No abstract available.
6-Mercaptopurine/*adverse effects/metabolism/therapeutic use ; Antimetabolites, Antineoplastic/adverse effects/therapeutic use ; Azathioprine/*adverse effects/therapeutic use ; Cohort Studies ; Drug Therapy, Combination ; Humans ; Inflammatory Bowel Diseases/*drug therapy/etiology ; Leukopenia/chemically induced

OBJECTIVETo explore 6-mercaptopurine (6-MP) treatment-related adverse reactions in children with acute lymphoblastic leukemia (ALL), and to assess the association between the polymorphisms of thiopurine methyltransferase (TPMT) gene and these 6-MP related toxicities.

METHODSTotal RNA was extracted from bone marrow samples of 46 children with ALL and was then reversed to cDNA. TPMT(*)1S and (*)3C were screened by denaturing gradient gel electrophoresis (DGGE) combining with DNA sequencing. Drug toxicities were classified according to national cancer institute-common toxicity criteria version 3.0 (NCI CTC 3.0). The relationship between TPMT gene polymorphisms and the adverse reactions of 6-MP treatment was analyzed.

RESULTSDuring the maintenance treatment period, 22% (10/46) of children discontinued 6-MP treatment because of serious adverse reactions. Two children with TPMT(*)3C genotypes presented severe adverse reactions, including 1 child with homozygotic mutation who had 6-MP dose-related myelosuppression and hepatotoxicity. The main side effects of 6-MP were myelosuppression, hepatotoxicity and gastrointestinal reaction. And there were no significant differences between TPMT(*)1S genotypes and severe myelosuppression or hepatotoxicity caused by 6-MP (P>0.05).

CONCLUSIONSTPMT(*)3C may correlate with severe adverse reactions caused by 6-MP.

Child ; Child, Preschool ; Female ; Humans ; Male ; Mercaptopurine ; adverse effects ; Methyltransferases ; genetics ; Polymorphism, Genetic ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics

This study was aimed to analyze the thiopurine S-methyltransferase (TPMT) gene sequence in acute lymphoblastic leukemia (ALL) children severely intolerant to 6-mercaptopurine (6-MP) and to investigate the causes resulting in tolerance difference to 6-MP in ALL children so as to provide evidence for safe and rational use of 6-MP. The adverse reactions of drug was evaluated in ALL children treated with BCH-2003-ALL chemotherapeutic protocol during 2004-10-1 to 2007-9-30 according to NCI-CTC V2.0. The TPMT gene sequences of ALL children with 3-4 grade of severe toxicity during the maintenance therapy were analyzed by PCR and direct DNA sequencing. To assure the accuracy of sequencing, the 738 bp fragment of coding region in TPMT gene (NM_000367) was divided into 3 subfragments and bidirectionally sequenced. The results indicated that among 133 ALL children, 61 were severely intolerant to 6-MP. The direct DNA sequencing showed that among 59 patients (excluding 2 cases without RNA samples), the simple myelotoxicity was found in 37 cases, hepato-myelotoxicity was observed in 9 cases, hepatotoxicity along appeared in 12 cases, 1 case showed skin rash. Out of 59 ALL children, the C474T mutation was found in 57 cases, with mutation rate 96.6%, including 21 cases with heterozygous mutation and 36 cases with homozygosis mutation. The TPMT gene sequencing of 10 cases tolerant to 6-MP indicated that C474T mutation was detected in 8 cases which was homozygous mutation. It is concluded that the C474T mutation in 738 bp fragment of coding region in TPMT gene is very frequent, but it is not related with tolerance to 6-MP, suggesting that severe intolerance to 6-MP in ALL children may be not related with the mutation of coding region in TPMT gene.
Adolescent ; Child ; Child, Preschool ; Drug Tolerance ; Female ; Humans ; Infant ; Male ; Mercaptopurine ; adverse effects ; Methyltransferases ; genetics ; Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics ; Sequence Analysis

OBJECTIVE: To investigate the association between single nucleotide polymorphism of NUDT15 gene (SNP rs116855232) and hepatotoxicity in children with acute lymphocytic leukemia (ALL). METHODS: A total of 135 children with ALL in Shandong Province were recruited in this study, and patients were divided into two groups based on the presence of liver injury. Genotypes of each patient were detected using PCR and Sanger sequencing. Clinical data and the average dose of 6-mercaptopurine (6-MP) were collected and analyzed by SPSS 19.0 software. RESULTS: Respectively, 99 patients were found with CC genotype, 32 patients with CT genotype and 4 patients with TT genotype. Compared with ALL patients without hepatotoxicity, there was a difference in genotypes between the two groups in the initial stage of chemotherapy for leukemia (Chi CONCLUSION The polymorphism of rs116855232 in NUDT15 gene was associated with hepatotoxicity induced by 6-mercaptopurine in children with ALL, and ALL patients with TT genotype should take a lower dose of 6-MP to avoided hepatotoxicity.
Antimetabolites, Antineoplastic/therapeutic use* ; Chemical and Drug Induced Liver Injury/genetics* ; Child ; Genotype ; Humans ; Mercaptopurine/adverse effects* ; Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Pyrophosphatases/genetics*

OBJECTIVE6-Mercaptopurine (6-MP) has been the backbone of maintenance chemotherapy for acute lymphoblastic leukemia (ALL), the response to 6-MP is highly variable, adverse events leading to discontinuation or dose-reduction (children intolerant) of 6-MP occur in many children with ALL. The aim of this study was to investigate the tolerability of 6-MP and to optimize thiopurine use.

METHODSThe authors evaluated in a prospective manner the tolerance of 6-MP in ALL children from Oct. 1, 2004 to Sept. 30, 2007 who were newly diagnosed in Beijing Children's Hospital, using BCH-ALL-2003 protocols, during the maintenance therapy and followed up to Sept. 30, 2008. All children had a treatment period of at least 3 months for maintenance therapy.

RESULTSTotally 133 children including 81 boys and 52 girls at median age of 67 months (18 - 188 months), 100% of the patients went into complete remission (CR) on day 33 of induction chemotherapy, and the median time to CR was 26 months (6 - 47 months). All the children had maintenance therapy from 3 to 25 months (mean 13.5 +/- 7.4) and 72(54%) received 6-MP standard doses continuously for total courses, the median daily dose of 6-MP was 46 mg/(m(2).d) 6-MP, their WBC was (3 - 4) x 10(9)/L, ANC (1.5 - 2) x 10(9)/L, they had no severe liver toxicity. In 4 children the dose of 6-MP was increased to 125% because WBC was higher than 6 x 10(9)/L, ANC higher than 3 x 10(9)/L. Sixty one children (46%) had poor tolerability to 6-MP, they experienced adverse events that led to discontinuation (n = 19) or dose reduction (n = 42) of 6-MP, the actual mean dose for the 42 cases was 25 - 30 mg/(m(2).d) and the time to occurrence of toxic effects was 2.5 weeks. Reasons for discontinuation or dose reduction were severe myelotoxicity occurred in 48 children, hepatotoxicity in 12, and skin rash in one.

CONCLUSIONSIn this cohort of ALL children, the difference of tolerance to oral 6-MP was obvious, 54% of the children well tolerated 6-MP during the whole course at oral standard dose, and severe granulocytopenia did not occur. However, 46% developed severe granulopenia or hepatotoxicity, the dosage had to be reduced in order to decrease the probability of severe toxicity. It is suggested that standard dose of 6-MP is not always the maximum tolerant dose in some children and inadequate dose may be the cause of therapy failure.

Adolescent ; Antimetabolites, Antineoplastic ; adverse effects ; pharmacology ; therapeutic use ; Child ; Child, Preschool ; Drug Resistance, Neoplasm ; Female ; Humans ; Infant ; Male ; Mercaptopurine ; adverse effects ; pharmacology ; therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; pathology ; Prospective Studies

BACKGROUND: Thiopurine S-methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurines including azathioprine (AZA), 6-mercaptopurine, and 6-thioguanine. TPMT genotyping is widely used for screening of AZA-related toxicity during routine clinical practice in Korea. However, the data of TPMT genotypes and its AZA-related toxicity have not been studied in the field of dermatology. OBJECTIVE: The aim of this study was to evaluate the genetic basis of TPMT polymorphism in Korean dermatologic patients and subsequently to investigate the relationship between mutant TPMT and adverse responses to AZA treatment. METHODS: This study was retrospective, single-center study. One hundred forty-nine Korean dermatologic patients who underwent TPMT screening test were included. Each patient's medical records, the result of TPMT screening test, dose and treatment period of AZA, and side effects, were reviewed. Laboratory tests were assessed at each visit in order to monitor adverse drug reactions. Leukopenia grading was used in accordance with the common terminology criteria for adverse events (CTCAE) ver. 4.03. RESULTS: Behçet's disease was the leading disorder among the patients. The frequency of TPMT mutation was 4.0% (6/149) among the participants in this study. Four of the six patients with genetic alterations were treated with a low-dose AZA regimen, but no AZA-related adverse events were observed. CONCLUSION: Our results suggest that 1) TPMT polymorphisms in Korean dermatologic patients are similar to those previously reported in Asian patients with the most common mutant allele being TPMT*3C and 2) AZA can be used in the patients with these polymorphisms under a careful dosing regimen.
6-Mercaptopurine ; Alleles ; Asian Continental Ancestry Group ; Azathioprine ; Behcet Syndrome ; Dermatology ; Drug-Related Side Effects and Adverse Reactions ; Genotype ; Humans ; Korea ; Leukopenia ; Mass Screening ; Medical Records ; Metabolism ; Retrospective Studies ; Thioguanine

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-alpha blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-alpha blocker naive and 160 TNF-alpha blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-alpha blockers compared to TNF-alpha-blocker-naive patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-alpha blocker users, and 0.45 for TNF-alpha-blocker-naive patients. The adjusted risk ratio of TB in IBD patients receiving TNF-alpha blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-alpha blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-alpha blockers. Treatment with TNF-alpha blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-alpha blocker therapy.
6-Mercaptopurine/adverse effects/analogs & derivatives/therapeutic use ; Adult ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/therapeutic use ; Antibodies, Monoclonal/adverse effects/therapeutic use ; Cohort Studies ; Colitis, Ulcerative/*drug therapy ; Crohn Disease/*drug therapy ; Female ; Humans ; Latent Tuberculosis/chemically induced/diagnosis/*epidemiology ; Male ; Mycobacterium tuberculosis/isolation & purification ; Republic of Korea ; Retrospective Studies ; Tuberculosis, Pulmonary/chemically induced/diagnosis/*epidemiology ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-alpha blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-alpha blocker naive and 160 TNF-alpha blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-alpha blockers compared to TNF-alpha-blocker-naive patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-alpha blocker users, and 0.45 for TNF-alpha-blocker-naive patients. The adjusted risk ratio of TB in IBD patients receiving TNF-alpha blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-alpha blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-alpha blockers. Treatment with TNF-alpha blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-alpha blocker therapy.
6-Mercaptopurine/adverse effects/analogs & derivatives/therapeutic use ; Adult ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/therapeutic use ; Antibodies, Monoclonal/adverse effects/therapeutic use ; Cohort Studies ; Colitis, Ulcerative/*drug therapy ; Crohn Disease/*drug therapy ; Female ; Humans ; Latent Tuberculosis/chemically induced/diagnosis/*epidemiology ; Male ; Mycobacterium tuberculosis/isolation & purification ; Republic of Korea ; Retrospective Studies ; Tuberculosis, Pulmonary/chemically induced/diagnosis/*epidemiology ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors

BACKGROUND/AIMS: This study was to evaluate the frequency and the course of the adverse effects of AZA/6-MP in Korean patients with inflammatory bowel disease (IBD). METHODS: Medical records of the patients with IBD treated with AZA/6-MP at Severance hospital from June 1996 to September 2006 were retrospectively analyzed. RESULTS: A total of 133 patients were studied. Male to female ratio was 1.3:1. The mean age was 31.7+/-10.9 year. Adverse effects included leukopenia occurred in 75 cases (56.4%), nausea/vomiting in 32 cases (24.1%), arthralgia in 6 cases (4.5%), hepatitis in 6 cases (4.5%), skin rash in 4 cases (3.0%), herpes zoster in 3 cases (2.3%), and headache in 1 case (0.8%). Most of leucopenia (58.7%) developed within 3 months after maximal tolerated dose of AZA/6-MP and nausea/vomiting frequently occurred within 3 months after start of AZA/6-MP treatment. Thirty-eight patients (28.6%) required the discontinuation of medication due to adverse effects. CONCLUSIONS: Leukopenia was the most common adverse effect of AZA/6-MP treatment. Leukopenia and nausea/vomiting developed frequently in the early period of treatment of AZA/6-MP in patients with IBD. AZA/6-MP should be used cautiously to scrutinize bone marrow suppression.
6-Mercaptopurine/*adverse effects/therapeutic use ; Adolescent ; Adult ; Azathioprine/*adverse effects/therapeutic use ; Behcet Syndrome/drug therapy/etiology ; Cohort Studies ; Drug Therapy, Combination ; Female ; Humans ; Immunosuppressive Agents/*adverse effects/therapeutic use ; Inflammatory Bowel Diseases/*drug therapy/etiology ; Leukopenia/chemically induced ; Male ; Middle Aged ; Retrospective Studies ; Time Factors