First Case of Azathioprine-Induced Severe Hematotoxicity in a Tunisian Patient With Homozygous TT for NUDT15 rs116855232

Azathioprine can induce severe myelosuppression, especially leucopenia, in some susceptible individuals. Genome-wide association studies have identified a missense variant in the NUDT15 (rs116855232; c.415C>T), a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives, which was strongly associated with thiopurine-related myelosuppression in Asian patients. Here, we report the first case of a Tunisian (North African) patient suffering from azathioprineinduced severe hematotoxicity who carried the NUDT15 c.415C>T mutant allele (NUDT15*3). This patient, a 42-year-old man with inflammatory bowel disease, was admitted to the hospital for anorexia and high fever. He was initiated on azathioprine (2.27 mg/kg/d) 3 weeks prior to admission. There was no history of azathioprine or mercaptopurine administration in the past. On admission, the patient was febrile (38.8°C). Laboratory values included a white blood cell count (WBC) of 0.640 × 10/L (normal range 4.5-11.0 × 109/L), hemoglobin of 92 g/L (normal range 140-175 g/L), and platelet count of 86 × 10/L (normal range 150-350 × 10/L). Prior to azathioprine therapy, WBC was 10.7 × 10/L, hemoglobin level was 144 g/L, and platelet count was 460 × 10/L. Azathioprine was discontinued immediately, whereas prednisone was continued, with addition of antibiotics (amikacin 1 g/d, imipenem 2 g/d, and vancomycin 2 g/d). He also received a daily subcutaneous administration of granulocyte colony-stimulating factor analogue. Ten days after the withdrawal of azathioprine, the patient was afebrile. His leucocyte count was 5.5 × 10/L, hemoglobin level was 103 g/L, and platelet count was 322 × 10/L. Antibiotics were discontinued. Total genomic DNA was extracted from peripheral blood using the QIAamp DNeasy Kit (QIAGEN, Germany) according to the manufacturer’s instructions. Genotype of NUDT15 was determined by polymerase chain reaction and Sanger sequencing using specific primers of coding regions of this gene (exons 1, 2, and 3). Sequence alignment and comparison were performed using the ClustalW2 program. Genetic testing revealed that our patient is a homozygous TT for SNP rs116855232 in the NUDT15 gene (Figure 1). According to the objective causality assessment by the Naranjo probability scale, azathioprineinduced hematotoxicity was probable. To the best of our knowledge, this is the first report in a North African patient with the TT genotype at rs116855232 (NUDT15*3) who developed severe hematotoxicity following azathioprine treatment. The NUDT15 polymorphism (rs116855232, p.Arg139Cys) was first reported in 2014 as being strongly correlated with leucopenia among patients with Crohn’s disease treated with azathioprine. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. Patients with TT genotype at rs116855232 were extremely sensitive to thiopurine drugs, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes. According to the ExAC database (available at http://exac.broadinstitute.org), the population frequency of the heterozygous genotype C/T (rs116855232) is high in East Asians (10.4%) and Latinos (7.1%), rare in Europeans (non-Finnish; 0.46%), and very rare in Africans (0.07%) (http://exac.broadinstitute.org/). However, the homozygous genotype TT has only been observed in 1% of the East Asian population and 0.078% in the worldwide population. There is a growing appreciation of NUDT15 variants as the primary genetic cause for thiopurine toxicity in Asians and Europeans. In particular, the variant C>T has been studied most extensively in patients receiving thiopurine therapy, thus providing the strongest evidence for clinical pharmacogenetics implementation. However, the importance of this gene in thiopurine pharmacogenetics was less understood in Africans, probably because of the very rarity 887921 AOPXXX10.1177/1060028019887921Annals of PharmacotherapyBen Salem et al letter2019