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 & times; 10(9)/L and/or ANC < 1.0 & times; 10(9)/L who present with a key clinical feature, such as sustained temperature >= 38 degrees 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 pound 732 to 727 pound 990. We propose ACKR1 testing as a cost-effective approach for facilitating access to clozapine, the optimal therapy for treatment-resistant schizophrenia.
Murtough, S., Stellakis, O., Mills, D., Bjourson, B., Chaplin, V., Chauhan, D., Chipp, B., Cotic, M., De Villiers, J., Dzahini, O., Elmslie, F., Evans, K., Gandhi, S., Hughes, D. A., Jin, H., Panconesi, D., Skowronska, A., Sisodiya, S. M., Silva, E., Stinton, V., Stuart-Smith, S., Tarrant, S., Taylor, D., Varney, L., Walters, J. T. R., Wood, M., Woodley, J., Dello Russo, C., Pirmohamed, M., Bramon, E., 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), <<BRITISH JOURNAL OF CLINICAL PHARMACOLOGY>>, 2026; 92 (7): 1977-1990. [doi:10.1002/bcp.70576] [https://hdl.handle.net/10807/341256]
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)
Dello Russo, Cinzia
;
2026
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 & times; 10(9)/L and/or ANC < 1.0 & times; 10(9)/L who present with a key clinical feature, such as sustained temperature >= 38 degrees 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 pound 732 to 727 pound 990. We propose ACKR1 testing as a cost-effective approach for facilitating access to clozapine, the optimal therapy for treatment-resistant schizophrenia.
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