Human leukocyte antigen-DRB1*04:05 might be associated with the development of clozapine-induced agranulocytosis in a Japanese patient with schizophrenia

To the Editor

Clozapine may cause serious adverse drug reactions, particularly clozapine-induced agranulocytosis (CIA; Alvir et al., 1993). CIA is associated with specific human leukocyte antigen (HLA) alleles (Numata et al., 2018). A pharmacogenetic study found that HLA-B*59:01 is a risk factor for CIA in Japanese (Saito et al., 2016). This study also revealed a trend of association between HLA-DRB1*04:05 and clozapine-induced agranulocytosis/granulocytopenia (CIAG). However, the authors reported that HLA-DRB1*04:05 is in linkage disequilibrium with HLA-B*59:01, and that the association between HLA-DRB1*04:05 and CIAG is nominal. We report a case of CIA in a Japanese schizophrenia patient who did not have HLA-B*59:01 and had HLA-DRB1*04:05.

A 49-year-old Japanese man with treatment-resistant schizophrenia was admitted to our university hospital for clozapine treatment. He received a combination of 20 mg/day of olanzapine, 16 mg/day of blonanserin and 800 mg/day of lithium. Before starting clozapine therapy, his white blood cell (WBC) count and absolute neutrophil count (ANC) were 9990 and 7752 cells/mm³, respectively. Clozapine was initiated on 27 March 2019 and gradually increased to 400 mg/day, whereas olanzapine and blonanserin were tapered off. His WBC count ranged between about 5000 and 10,000 cells/mm³. On 25 June, 91 days after clozapine initiation, his WBC count and ANC dropped precipitously to 260 and 20 cells/mm³, respectively. We diagnosed him with CIA. His body weight was 57.3 kg, and 100 μg of lenograstim was administered intramuscularly. Clozapine was discontinued immediately, and 12 mg/day of aripiprazole was initiated. Complete blood counts were measured daily. His WBC count and ANC did not increase to the normal range, and lenograstim increased to 250 μg on 29 June. On 5 July, 11 days after CIA occurrence, the patient’s ANC increased to 9560 cells/mm³. After that, his ANC returned to a stable range. Examination of HLA alleles revealed the following: HLA-A*11:01/24:02, HLA-B*54:01/55:02, HLA-Cw*01:02/03:03, HLA-DRB1*04:05/08:03, HLA-DQB1*04:01/06:01.

Several pharmacogenetic studies found that HLA alleles that differ between ethnics are implicated in the development of CIA (Numata et al., 2018). Because agranulocytosis is a rare adverse drug reaction, only 22 patients with CIA were included for detection of the responsible alleles in a study of Japanese (Saito et al., 2016). We suspected that HLA-DRB1*04:05 is in linkage disequilibrium and HLA-DRB1*04:05 might be an independent risk factor for CIA in Japanese. Further pharmacogenetic studies are needed to clarify the HLA alleles associated with CIA.