• Alyson L Dickson, Laura L Daniel, Elise Jackson, Jacy Zanussi, Wenjian Yang, W Dale Plummer, William D Dupont, Wei-Qi Wei, Puran Nepal, Adriana M Hung, Nancy J Cox, Sara L Van Driest, QiPing Feng, Jun J Yang, C Michael Stein, Jonathan D Mosley, and Cecilia P Chung.
• Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.D., L.L.D., E.J., J.Z., P.N., A.M.H., N.J.C., Q.F., C.M.S., C.P.C.).
• Ann. Intern. Med. 2022 Aug 1; 175 (8): 109210991092-1099.

BackgroundThiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among persons of African ancestries.ObjectiveTo test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing.DesignRetrospective cohort study.SettingTwo tertiary care centers.PatientsThiopurine users with White or Black race.MeasurementsAzathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count.ResultsThe rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years among patients with the CC genotype (n = 101) and 1.34 per 100 person-years among those with the TT or TC genotype (n = 1365) (hazard ratio [HR] from competing-risk model, 2.92 [95% CI, 1.57 to 5.41]). The risk remained significant after adjustment for race (HR, 2.61 [CI, 1.01 to 6.71]). The risk associated with race alone (HR, 2.13 [CI, 1.21 to 3.75]) was abrogated by adjustment for genotype (HR, 1.13 [CI, 0.48 to 2.69]). Lower last leukocyte count and lower dosing were significant among patients with the CC genotype. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia. The CC genotype was independently associated with lower 6-MP dose intensity relative to the target daily dose of 75 mg/m2 (median, 0.83 [IQR, 0.70 to 0.94] for the CC genotype vs. 0.94 [IQR, 0.72 to 1.13] for the TT or TC genotype; P = 0.013).LimitationsUnmeasured confounding; data limited to tertiary centers.ConclusionPatients with the CC genotype had higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine doses. Genotype was associated with those risks, even after adjustment for race.Primary Funding SourceNational Institutes of Health.

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