Study confirms clozapine safety with first big-data evidence on rare blood cancer cases

An inter-departmental research team at the LKS Faculty of Medicine of the University of Hong Kong (HKUMed) has conducted the world’s first analytic real-world cohort study on the association of clozapine, a highly efficacious antipsychotic drug, with the incidence of blood cancer.

Their findings show that the risk of blood cancer associated with the use of clozapine is very low, with an average increase of less than six cases per 10,000 persons using clozapine for one year. Therefore, the clinical significance of such a risk is plausibly low.

While previous preliminary Western studies have shown a potentially significant increase in risk, this study suggests that with stringent blood monitoring measures before and during clozapine use in Hong Kong and around the world, it may not be necessary to further restrict the use of clozapine or issue special warnings by the Department of Health or local drug regulatory authorities, thus facilitating early and effective treatment of mental illness. The study is published in PLOS Medicine.

Clozapine is currently the only antipsychotic drug approved by the Food and Drug Administration (FDA) of the United States for treatment-resistant schizophrenia. It is widely known for its high efficacy in reducing symptoms, relapse rate, and all-cause mortality in schizophrenia and is widely regarded as a drug of last resort.

Recent Finnish and American studies have suggested that clozapine may be associated with a significantly increased risk of blood cancer. However, due to data restrictions and study design, the additional number of blood cancer cases associated with prior clozapine exposure could not be estimated and remained unclear. The clinical significance of this risk, therefore, had yet to be determined.

The research team used territory-wide electronic health records from the Hospital Authority of Hong Kong to comb through 400,000 patient records to construct a retrospective cohort of approximately 10,000 patients diagnosed with schizophrenia between 2001 and 2022 and followed up for a median of seven years since their drug initiation.

The team’s observations of the patients showed that the absolute risk of blood cancer is very rare. In the cohort of 10,000 patients followed over a period of about seven years, only 39 developed blood cancer. After statistical adjustment, the study estimated that there were fewer than six cases of blood cancer per 10,000 patients using clozapine for one year.

The weighted incidence rate ratio of blood cancer in clozapine users versus controls was estimated at 2.22, suggesting that there is a slight association. This observation is consistent with the findings of previous Finnish and American case-control studies. No association was observed for other cancer types.

“In response to Western studies suggesting a potential risk of blood cancer after clozapine use, this study provides reliable evidence for patients and health care professionals supporting the safety of the drug. The current blood monitoring measures are very comprehensive. Patients do not need to be overly concerned about the risk of blood cancer caused by clozapine given the rarity of its occurrence demonstrated in this study.

“Clinicians should weigh the risks and benefits of the drug, taking into account the rarity of the association between clozapine and blood cancer, and make appropriate arrangements according to patients’ needs,” said Professor Francisco Lai Tsz-tsun, the project leader and Assistant Professor in both the Department of Pharmacology and Pharmacy and the Department of Family Medicine and Primary Care under the School of Clinical Medicine of HKUMed.

“Because of the readily linked and longitudinally available data across all public health care facilities in Hong Kong, we were able to come up with a better study design than those in other countries,” said Professor Lai.

“This enabled us to make immediate use of big data to better address clinically meaningful health care issues than researchers in many other countries, highlighting the key strengths of Hong Kong’s health care big data and its potential application in drug safety monitoring.”

The research team is currently re-examining a wide range of potential adverse effects of other psychotropic drugs, especially cancer risks, and their overall long-term safety and effectiveness. “Ultimately, through our joint interdisciplinary efforts, we hope to better inform day-to-day clinical decisions and make medication use in patients with mental illness much safer and more effective,” Professor Lai added.

An inter-departmental research team at the LKS Faculty of Medicine of the University of Hong Kong (HKUMed) has conducted the world’s first analytic real-world cohort study on the association of clozapine, a highly efficacious antipsychotic drug, with the incidence of blood cancer.

Their findings show that the risk of blood cancer associated with the use of clozapine is very low, with an average increase of less than six cases per 10,000 persons using clozapine for one year. Therefore, the clinical significance of such a risk is plausibly low.

While previous preliminary Western studies have shown a potentially significant increase in risk, this study suggests that with stringent blood monitoring measures before and during clozapine use in Hong Kong and around the world, it may not be necessary to further restrict the use of clozapine or issue special warnings by the Department of Health or local drug regulatory authorities, thus facilitating early and effective treatment of mental illness. The study is published in PLOS Medicine.

Clozapine is currently the only antipsychotic drug approved by the Food and Drug Administration (FDA) of the United States for treatment-resistant schizophrenia. It is widely known for its high efficacy in reducing symptoms, relapse rate, and all-cause mortality in schizophrenia and is widely regarded as a drug of last resort.

Recent Finnish and American studies have suggested that clozapine may be associated with a significantly increased risk of blood cancer. However, due to data restrictions and study design, the additional number of blood cancer cases associated with prior clozapine exposure could not be estimated and remained unclear. The clinical significance of this risk, therefore, had yet to be determined.

The research team used territory-wide electronic health records from the Hospital Authority of Hong Kong to comb through 400,000 patient records to construct a retrospective cohort of approximately 10,000 patients diagnosed with schizophrenia between 2001 and 2022 and followed up for a median of seven years since their drug initiation.

The team’s observations of the patients showed that the absolute risk of blood cancer is very rare. In the cohort of 10,000 patients followed over a period of about seven years, only 39 developed blood cancer. After statistical adjustment, the study estimated that there were fewer than six cases of blood cancer per 10,000 patients using clozapine for one year.

The weighted incidence rate ratio of blood cancer in clozapine users versus controls was estimated at 2.22, suggesting that there is a slight association. This observation is consistent with the findings of previous Finnish and American case-control studies. No association was observed for other cancer types.

“In response to Western studies suggesting a potential risk of blood cancer after clozapine use, this study provides reliable evidence for patients and health care professionals supporting the safety of the drug. The current blood monitoring measures are very comprehensive. Patients do not need to be overly concerned about the risk of blood cancer caused by clozapine given the rarity of its occurrence demonstrated in this study.

“Clinicians should weigh the risks and benefits of the drug, taking into account the rarity of the association between clozapine and blood cancer, and make appropriate arrangements according to patients’ needs,” said Professor Francisco Lai Tsz-tsun, the project leader and Assistant Professor in both the Department of Pharmacology and Pharmacy and the Department of Family Medicine and Primary Care under the School of Clinical Medicine of HKUMed.

“Because of the readily linked and longitudinally available data across all public health care facilities in Hong Kong, we were able to come up with a better study design than those in other countries,” said Professor Lai.

“This enabled us to make immediate use of big data to better address clinically meaningful health care issues than researchers in many other countries, highlighting the key strengths of Hong Kong’s health care big data and its potential application in drug safety monitoring.”

The research team is currently re-examining a wide range of potential adverse effects of other psychotropic drugs, especially cancer risks, and their overall long-term safety and effectiveness. “Ultimately, through our joint interdisciplinary efforts, we hope to better inform day-to-day clinical decisions and make medication use in patients with mental illness much safer and more effective,” Professor Lai added.