added. [Lancet Infect Dis 2020;20:1089-1098]

Recent evidence indicated that the increased risk of agranulocytosis after using clozapine seemed to persist for many years. Such mechanism could lead to an increased risk of other blood-related disorders among clozapine users, such as HM. [Arch Intern Med 2003;163:1009-1021]

“Although the absolute rate difference is small, a very long duration of clozapine use, which is not uncommon, may constitute a non-negligible cumulative risk of HM,” the investigators said, noting that further research should examine specific HM types.

Moreover, “the potential reasons for the weighted IRR estimated for all other cancers being significantly lower than one requires further research to investigate, which may include potential protective effect of clozapine on certain types of cancer suggested by previous cell line studies,” they added. [PLoS ONE 2011;6:e20755]

The present study was limited by the potential residual confounding effects, which could have been driven by the lack of randomization in clozapine and olanzapine use.