ACKR1 variant increases risk of azathioprine-related hematopoietic toxicity

1. Patients with the ACKR1 variant (CC genotype) had an elevated risk of azathioprine discontinuation attributed to hematopoietic toxicity.

2. The CC genotype group remained at elevated risk after adjustment for sociodemographic characteristics, including race.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Azathioprine is a thiopurine drug and widely used immunosuppressant for conditions such as systemic lupus erythematosus and inflammatory bowel disease. However, azathioprine has a narrow therapeutic index and thus may be discontinued due to adverse effects, primarily hematopoietic toxicity. The ACKR1 gene variant (the CC genotype) is found in approximately half of the individuals living in the United States with African ancestries. Further, this variant has been proposed to confer a higher rate of hematopoietic toxicity associated with discontinued use of azathioprine. However, there is a gap in knowledge as to understanding whether the CC genotype is associated with differences in thiopurine discontinuation and hematopoietic toxicity, particularly stratified by race, and age as well as TMPT and NUDT15 metabolizer status. This study found that patients with the CC genotype have a higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and received lower doses of thiopurines, even after adjustment for race. This study was limited by data being restricted to tertiary centers, potentially resulting in preselection for access to care and/or socioeconomic factors. Nevertheless, these findings are significant, as they demonstrate that patients with the CC genotype are more likely to discontinue the use of azathioprine primarily due to hematopoietic toxicity.

Click to read the study in AIM

Relevant Reading: Beyond Race: A Wake-up Call for Drug Therapy Informed by Genotyping

In-Depth [retrospective cohort study]: This retrospective cohort study was conducted at a clinical practice-based biobank at Vanderbilt University Medical center, including 1,466 patients. Patients who were new azathioprine users, were prescribed azathioprine for inflammatory conditions, and had reported Black or White race were eligible for the study. Patients who had documented previous treatment with a thiopurine and previous medical history that could indicate compromised genetic material, such as a history of stem cell transplant, were excluded from the study. The primary outcome was discontinuation of azathioprine attributed to hematopoietic toxicity, defined as leukopenia, neutropenia, thrombocytopenia, pancytopenia, and/or anemia. Outcomes in the primary analysis were assessed via sensitivity analysis and estimation of incidence rates of azathioprine discontinuation attributed to hematopoietic toxicity. Based on the primary analysis, the rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years in the CC-genotype patient group and 1.34 per 100 person-years in the TT or TC genotype (comparison group), resulting in a hazard ratio (HR) of 2.92 (95% Confidence Interval [CI], 1.57 to 5.41). The risk remained significant after race adjustment (HR 2.61, 95% CI 1.01 to 6.71). Lower last leukocyte count and lower dosing were also significant among the CC genotype patient group. The CC genotype was also independently associated with a lower 6-MP dose intensity relative to the target daily dose of 75 mg/m^2. Overall, this study demonstrates that patients with the CC genotype have a significantly higher risk of discontinuing azathioprine due to hematopoietic toxicity and lower overall thiopurine dose, which is independent of race.

Image: PD

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