Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals

Abstract

Background Benign ethnic neutropenia (BEN) is the most common cause of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent. This phenotype is broadly defined by an absolute neutrophil counts (ANC) below 1.8 × 109 cells/L in the absence of other causes, without an increased risk of infection. BEN has been implicated as a potential source of disparity in patients treated with clozapine, the antipsychotic of choice in treatment-resistant schizophrenia. Our main objective was to examine the current level of BEN recognition in a cohort of patients treated with clozapine and the potential impact of unidentified BEN on the initiation and maintenance of clozapine treatment. Methods This was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again. Results The study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation. Conclusions Current evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.

A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia

“…Findings from genomic studies suggest the involvement of multiple genes, including the solute carrier organic anion transporter 1B3/1B7 and members of the human leukocyte antigen complex [ 116 ]. People of African, Middle Eastern, or West Indian descent may present with benign ethnic neutropenia (BEN; absolute neutrophil counts 1000–1800/mm 3 ) [ 117 ]. BEN is not associated with frequent or severe infections, or a higher risk of agranulocytosis with clozapine treatment [ 118 ]; however, the lower baseline neutrophil levels require a separate monitoring scheme [ 62 ].…”

Frequency of benign neutropenia among Black versus White individuals undergoing a bone marrow assessment

“…However, the underlying problem of health care disparities among those with the Duffy Null phenotype manifests in other, and sometimes more subtle, contexts beyond repeated testing for low WBC levels. For instance, these individuals are more likely to have medications stopped or delayed because of a low ANC not recognized to be related to the Duffy Null phenotype 24–26 27,28 .…”

“…For instance, these individuals are more likely to have medications stopped or delayed because of a low ANC not recognized to be related to the Duffy Null phenotype. 24 , 25 , 26 They are also more likely to be excluded from clinical trials and other studies that have ANC thresholds for inclusion. 27 , 28 Again, many of these disparities could be attenuated with WBC and ANC reference ranges calibrated to the underlying biology.…”

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

“…Qubad & Bittner -Clozapine treatment in schizophrenia In cases of mild neutropenia even before treatment onset, benign ethnic neutropenia (BEN) is an important differential diagnosis, which does not constitute a contraindication [167][168][169][170][171] . Safety thresholds for patients with a confirmed diagnosis of BEN are lower (Figure 3a, Table 3) 172 .…”

“…Monitoring twice per week 91,151,[157][158][159]170  Eosinophilia > 3/nl: search for CIM, pancreatitis, DRESS syndrome, CIA  BEN: does not constitute a contraindication; consider expanding monitoring [167][168][169][170][171]  Most hematological changes are only transient 236 Qubad & Bittner -Clozapine treatment in schizophrenia 35 Sedation* 270,372,396  Regular clinical assessment  Most commonly transient in nature 270,372,396  Titration to lowest effective dose 16,270,372  Minimize day-time doses 270,372  Avoid concomitant sedating drugs 91,270,372 Qubad & Bittner -Clozapine treatment in schizophrenia 36 Myocarditis, cardiomyopathy 199,206  Highest risk during the first four weeks of treatment ULN 148,180,199,206  Cardioprotective treatment: ACEinhibitors and beta blockers 317  In severe cases transfer to intensive care unit 91,191  Symptoms improve within 5 days of treatment termination; most common course: restitutio ad integrum 91,180 , cardiomyopathy is a potential complication…”