Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis

Abstract

The wider use of clozapine is limited by the risk of agranulocytosis and the associated requirement for monitoring of neutrophil counts. We searched local electronic patient records for cases of agranulocytosis occurring during clozapine treatment during the period 2007–2020. We found 23 episodes recorded as agranulocytosis in clozapine patients. Of these, nine met pre-defined criteria and were considered episodes of life-threatening agranulocytosis (LTA). These episodes of clozapine-induced LTA exhibited a distinct pattern of continuous and rapid neutrophil count decline to zero or near zero. Mean time for neutrophils to fall from ANC > 2 to ANC <0.5 × 109/L was 8.4 days (range 2–15 days). Each event was also characterised by a prolonged nadir and delayed recovery (range 4–16 days). Non-LTA episodes were, in contrast, brief and benign. We conclude that an important proportion of cases of agranulocytosis identified in people prescribed clozapine are not life-threatening and may not even be clozapine-related. Monitoring schemes should aim to identify true clozapine-induced LTA as opposed to threshold-defined nominal agranulocytosis. Genetics studies might benefit from examining associations with clozapine-induced LTA rather than with recorded cases of agranulocytosis or neutropenia.

Clozapine haematological monitoring for neutropenia: a global perspective

“…However, meta-analytic evidence suggests that the rate of severe neutropenia is closer to 0.4% and estimated that fatalities are closer to 10%, even without strict monitoring, thus overestimating the impact of stringent monitoring (Myles et al ., 2018; Xiao-Hong et al ., 2020). Moreover, a recent case series has demonstrated how monitoring schemes should aim to identify true clozapine-induced severe neutropenia as opposed to threshold-defined nominal severe neutropenia (Taylor et al ., 2022). In addition, several recent meta-analyses have shown that the risk of clozapine-induced severe neutropenia is highest in the first 6 months (Myles et al ., 2018; Myles et al ., 2019).…”

“…Indefinite monitoring is increasingly questioned from both a safety and a health economics perspective (Lee, 1990;Zhang et al, 1996;Shrivastava and Shah, 2009;Nooijen et al, 2011;Lahdelma and Appelberg, 2012;Cohen and Monden, 2013;Myles et al, 2018Myles et al, , 2019. Routine monitoring increases the likelihood of detecting transient fluctuations in neutrophil count that are unrelated to clozapine treatment, particularly when patients have been established on treatment for many years and have unrecognised haematological phenotypes such as benign neutropenia (Oloyede et al, 2021a(Oloyede et al, , 2021bTaylor et al, 2022). To this end, limiting monitoring to the first few months of treatment, as used in Bulgaria, Mexico and Colombia, is arguably the most evidence-based approach.…”

The history of clozapine in clinical practice: From its introduction to a guideline proposing personalized titrations

“…However, broad myocarditis produced 539 deaths with a relative lethality of 11.7% (539/4586) and broad pneumonia 2077 deaths with 29.7% (2077/6983) (de Leon et al, 2020b). Recently, Taylor et al (2022) have proposed that a significant proportion of cases of agranulocytosis identified in people prescribed clozapine are not life threatening and may not even be clozapine related. on ancestry or pharmacogenetics) were not required in 1989.…”

Safer use of clozapine

“…Clozapine is most famously associated with neutropenia and agranulocytosis, although recent evidence suggests that it does not cause neutropenia and that life-threatening agranulocytosis occurs more rarely than previously thought. 3 Safety monitoring is concentrated on detecting blood toxicity, but other adverse effects such as constipation 4 may be a greater threat to life.…”

“…It does not help, of course, that clozapine has a dizzying range of adverse effects, many of them potentially fatal, and in most countries, can only be prescribed within an arduous regimen of blood testing. Clozapine is most famously associated with neutropenia and agranulocytosis, although recent evidence suggests that it does not cause neutropenia and that life‐threatening agranulocytosis occurs more rarely than previously thought 3 . Safety monitoring is concentrated on detecting blood toxicity, but other adverse effects such as constipation 4 may be a greater threat to life.…”