Mercaptopurine Therapy Intolerance and Heterozygosity at the Thiopurine S-Methyltransferase Gene Locus

Relling, Mary V.; Hancock, Michael L.; Rivera, Gaston K.; Sandlund, John T.; Ribeiro, Raul C.; Krynetski, Eugene Y.; Pui, Ching‐Hon; Evans, William E.

doi:10.1093/jnci/91.23.2001

Cited by 669 publications

(481 citation statements)

References 34 publications

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“…Indeed, it has been shown that patients with TPMT deficiency tolerate high 6-TGN levels better than patients with normal TPMT activity. 35 Other side-effects due to AZA, including arthralgia, digestive intolerance and rash, did not recur under TG. Some of them have recently been attributed to the nitroimidazole metabolites released from AZA to give MP.…”

Section: Discussionmentioning

confidence: 92%

Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine

Bonaz

Boitard

Marteau

et al. 2003

Aliment Pharmacol Ther

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Summary Background: Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases. Aims : To evaluate the tolerance and efficacy of TG in patients with Crohn's disease, intolerant or resistant to AZA/MP. Methods : An open prospective study was made on Crohn's disease patients treated with TG. Intolerance to AZA/MP was defined as a reaction occurring within 1 month after introduction of AZA/MP, including pancreatitis, abdominal pain, fever, arthralgia, myalgia, cutaneous rash, fatigue, alopecia, hepatitis and digestive intolerance. Resistance to AZA/MP was defined as the persistence of activity after at least 3 months of AZA/MP therapy. Results : Forty‐nine Crohn's disease patients (36 women, 13 men; intolerance: n = 39; resistance: n= 10) were treated with TG (20 mg/day). Clinical pancreatitis did not recur under TG. Five patients (10%) had to stop TG due to intolerant reactions observed 13–21 days after TG was started. No haematological side‐effects were observed under TG. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79%, respectively, in the 40 patients with active disease at baseline. The probability of clinical relapse during maintenance TG therapy at 6 and 12 months was 29% and 53%, respectively, in the 28 patients in remission at baseline or who had achieved remission on TG. Conclusions : TG is a possible alternative treatment in Crohn's disease patients, intolerant (especially for pancreatitis) or resistant to AZA/MP.

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Section: Discussionmentioning

confidence: 92%

Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine

Bonaz

Boitard

Marteau

et al. 2003

Aliment Pharmacol Ther

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“…In childhood ALL thiopurines constitute a major part of long-term continuing chemotherapy and it is important to identify treatment variables that could in¯uence the systemic exposure to active drug metabolites. TPMT activity has been related to the outcome and/or toxicity of therapy retrospectively [9,11,26]. For the TPMT de®cient child a knowledge of complete absence of TPMT activity can predict dose limiting severe myelotoxicity [13±15].…”

Section: Discussionmentioning

confidence: 99%

Human thiopurine methyltransferase activity varies with red blood cell age

Lennard

Chew

Lilleyman

2001

Brit J Clinical Pharma

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Aims Inherited differences in thiopurine methyltransferase (TPMT) activity are an important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The aim of this study was to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that can influence TPMT activity within the RBC. Methods Blood samples were collected from children with ALL at disease diagnosis, prior to any blood transfusions, as part of the nationwide UK MRC ALL97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age‐fractionated on Percoll density gradients. Results Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654–18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P < 0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a median of 11.98 units with a CV of 11.6%. Seven children had their RBCs age‐fractionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradient (old cells) 1.5–12.6 units (median 4.7 units), median difference 2.3 units, 95% CI 0.7, 4.1, P = 0.035. Conclusions Circulating RBCs do not constitute a homogeneous population. They have a life span of around 120 days and during that time undergo a progressive ageing process. The anaemia of ALL is due to deficient RBC production. The results of this study indicate that RBC TPMT activities are significantly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs.

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“…Rare individuals who are homozygous for loss of function variants are at high risk for bone marrow aplasia during therapy with standard doses, and this is stated in the package label. Ten percent of persons carry a single abnormal allele and are also at increased risk for bone marrow toxicity (18,19). Conversely, "standard" doses of mercaptopurine that are used in the 90% of patients with functional alleles mutations (see Glossary) may in fact be inadequate for achieving an optimal antileukemic effect (20).…”

Section: Coding-region Variantsmentioning

confidence: 99%

Pharmacogenomics: Challenges and Opportunities

Roden¹

2006

Ann Intern Med

228

136

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Mercaptopurine Therapy Intolerance and Heterozygosity at the Thiopurine S-Methyltransferase Gene Locus

Abstract: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.

Cited by 669 publications

References 34 publications

Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine

Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine

Human thiopurine methyltransferase activity varies with red blood cell age

Pharmacogenomics: Challenges and Opportunities

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