ACKR1/Duffy-null genotype testing for clozapine: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).
ACKR1/Duffy-null genotype testing for clozapine: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
London, GB · Author affiliation
Division of Psychiatry, University College London, London, UK.Location evidence
Belfast, GB · Author affiliation
Belfast Health and Social Care Trust, Belfast, UK.Location evidence
GB · Author affiliation · country only
High Secure Intellectual Disability Service for Scotland and Northern Ireland, Carstairs, UK.Location evidence
IE · Author affiliation · country only
High Secure Intellectual Disability Service for Scotland and Northern Ireland, Carstairs, UK.Location evidence
Cardiff, GB · Author affiliation
Cardiff and Vale University Health Board, Cardiff, UK.Location evidence
Birmingham, GB · Author affiliation
Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.Location evidence
Warrington, GB · Author affiliation
Specialist Community Forensic Team for People With Learning Disability and Autism, Hollins Park Hospital, Warrington, UK.Location evidence
Manchester, GB · Author affiliation
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, UK.Location evidence
Bristol, GB · Author affiliation
NHS Blood and Transplant, Bristol, UK.Location evidence
Liverpool, GB · Author affiliation
Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.Location evidence
Cattolica, IT · Author affiliation
Department of Translational Medicine and Surgery, Section of Pharmacology, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.Location evidence
Rome, IT · Author affiliation
Department of Translational Medicine and Surgery, Section of Pharmacology, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.Location evidence
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Original abstract
Clozapine is licenced for treatment-resistant schizophrenia and psychosis in Parkinson's disease. In the United Kingdom, there is a mandatory requirement for absolute neutrophil count (ANC) and white blood cell count (WBC) monitoring to safeguard against agranulocytosis. Some people have naturally low ANCs without increased infection risk, caused by a homozygous T > C variant in ACKR1, commonly called the Duffy-null genotype. This condition is known as ADAN (ACKR1/DARC-associated neutropenia) and synonyms include DANC (Duffy-null associated neutrophil count) and BEN (benign ethnic neutropenia). It is usual UK practice to lower WBC/ANC thresholds for people confirmed to have ADAN. However, ADAN often remains undetected, resulting in unnecessary discontinuation and exclusion from clozapine. This CERSI-PGx guideline provides a framework to offer ACKR1 genotype testing within the existing clinical pathway. We recommend three eligibility criteria, including pre-emptive testing for all people starting clozapine, testing for people registered in the Central Non-Rechallenge Database and reactive testing following a below-threshold blood result (defined as 'amber' or 'red'). We recommend that people with the Duffy-null genotype should be monitored using revised WBC/ANC thresholds for ADAN. Regardless of ACKR1 genotype, haematology input is required for people returning a WBC < 2.0 × 109/L and/or ANC < 1.0 × 109/L who present with a key clinical feature, such as sustained temperature ≥38°C. Finally, we summarize health economic evidence, estimating in the first year of testing, 129 people with the Duffy-null genotype could be identified, resulting in savings ranging from £42 732 to £727 990. We propose ACKR1 testing as a cost-effective approach for facilitating access to clozapine, the optimal therapy for treatment-resistant schizophrenia.