Broekman M M T J, Coenen M J H, Wanten G J, van Marrewijk C J, Klungel O H, Verbeek A L M, Hooymans P M, Guchelaar H-J, Scheffer H, Derijks L J J, Wong D R, de Jong D J
Department of Gastroenterology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Human Genetics, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Aliment Pharmacol Ther. 2017 Nov;46(10):953-963. doi: 10.1111/apt.14323. Epub 2017 Sep 15.
Leucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S-methyltransferase (TPMT) gene are the best-known risk factor, but only explain up to 25% of leucopenia cases.
To identify the clinical risk factors for thiopurine-induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections.
Post hoc analysis of the Thiopurine response Optimisation by Pharmacogenetic testing in Inflammatory bowel disease Clinics (TOPIC) trial. For this analysis, patients without a variant in TPMT (*2, 3A or3C) were included. Uni- and multivariate Cox-proportional hazard models were used to identify risk factors for leucopenia and infections. Leucopenia was defined as a white blood cell (WBC) count <3.0 × 10 /L and infections were classified according to the Common Terminology Criteria for Adverse Events.
Sixty hundred and ninety-five patients (90.6%) included in the TOPIC-trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29-112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39-4.88; P < .01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71-0.89; P < .01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18-3.63; P = .01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14-4.07; P = .02]).
Low baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine-induced leucopenia in patients without a TPMT variant.
白细胞减少是硫唑嘌呤治疗患者常见的副作用。硫嘌呤甲基转移酶（TPMT）基因变异是最知名的风险因素，但仅能解释25%的白细胞减少病例。
确定无常见TPMT变异患者中硫唑嘌呤诱导白细胞减少的临床风险因素，并探讨这些患者是否有更高的感染风险。
对炎症性肠病诊所通过药物遗传学检测优化硫嘌呤反应（TOPIC）试验进行事后分析。该分析纳入了TPMT无变异（*2、3A或3C）的患者。采用单因素和多因素Cox比例风险模型确定白细胞减少和感染的风险因素。白细胞减少定义为白细胞（WBC）计数<3.0×10⁹/L，感染根据不良事件通用术语标准进行分类。
TOPIC试验纳入的695例患者（90.6%）TPMT无变异，其中45例（6.5%）发生白细胞减少。白细胞减少的中位时间为56（29 - 112）天。多因素分析显示，与硫唑嘌呤相比，使用巯嘌呤与白细胞减少相关（风险比[HR]2.61[95%可信区间，1.39 - 4.88；P <.01]），较高的基线WBC计数具有保护作用（HR 0.80[95%可信区间，0.71 - 0.89；P <.01]）。感染的风险因素为年龄较大（每10岁；HR 2.07[95%可信区间，1.18 - 3.63；P =.01]）和同时使用生物药物（HR 2.15[95%可信区间，1.14 - 4.07；P =.02]）。
低基线WBC计数和由于剂量相对较高的巯嘌呤是无TPMT变异患者硫唑嘌呤诱导白细胞减少的风险因素。
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