Azathioprine-related myelosuppression in a patient homozygous for TPMT*3A

Budhiraja, Pooja; Popovtzer, Mordecai M.

doi:10.1038/nrneph.2011.74

Cited by 23 publications

(19 citation statements)

References 29 publications

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“…TPMT genotypes have been proven to be an important molecular biomarker in the response prognosis of drugs currently used in the treatment of hematological malignancies, autoimmune diseases, and organ transplant (8, 41). On the basis of population studies, three alleles account for more than 95% of the clinically relevant TPMT variants: TPMT *2, TPMT *3A, TPMT *3C and subjects who have absent or a reduced rate of enzyme activity than normal have higher circulating drug concentrations and are vulnerable to toxicity when the standard dosage is used.…”

Section: Discussionmentioning

confidence: 99%

“…Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that metabolizes drugs, such as 6-mercaptopurine (6-MP), thioguanine (TG) and azathioprine (AZA), commonly used in chemotherapy and immunosuppressive therapies (8, 41). TPMT activity is a good predictive factor for the toxicity of these drugs and their effectiveness in the treatment of acute lymphocytic leukemia, autoimmune diseases and solid organ transplant.…”

Section: Introductionmentioning

confidence: 99%

“…TPMT activity is a good predictive factor for the toxicity of these drugs and their effectiveness in the treatment of acute lymphocytic leukemia, autoimmune diseases and solid organ transplant. A very low or undetectable enzyme activity results in adverse pharmacokinetics and pharmacodynamics causing decreased turnover and resulting in myelosuppression, infections and secondary tumors (8, 10, 15, 39, 41, 44). It has been well established that the decreased levels of TPMT enzyme activity, is caused by single nucleotide polymorphisms (SNPs) in the TPMT gene.…”

Section: Introductionmentioning

confidence: 99%

“…The most common alleles are TPMT *2 (rs1800462, c.280G>A), TPMT *3A (rs1800460, c.460G>A and rs1142345, c.719A>G), TPMT *3B (rs1800460, c.460G>A) and TPMT *3C (rs1142345, c.719A>G) (1-5, 7, 9, 12, 14, 17-20, 22-25, 27, 28, 30-36, 40, 42, 43, 45-48, 51). These TPMT variants lead to a reduction in TPMT enzyme activity, and patients who are heterozygous for a TPMT mutant allele have an intermediate risk of hematological toxicity, whereas in TPMT *3A homozygote subjects or compound heterozygotes the enzyme activity is very low or undetectable and the risk of toxicity is high (6, 8, 13, 20, 41, 47). Hence, independent groups have suggested a dose reduction of thiopurines or the selection of alternative therapies in mutant allele carriers to avoid side-effects that can be life-threatening due to therapy toxicity (21, 37).…”

Section: Introductionmentioning

confidence: 99%

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Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia

Garrido¹,

Santizo²,

Müllers³

et al. 2013

Med Oncol

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Thiopurine S-methyltransferase (TPMT) polymorphisms affect the enzyme's activity and are predictive for the efficacy and toxicity of thiopurine treatment of acute lymphoblastic leukemia (ALL), autoimmune diseases and organ transplants. Because inter-ethnic differences in the distribution of these polymorphisms have been documented, we sequenced the TMPT gene in 95 Guatemalans, yet identified no new alleles. We also determined the frequency of the TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C alleles in 270 admixed and 177 indigenous pediatric patients with ALL and healthy subjects from Guatemala using TaqMan assays and DNA sequencing. Among the 447 subjects genotyped, 10.0% of the ALL cases and 13.6% of the healthy controls were heterozygous for one of the four TPMT variants screened. The genotype frequencies in ALL and control populations were 0.7% and 1.7% for TPMT*1/*2, 7.4% and 10% for TPMT*1/*3A, 0.3% and 0% for TPMT*1/*B, and 1.5% and 1.1% for TPMT*1/*C, respectively (p= 0.30). No statistically significant differences between admixed and indigenous ALL (p= 0.67) or controls (p= 0.41) groups were detected; however 17% of the admixed healthy group bore one TPMT mutant allele and they have one of the highest reported frequencies of TPMT mutant allele carriers. Because of the clinical implications of these variants for therapeutic response, TPMT allele testing should be considered in all Guatemalan patients to reduce adverse side-effects from thiopurine drug treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia

Garrido¹,

Santizo²,

Müllers³

et al. 2013

Med Oncol

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“…After discontinuation of azathioprine, cell counts typically decrease for several days before returning to baseline levels, with one case documenting pancytopenia as long as 3 weeks after the discontinuation of azathioprine 14. This delayed improvement has been attributed to the persistence of serum and intracellular levels of 6-thioguanine nucleotides after azathioprine has been discontinued 14 21.…”

Section: Discussionmentioning

confidence: 99%

Azathioprine-induced pancytopenia with normal TPMT activity presenting with HSV oral ulcers

2018

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A 65-year-old man with treatment-resistant psoriatic arthritis, hypertension, dyslipidaemia and benign prostatic hyperplasia (BPH) presented with herpes simplex virus (HSV) oral ulcers and a recent 15 lb weight loss due to reduced consumption. Five weeks previously, his methotrexate was tapered and he had begun taking azathioprine. The patient's thiopurine S-methyltransferase (TPMT) activity level was normal prior to starting azathioprine. He was found to have pancytopenia with normal folate levels and azathioprine was discontinued. His pancytopenia worsened, with a nadir 8 days after stopping azathioprine, before returning to normal levels. His oral ulcers improved and he was able to tolerate solid food. This case illustrates that decreased TPMT activity is not the only risk factor for pancytopenia as an adverse reaction to azathioprine. Furthermore, HSV stomatitis may be the presenting symptom of pancytopenia. The timeline of improvement in cell counts illustrated in this patient has implications for the management of suspected azathioprine-induced pancytopenia.

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Implementation of NUDT15 Genotyping to Prevent Azathioprine‐Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population

Wang

Chi

Tsai

et al. 2022

Clin Pharma and Therapeutics

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Azathioprine (AZA) is commonly used for many autoimmune disorders; however, the limitation of its clinical use is due to potential toxicities, including severe leukopenia. Recent studies have identified genetic NUDT15 variants strongly associated with AZA-induced leukopenia in Asian patients. This study aimed to investigate the strength of above genetic association and evaluate the usefulness of prospective screening of the NUDT15 variants to prevent AZA-induced leukopenia in Chinese patients. AZA-induced leukopenia in patients with autoimmune disorders were enrolled from multiple medical centers in Taiwan/China between 2012 and 2017 to determine the strength of genetic association of NUDT15 or TPMT variants by whole exome sequencing (WES). Furthermore, a prospective study was conducted between 2018 and 2021 to investigate the incidence of AZA-induced leukopenia with and without genetic screening. The WES result showed the genetic variants of NUDT15 R139C (rs116855232) (P = 3.7 × 10 −25 , odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1-38.8) and NUDT15 rs746071566 (P = 4.2 × 10 −9 , OR = 7.1, 95% CI = 3.7-13.7), but not TPMT, were associated with AZA-induced leukopenia and NUDT15 R139C variant shows the highest sensitivity with 92.5%. Furthermore, the targeted screening of 1,013 participants for NUDT15 R139C enabled those identified as carriers to use alternative immunosuppressants. This strategy resulted in a significant decrease in the incidence of AZA-induced leukopenia compared with historical incidence (incidence rate = from 7.6% decreased to 0.4%; P = 9.3 × 10 −20 ). In conclusion, the NUDT15 R139C variant was strongly associated with AZA-induced leukopenia in Chinese patients. The genetic screening of NUDT15 R139C followed by use of alternative immunosuppressants in identified carriers effectively decreased the incidence of AZA leukopenia for patients with autoimmune disorders.

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Azathioprine-related myelosuppression in a patient homozygous for TPMT*3A

Abstract: Discontinuation of azathioprine, treatment with an erythropoiesis-stimulating agent, red blood cell transfusions, filgrastim (a granulocyte colony-stimulating factor analogue) and folic acid.

Cited by 23 publications

References 29 publications

Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia

Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia

Azathioprine-induced pancytopenia with normal TPMT activity presenting with HSV oral ulcers

Implementation of NUDT15 Genotyping to Prevent Azathioprine‐Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population

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