CC genotype ups risk for azathioprine cessation

The risk for azathioprine discontinuation attributed to haematopoietic toxicity and lower thiopurine doses is higher among patients with the rs2814778-CC genotype, reveals a study. Genotype remains associated with the risk even after adjustment for race.

This retrospective study was conducted at two tertiary care centres and included thiopurine users with White or Black race. The investigators determined whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing.

The primary outcome was azathioprine discontinuation attributed to haematopoietic toxicity, while secondary ones were weight-adjusted final dose, leukocyte count, and change in leukocyte count.

Patients with the CC genotype (n=101) had a higher rate of azathioprine discontinuation attributed to haematopoietic toxicity compared to those with the TT or TC genotype (n=1,365; 3.92 vs 1.34 per 100 person-years; hazard ratio [HR] from competing-risk model, 2.92, 95 percent confidence interval [CI], 1.57‒5.41).

Such risk persisted after adjustment for race (HR, 2.61, 95 percent CI, 1.01‒6.71). The risk associated with race alone (HR, 2.13, 95 percent CI, 1.21‒3.75) was attenuated after adjusting for genotype (HR, 1.13, 95 percent CI, 0.48‒2.69).

Patients with the CC genotype had significantly lower last leukocyte count and lower dosing, which was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukaemia.

Additionally, the CC genotype showed an independent association with lower 6-MP dose intensity compared with the target daily dose of 75 mg/m² (median 0.83 for the CC genotype vs 0.94 for the TT or TC genotype; p=0.013).

This study was limited by unmeasured confounding. The data was also limited to tertiary centres only.

“Thiopurines are an important class of immunosuppressants despite their risk for haematopoietic toxicity and narrow therapeutic indices,” the investigators said. “Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among persons of African ancestries.”