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. 2022 Aug;175(8):1092-1099.
doi: 10.7326/M21-4675. Epub 2022 Jun 21.

Race, Genotype, and Azathioprine Discontinuation : A Cohort Study

Alyson L Dickson  1 , Laura L Daniel  1 , Elise Jackson  1 , Jacy Zanussi  1 , Wenjian Yang  2 , W Dale Plummer  3 , William D Dupont  3 , Wei-Qi Wei  4 , Puran Nepal  1 , Adriana M Hung  1 , Nancy J Cox  1 , Sara L Van Driest  5 , QiPing Feng  1 , Jun J Yang  2 , C Michael Stein  1 , Jonathan D Mosley  6 , Cecilia P Chung  1
Affiliations

Race, Genotype, and Azathioprine Discontinuation : A Cohort Study

Alyson L Dickson et al. Ann Intern Med. 2022 Aug.

Abstract

Background: Thiopurines 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.

Objective: To test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing.

Design: Retrospective cohort study.

Setting: Two tertiary care centers.

Patients: Thiopurine users with White or Black race.

Measurements: Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count.

Results: The 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).

Limitations: Unmeasured confounding; data limited to tertiary centers.

Conclusion: Patients 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 source: National Institutes of Health.

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Figures

Figure 1:
Figure 1:
Inclusion Criteria in the VUMC Cohort
Figure 2:
Figure 2:
Probability of Azathioprine Discontinuation for Hematopoietic Toxicity in the VUMC Cohort by rs2814478 Genotype HR=hazard ratio
Figure 3:
Figure 3:
Probability of Azathioprine Discontinuation for Hematopoietic Toxicity in the VUMC Cohort by EHR-Reported Race and rs281447S Genotype EHR=electronic health record, HR=hazard ratio *White-CC patients excluded due to small numbers (n=5)
Figure 4:
Figure 4:
Average Dose Intensity for 6-MP by rs2814478 Genotype in the Validation Cohort 6-MP=6-mercaptopurine
See this image and copyright information in PMC

Comment in

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