The timing and severity of clozapine-associated neutropenia in the US: Is the risk overstated?

Background Concern about clozapine-associated neutropenia contributes to clozapine's underutilization and racial disparities in access. People with African ancestry are more likely to have lower normative absolute neutrophil counts (ANC), associated with the Duffy null genetic polymorphism. Recent data on clozapine-associated neutropenia in the US are lacking. Methods Patients prescribed clozapine in the Johns Hopkins Medicine electronic medical record (EMR) between 2013 and 2023 were identified. Duffy null Associated Neutrophil Count (DANC) was assigned if there were two ANC's < 2000 cells/μL, >30 days apart, before starting clozapine. Rates of neutropenia, timing of first neutropenia, and demographic differences were explored. Results 974 received clozapine and had ANC's available, with 63.9 % male, 51.1 % White, and 39 % Black. 287 were presumed to start clozapine during the study period, and were 62.4 % male, 46 % White, and 44.9 % Black. No patients developed severe neutropenia. 59 (6.1 %) developed mild or moderate neutropenia. 19 (6.6 %) new starts had presumed DANC, and none developed neutropenia. 11 of 16 presumed new starts who developed neutropenia did so within eight months. No demographic differences were found between groups for presumed new starts. For non-new starts, where DANC assignment was not possible, Black patients were more likely than White patients to develop neutropenia (OR 3.48, 95 % CI [1.65, 7.73]). Discussion To our knowledge, this is the first observational study of clozapine-associated neutropenia in the US in the past decade, and it includes a substantial proportion of Black patients. ANC monitoring requirements may be too strict, contributing to clozapine underutilization.

背景 对氯氮平相关中性粒细胞减少症的担忧导致氯氮平使用不足以及获取方面的种族差异。非洲裔人群更有可能具有较低的正常绝对中性粒细胞计数（ANC），这与达菲血型阴性基因多态性有关。美国近期缺乏关于氯氮平相关中性粒细胞减少症的数据。 方法 确定了2013年至2023年间在约翰霍普金斯医学电子病历（EMR）中开具氯氮平处方的患者。如果在开始使用氯氮平之前有两次ANC＜2000个细胞/微升，且间隔＞30天，则确定为达菲血型阴性相关中性粒细胞计数（DANC）。研究了中性粒细胞减少症的发生率、首次出现中性粒细胞减少症的时间以及人口统计学差异。 结果 974名患者接受了氯氮平治疗且有可用的ANC数据，其中63.9%为男性，51.1%为白人，39%为黑人。推测有287名患者在研究期间开始使用氯氮平，其中62.4%为男性，46%为白人，44.9%为黑人。没有患者出现严重的中性粒细胞减少症。59名（6.1%）患者出现轻度或中度中性粒细胞减少症。19名（6.6%）新开始使用氯氮平的患者被推测有DANC，且无人出现中性粒细胞减少症。16名被推测为新开始使用且出现中性粒细胞减少症的患者中有11名是在8个月内出现的。在被推测为新开始使用的患者组之间未发现人口统计学差异。对于无法确定DANC的非新开始使用的患者，黑人患者比白人患者更有可能出现中性粒细胞减少症（比值比3.48，95%置信区间[1.65, 7.73]）。 讨论 据我们所知，这是过去十年美国首次对氯氮平相关中性粒细胞减少症进行的观察性研究，且其中包括相当比例的黑人患者。ANC监测要求可能过于严格，导致氯氮平使用不足。