Dr Jari Tiihonen
Long-term treatment with clozapine is associated with a small, but significant, risk of hematological malignancies in individuals with schizophrenia, new research shows.
Investigators found long-term clozapine use of more than 5 years was linked to a 2.7-fold increased risk of hematological malignancies in a dose-dependent manner compared with other antipsychotics.
“Our results suggest long-term clozapine use is associated with increased risk of hematological malignancy, but the absolute risk is small compared with the absolute risk reduction in all-cause mortality associated with clozapine treatment compared with other antipsychotics,” lead researcher Jari Tiihonen, MD, PhD, professor, Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, Sweden, told Medscape Medical News.
The study was published online March 22 in Lancet Psychiatry.
An Unresolved Issue
Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality compared with other antipsychotics, but its use is restricted in many countries, the researchers note.
Reports of nine deaths associated with clozapine use — eight due to agranulocytosis and one due to leukemia — in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.
Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.
“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Tiihonen.
Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries clozapine use is less than half of that in Finland largely because of agranulocytosis concerns.
To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.
“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Tiihonen noted.
The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.
Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18 to 85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
Patient Education, Vigilant Monitoring
The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.
Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3743 study participants.
Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.
Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% CI, 2.22 – 5.05] for ≥ 5000 defined daily dose cumulative exposure (P < .0001).
Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.
Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.
The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.
These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
A “Vital” Medication
Dr Stephen Marder
Commenting on the findings for Medscape Medical News, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the Department of Psychiatry at UCLA in Los Angeles, California, noted the link between clozapine and agranulocytosis.
“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.
In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.
The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Marder.
“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.
“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Marder.
The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Tiihonen and Marder have reported no relevant financial relationships.
Lancet Psychiatry. 2022;9:353-362. Abstract
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