Clozapine-Associated Neutropenia and Agranulocytosis

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To the Editors
We read with interest the article of Lally et al1 on “clozapine-associated agranulocytosis treatment with granulocyte colony-stimulating factor/granulocyte-macrophage colony-stimulating factor.” It is a well-documented systematic review on a potential life-threatening idiosyncratic drug effects.
Most of the data regarding the efficacy of hematopoietic growth factors (HGF), as granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF), comes from case reports and case series using a comparison control group obtained from historic data.2 Nevertheless, in our opinion, it may be difficult—even unethical—in view of the HGF results to study the effects of these HGF using the criteria for evidence-based medicine, that is, prospective controlled randomize trials.2
In the present letter, we report additional data of our experience and the literature on drug-associated (not exclusively Clozapine) severe neutropenia or agranulocytosis.
Since 1985, two thirds of reported cases of drug-associated agranulocytosis have been treated with HGF.2 The most recent, major studies on HGF use in drug-associated agranulocytosis are described in Table 1.2–4 In our experience, G-CSF and GM-CSF (at a mean dose of 300 μg/d) were found to be useful in shortening the duration of blood count recovery time, without inducing any major toxic or adverse effects, particularly in patients with poor prognostic factors.2 In a multivariate analysis of our patients with idiosyncratic drug-associated agranulocytosis (n = 91), we have previously demonstrated that G-CSF use is an independent variable which positively affected the duration of hematological recovery time.5 We have also demonstrated that the duration of antibiotic therapy and hospital stay are significantly shorter in patients treated with HGF.5
A systematic review of all published case reports of nonchemotherapy drug-induced agranulocytosis by Andersohn et al4 (n = 492) confirms these data. The study by Ibanez et al (Barcelona cohort, n = 162) also concludes that G-CSF shortens recovery time in patients with agranulocytosis (review in Andres et al2). Only one study reported a lower mortality rate with this therapy.2 However, it is worth noting that the only prospective randomized study available did not confirm the benefit of G-CSF (review in Andres et al2). A total of 24 patients with antithyroid-related drug-induced agranulocytosis were enrolled; it is likely that both the small size of the study and the administration of an inappropriately low dose of G-CSF (100 to 200 μg per day) contributed to these negative results.
In an update of our cohort study (n = 201), including 8 patients under clozapine therapy, we have documented that the mean duration of hematological recovery was reduced to 2.1 days (range, 2–16) in patients treated with HGF (n = 107) (P = 0.057).3 The mean duration of antibiotherapy and hospitalization are not impacted (positively) with the use of HGF: 22.3 (range, 7–120) and 30.9 (range, 5–200), respectively (all P >0.4). Importantly, it is important to keep in mind that we have previously established the long-term safety of HGF (mean follow-up >52 months) in the absence of hematological adverse events, such as myelodysplastic syndrome or hematological proliferative disorders.2
To date, no data are available on the use of pegfilgrastim (a long-acting recombinant G-CSF) in idiosyncratic drug-induced neutropenia.
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