Thiopurine S‐methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6‐mercaptopurine doses during maintenance therapy: The Polish multicenter analysis

Peregud-Pogorzelski, Jarosław; Tetera-Rudnicka, Edyta; Kurzawski, Mateusz; Brodkiewicz, Andrzej; Adrianowska, Natalia; Młynarski, Wojciech; Januszkiewicz, Danuta; Droździk, Marek

doi:10.1002/pbc.23013

Cited by 29 publications

(18 citation statements)

References 32 publications

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“…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. In single TPMT functional and non-functional allele carriers, the initial doses of AZA or 6-mercaptopurine should be reduced by 30-70%, whereas in homozygote non-functional allele carriers the doses of thiopurine drugs should be reduced 10-fold, or patients should receive alternative therapy (35). Therefore a simple test for TPMT genotypes can provide an important molecular biomarker that predicts drug response for hematological malignancies, autoimmune diseases, and organ transplantation (8, 41).…”

Section: Discussionmentioning

confidence: 99%

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%

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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“…In western researches, both thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variant alleles have been reported to influence the need for 6-MP dose reduction or therapy interruption during maintenance therapy. [1][2][3][4] TPMT variant alleles are rare in the Japanese population, and even patients with wild-type TPMT alleles have shown severe toxicities that require therapy interruption or 6-MP dose reduction in Japanese. We have previously reported that patients with low ITPA activity frequently required therapeutic dose reduction.…”

Section: Introductionmentioning

confidence: 99%

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

et al. 2014

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Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30 − 50 mg m − 2 in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m − 2 , P = 0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

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“…Those patients with TPMT*3A and TPMT*3C alleles required more frequent 6-MP dose reduction due to side effects such as anaemia and/or thrombocytopenia, leucopenia with respiratory tract infection. The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6-MP therapy [22]. De Jonge et al investigated the influence of polymorphisms of genes involved in folate metabolism on methotrexate sensitivity in vitro in 157 cases of paediatric ALL.…”

Section: Polymorphism In Drug Metabolising Genes and Treatment Responsementioning

confidence: 99%

How Have Advances in Our Understanding of the Molecular Genetics of Paediatric Leukaemia Led to Improved Targeted Therapies for These Diseases?

Szychot¹,

Brodkiewicz²,

Peregud-Pogorzelski³

2014

Adv Clin Exp Med

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The term "leukaemia" refers to a large and heterogenous group of diseases, with treatment response and outcome dependent on the specific type of malignancy. New molecular methods allow us to specifically evaluate the type of disorder, and provide treatment of necessary intensity. The aim of this review is to provide insight into the progress in leukaemia treatment that had been possible due to advances in molecular genetics over the last few decades. Those new sophisticated diagnostic methods have allowed us not only to predict patients' prognosis but also to provide a specific therapy depending on the molecular and genetic characteristics of patients. Our review is based on 25 articles regarding novel diagnostic and therapeutic methods as well as prognostic factors, released between 1992 and 2011. Those articles focus mostly on molecular and cytogenetic testing allowing revolutionary methods of patient classification and individual therapy for this highly heterogeneous group of disorders. Implementation of molecular genetic testing to evaluate the type of leukaemia allowed paediatric oncologists and haematologists to adjust the intensity of treatment, improve outcome, minimize toxicity of therapies and considerably lower the risk of side effects. In the last few decades there has been a great improvement in survival among children suffering from haematopoietic malignancies. Progress made in molecular genetics allowed the creation of new treatment protocols that are designed to maintain a high cure rate for children with leukaemia while reducing toxicity (Adv Clin Exp Med 2014, 23, 3, 469-474).

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Thiopurine S‐methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6‐mercaptopurine doses during maintenance therapy: The Polish multicenter analysis

Abstract: The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6-MP therapy.

Cited by 29 publications

References 32 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

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

How Have Advances in Our Understanding of the Molecular Genetics of Paediatric Leukaemia Led to Improved Targeted Therapies for These Diseases?

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