Add-On Filgrastim During Clozapine Rechallenge in Patients With a History of Clozapine-Related Granulocytopenia/Agranulocytosis
To the Editor: Clozapine treatment is often discontinued as a result of clozapine-related granulocytopenia/agranulocytosis, even among patients who are resistant to other antipsychotics. Moreover, clozapine re-exposure is sometimes undertaken among patients with a history of clozapine-related granulocytopenia/agranulocytosis whose previous good response to the drug cannot be maintained with other treatments. Prior to a recent report of the failure to prevent clozapine-related granulocytopenia/agranulocytosis with concomitant granulocyte colony stimulating factor filgrastim (1) , we used a clozapine-filgrastim combination to treat five patients with a history of clozapine-related granulocytopenia/agranulocytosis. Our attempts were encouraged by several earlier successful case reports (2) .
We examined five schizophrenia patients who were resistant to numerous antipsychotic drugs (demographic and clinical characteristics of these patients are presented in a supplemental table that accompanies the online version of this letter). During previous clozapine exposure, these patients achieved a clinical response rating (physician’s global impression based on patient records) of at least “fair.” In all cases, treatment with clozapine had to be discontinued as a result of clozapine-related granulocytopenia/agranulocytosis. One patient (patient 2) also developed sepsis, which was successfully treated.
Despite usual treatment, severe and prolonged psychotic states re-emerged in the patients. Consequently, a clinical decision for the use of clozapine rechallenge with concomitant filgrastim was made following a thorough risk-benefit consideration. After complete description of the possible risks was given, oral informed consent was obtained from each patient. In four patients, clozapine (step-wise increase) and filgrastim (dosage was according to clinical judgment, with no standard schedule applied) were started simultaneously, and in one patient, filgrastim was added to clozapine 2 weeks after reonset of clozapine-related granulocytopenia/agranulocytosis.
For each patient, a clinical response of at least “fair” was reachieved. However, four patients redeveloped clozapine-related granulocytopenia/agranulocytosis. Among these, clozapine treatment was discontinued for two patients whose granulocyte count dropped below the critical <1xE/l level. At the time of the present report, clozapine treatment was continued for the three remaining patients, despite the reoccurrence of noncritical clozapine-related granulocytopenia/agranulocytosis in two of these patients.
The patient (who had sepsis at first clozapine exposure) whose clozapine treatment was discontinued developed full-blown agranulocytosis, with peritonsillitis, epiglottitis, and sepsis. The condition was resolved later, with no sequelae.
As a result of our small data size, we were unable to identify a clear-cut relationship between filgrastim dosing and a clozapine-related granulocytopenia/ agranulocytosis protecting effect. However, both patients who received a filgrastim dose of >0.3 mg/week were able to continue clozapine treatment, despite re-emergence of clozapine-related granulocytopenia/agranulocytosis, and one patient who received a dose of 0.3 mg/week developed agranulocytosis and sepsis.
It has been previously suggested that severe clozapine-induced agranulocytosis is caused by an immunoallergic idiosyncratic mechanism that is unrelated to a granulocyte colony stimulating factor, while mild granulocytopenia results from prolonged clozapine exposure and decreased granulocyte production by hypoplastic bone marrow.
We feel that, despite an add-on filgrastim, clozapine rechallenge is potentially dangerous, at least for patients who have a history of severe clozapine-related agranulocytosis and sepsis. In the future, if clinicians decide to use the clozapine-filgrastim combination, it is important that they seek to publish their cases, since a greater number of cases in the literature may enable the detection of plausible risk factors.
1. Majczenko T, Stewart J: Failure of filgrastim to prevent severe clozapine-induced agranulocytosis. South Med J 2008; 101:639–640Google Scholar
2. Hagg S, Rosenius S, Spigset O: Long-term combination treatment with clozapine and filgrastim in patients with clozapine- induced agranulocytosis. Int Clin Psychopharmacol 2003; 18:173–174Google Scholar
