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Race, Genotype, and Azathioprine Discontinuation : A Cohort Study.

Authors :
Dickson AL
Daniel LL
Jackson E
Zanussi J
Yang W
Plummer WD
Dupont WD
Wei WQ
Nepal P
Hung AM
Cox NJ
Van Driest SL
Feng Q
Yang JJ
Stein CM
Mosley JD
Chung CP
Source :
Annals of internal medicine [Ann Intern Med] 2022 Aug; Vol. 175 (8), pp. 1092-1099. Date of Electronic Publication: 2022 Jun 21.
Publication Year :
2022

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.<br />Objective: To test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing.<br />Design: Retrospective cohort study.<br />Setting: Two tertiary care centers.<br />Patients: Thiopurine users with White or Black race.<br />Measurements: Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count.<br />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/m <superscript>2</superscript> (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).<br />Limitations: Unmeasured confounding; data limited to tertiary centers.<br />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.<br />Primary Funding Source: National Institutes of Health.

Details

Language :
English
ISSN :
1539-3704
Volume :
175
Issue :
8
Database :
MEDLINE
Journal :
Annals of internal medicine
Publication Type :
Academic Journal
Accession number :
35724382
Full Text :
https://doi.org/10.7326/M21-4675