mercaptopurine and Leukopenia

We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review. Among these, 16 studies were available for the meta-analysis of rs116855232, 6 studies for rs186364861 and 5 studies for rs554405994 of NUDT15. A higher DOR was found for rs116855232 (8.44, 95% CI: 5.46-13.03), as compared to rs554405994 (4.336, 95% CI 2.924-6.429) or rs186364861 (2.742, 95% CI 1.453-5.175). Results of meta-regression analysis showed that incidence of leukopenia (relative DOR: 0.96; 95%CI: 0.93-1.00, p = 0.037) and leukopenia onset (late vs early leukopenia, relative DOR: 0.41, 95% CI 0.20-0.85, p = 0.0189) significantly influenced diagnostic accuracy of rs116855232. Subgroup analysis for rs186364861 and rs554405994 revealed a significant DOR for early-onset leukopenia (rs186364861: 4.04, 95% CI 1.78-9.20; rs554405994: 2.94, 95% CI 1.74-4.95), but not for late-onset leukopenia (rs186364861: 1.52, 95% CI 0.52-4.43; rs554405994: 2.02, 95% CI 0.93-4.40). The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. Nevertheless, prospective studies of genotype-guided dosing of thiopurines are warranted to prove clinical benefit and cost-effectiveness of pretreatment NUDT15 gene testing across different populations.

Topics: Antineoplastic Agents; Azathioprine; Humans; Leukopenia; Mercaptopurine; Polymorphism, Genetic; Pyrophosphatases; Thioguanine

To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications.. MEDLINE®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, Genetics Abstracts, and EconLit™ to May 2009, for English language records.. A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations.. 1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability. There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events. Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent. The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent. Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous.. There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature.

Topics: Autoimmune Diseases; Chronic Disease; Female; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Reproducibility of Results

Probably, the most important and potentially lethal adverse event of azathioprine (AZA) and mercaptopurine (MP) is myelosuppression. Our aim was to conduct a review of AZA/MP-induced myelotoxicity in inflammatory bowel disease (IBD) patients.. Bibliographical searches were performed in MEDLINE/EMBASE. The studies evaluating thiopurine-induced myelotoxicity in patients with IBD were reviewed. The cumulative incidence and the incidence rate of AZA/MP-induced myelotoxicity were calculated by a meta-analysis.. In total, 66 studies (8,302 patients) were included. The cumulative incidence of AZA/MP-induced myelotoxicity was 7% (95% confidence interval [CI] 6-8%). The incidence rate (per patient and year of treatment) of the drug-induced myelotoxicity was 3% (95% CI 3-4%). The risk was roughly similar with AZA and with MP (7%vs 9%). The duration of AZA/MP treatment in patients with myelotoxicity ranged from 12 days to 27 yr. The cumulative incidence of infections among AZA/MP-induced myelotoxicity patients was 6.5%. The cumulative incidence of severe myelotoxicity was 1.1% (incidence rate 0.9%). Three deaths were reported due to myelotoxicity (cumulative incidence 0.06%, 95% CI 0.02-0.17%). The risk of death among patients who developed myelotoxicity was 0.94% (95% CI 0.32-2.70%).. The incidence rate of myelotoxicity in IBD patients receiving AZA/MP is approximately 3% per patient and year of treatment. Although bone marrow toxicity may develop at any time after starting the therapy, this happens more frequently during the first months. The incidence rate of severe myelotoxicity is less than 1% per patient and year of treatment, and the mortality risk is less than 0.1% (which means that the risk of death among IBD patients who develop myelotoxicity is approximately 1%).

Topics: Azathioprine; Bone Marrow Diseases; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine

Metabolism of thiopurine drugs--azathioprine, 6-mercaptopurine, and 6-thioguanine--has provided a powerful pharmacogenetic model incorporating polymorphism of the enzyme thiopurine methyltransferase (TPMT) and the primary active metabolite, thioguanine nucleotide (TGN). However, a sense of uncertainty about the usefulness of TGNs and other thiopurine metabolites has appeared. This review critically appraises the basis of thiopurine metabolism and reveals the problems and complexities in TGN research. Erythrocyte TGN is used in transplantation medicine and in chronic inflammatory conditions such as Crohn's disease, as a "surrogate" pharmacokinetic parameter for TGN in the target cells: leukocytes or bone marrow. It is not generally appreciated that erythrocytes do not express the enzyme IMP dehydrogenase and cannot convert mercaptopurine to TGN, which explains some of the confusion in interpretation of erythrocyte TGN measurements. TGN routinely measured in erythrocytes derives from hepatic metabolism. Another concern is that TGN are not generally assayed directly: most methods assay the thiopurine bases. Ion-exchange HPLC and enzymatic conversion of TGNs to nucleosides have been used to overcome this, and may reveal undisclosed roles for an unusual cytotoxic nucleotide, thio-inosine triphosphate, and methylated thiopurines. There appear to be additional interactions between xanthine oxidase and TPMT, and folate and TPMT, that could predict leukopenia. Difficult questions remain to be answered, which may be assisted by technological advances. Prospective TGN studies, long overdue, are at last revealing clearer results.

Topics: Azathioprine; Drug Monitoring; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Leukopenia; Mercaptopurine; Methylation; Methyltransferases; Nausea; Thioguanine; Thionucleotides; Xanthine Oxidase

Azathioprine (AZA) is widely used in the management of rheumatological diseases. Despite its efficacy, AZA can often cause bone marrow suppression, notably leucopenia, which has been recorded in up to 17% of patients taking AZA for rheumatoid arthritis, though this can be considered clinically significant in about 3% overall. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism. TPMT status can be assessed prior to AZA treatment by measuring enzyme activity or genotyping techniques. Analysis of recent data suggests that by optimizing the AZA dose on the basis of TPMT status testing (with a substantial reduction in dose for patients homozygous for mutant TPMT alleles), a reduction in drug-induced morbidity and cost savings can be made by avoiding hospitalization and rescue therapy for leucopenic events. In this article we review the pharmacogenetic and clinical implications of the TPMT polymorphism, emphasizing its relevance to rheumatologists managing diseases with AZA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azathioprine; Biomarkers; Erythrocytes; Genotype; Humans; Leukopenia; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic

To identify the frequency of use and appropriate monitoring guidelines for the adverse effects of azathioprine and 6-mercaptopurine (6-MP) in the therapy of patients with inflammatory bowel disease (IBD).. Surveys were sent to all physician members of the Canadian Association of Gastroenterology. Physicians were asked to describe their monitoring practices for IBD patients receiving azathioprine or 6-MP. A systematic literature search was also performed using MEDLINE for articles published in English between 1966 and 1999 using the MeSH terms 'azathioprine', '6-mercaptopurine', 'inflammatory bowel disease' and 'drug monitoring'.. Azathioprine and 6-MP were used to treat an average of 7% of patients - a surprisingly low number given the proven efficacy of these agents. All respondents reported monitoring complete blood counts (CBC), while liver enzyme and pancreatic enzyme levels were monitored by 62% and 29% of respondents, respectively. The most commonly reported initial CBC testing frequencies were weekly (42%), monthly (26%) and biweekly (23%). From the literature, it was determined that severe leukopenia (less than 2.10 g/L) occurs in less than 2% of cases and is sometimes associated with serious outcomes, including death. Most cases of severe leukopenia occurred abruptly, early in treatment. Other reported adverse effects and incidences were pancreatitis (3% to 5%), hepatotoxicity (less than 1%) and hypersensitivity (2% to 3%). Data concerning an increased risk of non-Hodgkin's lymphoma were equivocal.. Use of azathioprine or 6-MP is low in patients with IBD. A CBC should be performed at weeks 1, 2, 4, 6, 8 and 12, with subsequent testing every eight weeks for the duration of azathioprine or 6-MP treatment. The evidence in support of pancreatic and hepatic monitoring is weak. The risk of non-Hodgkin's lymphoma is likely low.

Topics: Azathioprine; Canada; Drug Utilization; Gastroenterology; Health Care Surveys; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine; Practice Patterns, Physicians'

Different hematologic abnormalities are often encountered in patients with inflammatory bowel disease. Among them anemia, leukocytosis, and thrombocytosis are commonly seen. Leukopenia and thrombocytopenia are observed mostly as a side effect of therapy, particularly with use of immunosuppressive drugs. Immune thrombocytopenic purpura is rarely reported in association with inflammatory bowel disease. We present two cases with combination of these entities along with a literature review and treatment options. Immune thrombocytopenic purpura in these patients presented as an extraintestinal manifestation of inflammatory bowel disease mediated by a disturbance of the immune system.

Topics: Adolescent; Adult; Anemia; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocytosis; Leukopenia; Male; Mercaptopurine; Prednisone; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Thrombocytosis

A review of experimental studies of chemotherapeutic agents and wound healing has demonstrated impairment of healing by a wide variety of agents. The extent of impairment by several agents (corticosteroids, Adriamycin, methotrexate, and cyclophosphamide) is dependent upon the interval between administration and wounding. If given within three to four days of wounding significant impairment results, but beyond that interval, impairment is minimal. Studies in animals with some agents (adriamycin, nitrogen mustard, cyclophosphamide, and methotrexate) have shown a dose-dependent impairment of healing, but extrapolation of these doses to regimens employed in man is impossible. Information regarding complications of chemotherapeutic agents in wound healing in man is available from adjuvant studies. No increased frequency of complications from nitrogen mustard, thio-TEPA, or cyclophosphamide occurred, even when these agents were given in the immediate perioperative period. Increased wound complications occurred with 5-fluorouracil when a 60 mg/kg dose was begun seven days after surgery but not when it was begun 14 days after surgery. These results stress the need for continued attention to wound complication occurring in adjuvant studies, and suggest that delay of treatment until seven days after surgery should produce minimal impairment.

Topics: Adrenal Cortex Hormones; Anemia; Animals; Antineoplastic Agents; Azathioprine; Collagen; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Fluorouracil; Humans; Leukopenia; Mechlorethamine; Mercaptopurine; Methotrexate; Neoplasms; Tensile Strength; Thiotepa; Time Factors; Wound Healing

Topics: Abnormalities, Multiple; Abortion, Spontaneous; Collagen Diseases; Cyclophosphamide; Female; Gastrointestinal Diseases; Hematologic Diseases; Immune System Diseases; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Leukopenia; Liver Function Tests; Lymphoma; Mercaptopurine; Methotrexate; Nervous System Diseases; Pregnancy

Topics: Adult; Agranulocytosis; Animals; Azathioprine; Child; Cyclophosphamide; Fertility; Glomerulonephritis; Humans; Leukopenia; Mercaptopurine; Mice; Nephrotic Syndrome; Prednisolone; Rats; Remission, Spontaneous

Topics: Adolescent; Adult; Antineoplastic Agents; Central Nervous System Diseases; Child; Cyclophosphamide; Cytarabine; Female; Guanidines; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Nitroso Compounds; Prednisone; Thrombocytopenia; Urea; Uric Acid; Vincristine

Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia.. To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease.. The rate of thiopurine-induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53-1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28-0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow-up.. Among Chinese patients with Crohn's disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine-induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies. Clinical trial number: NCT02929706.

Topics: Anemia; Azathioprine; Crohn Disease; Genotype; Humans; Leukopenia; Mercaptopurine; Pyrophosphatases

There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy.. Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care. For this study, Cox proportional hazard ratios (HRs) were calculated to compare AZA and MP for discontinuation rates within 5 months, incidence of hepatotoxicity, leukopenia, and gastrointestinal side effects. Treatment efficacy was compared by logistic regression.. Patient characteristics were similar for patients treated with AZA (n = 494, 64.4%) and MP (n = 273, 35.6%), yet patients with MP were relatively higher dosed compared with those on AZA. Discontinuation rates within 5 months were not different, 39.3% (AZA) and 38.1% (MP), HR 0.92 (95% confidence interval, 0.72-1.17; P = 0.50); however, patients on MP were more often subjected to dose reductions (30% versus 14%, P < 0.01). Higher rates of hepatotoxicity, HR 1.93 (95% confidence interval, 1.35-2.76; P < 0.01) and leukopenia, HR 2.55 (95% confidence interval, 1.51-4.30; P < 0.01) were observed with MP, which annulled in a secondary analysis with adjustment for the higher dose and metabolite levels.. Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions.

Topics: Adult; Azathioprine; Chemical and Drug Induced Liver Injury; Female; Humans; Inflammatory Bowel Diseases; Leukopenia; Logistic Models; Male; Mercaptopurine; Middle Aged; Netherlands; Proportional Hazards Models; Retrospective Studies; Treatment Outcome

Leucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S-methyltransferase (TPMT) gene are the best-known risk factor, but only explain up to 25% of leucopenia cases.. To identify the clinical risk factors for thiopurine-induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections.. Sixty hundred and ninety-five patients (90.6%) included in the TOPIC-trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29-112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39-4.88; P < .01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71-0.89; P < .01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18-3.63; P = .01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14-4.07; P = .02]).. Low baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine-induced leucopenia in patients without a TPMT variant.

Topics: Adult; Azathioprine; Case-Control Studies; Female; Genotype; Humans; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Polymorphism, Genetic; Risk Factors

Genotyping of TPMT prior to 6-mercaptopurine (6-MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6-MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6-MP toxicity-related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6-MP dose reduction, therapy interruption and event-free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49-20·80; P = 2·7 × 10(-4) ). As leucopenia results in 6-MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m(2) for patients with CC, CT and TT genotypes, respectively (P < 0·001). Hepatotoxicity was observed only in CC genotype patients. Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. Considerations for clinical application may be warranted.

Topics: Adolescent; Alleles; Antimetabolites, Antineoplastic; Asian People; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Infant; Japan; Leukopenia; Male; Mercaptopurine; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD.. In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT (TPMT*2, TPMT*3A, and TPMT*3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n = 405) and control groups (n = 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*10(9)/L or reduced platelet count < 100*10(9)/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n = 356] or the partial Mayo score for ulcerative colitis [n = 253]).. Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity (P = .18 for Crohn's disease and P = .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85).. Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Dosage Calculations; Female; Gastrointestinal Agents; Genetic Testing; Genetic Variation; Heterozygote; Homozygote; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Netherlands; Pharmacogenetics; Phenotype; Predictive Value of Tests; Prospective Studies; Risk Factors; Thrombocytopenia; Treatment Outcome; Young Adult

A prospective randomized trial in patients with Crohn disease studied whether 6-thioguanine nucleotide (6-TGN) concentration-adapted azathioprine (AZA) therapy is clinically superior to a standard dose of 2.5 mg/kg/day AZA.. After 2 weeks of standard therapy, patients (n = 71) were randomized into standard (n = 32) or adapted-dose (n = 25) groups; 14 patients dropped out before randomization. In the adapted group, the AZA dose was adjusted to maintain 6-TGN concentrations between 250 and 400 pmol/8 x 10(8) erythrocytes (Ery). Response criteria were the number of patients in remission after 16 weeks without steroids (primary) and remission after 24 weeks, frequency of side effects, and quality of life (secondary).. After 16 weeks, 14 of 32 (43.8%) patients in the standard group vs 11 of 25 (44%) in the adapted group were in remission without steroids (intent-to-treat analysis). After 24 weeks, 43.8% vs 40% were in remission. No significant differences were found concerning quality of life, disease activity, 6-TGN concentrations, AZA dose, or dropouts due to side effects. Sixty-six patients had a wild-type thiopurine S-methyltransferase (TPMT) genotype, with TPMT activities of 8 to 20 nmol/(mL Ery x h). Five patients (dropouts after randomization) were heterozygous, with TPMT activities <8 nmol/(mL Ery x h). 6-Methyl mercaptopurine (6-MMP) concentrations >5700 pmol/8 x 10(8) Ery were not associated with hepatotoxicity.. Standard and adapted dosing with the provided dosing scheme led to identical 6-TGN concentrations and remission rates. Adapted dosing had no apparent clinical benefit for patients with TPMT activity between 8 and 20 nmol/(mL Ery x h). Additionally, 6-MMP monitoring had no predictive value for hepatotoxicity.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Crohn Disease; Dose-Response Relationship, Drug; Erythrocyte Indices; Female; Genotype; Guanine Nucleotides; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Remission Induction; Thionucleotides; Thrombocytopenia

There is some uncertainty regarding how to best dose and therapeutically monitor 6-mercaptopurine or azathioprine in patients with inflammatory bowel disease. The purpose of this study was to assess the relation between clinical response, 6-mercaptopurine metabolite levels, relative leukopenia, and drug dose.. 60 patients with inflammatory bowel disease who were on stable doses of 6-mercaptopurine or azathioprine for > or = 3 months and who had measurements of 6-mercaptopurine metabolite levels were evaluated. Patients were classified as complete responders (N = 24), partial responders (N = 7), or non-responders (N = 29).. Drug dose was associated with clinical response when we analyzed adjusted doses based on molecular drug weight (P = 0.002). 6-Thioguanine levels also were associated with clinical response (P = 0.003) and the maximal difference between responders and non-responders was seen at 6-thioguanine levels greater than 260 pmol/8 x 10(8) RBC. Relative leukopenia, defined as white blood cell count less than either 5.0 or 4.0 K/uL, was not associated with clinical response (P = 0.13 and 0.77 respectively).. 1. Drug dose and 6-thioguanine levels are related to clinical response in patients with inflammatory bowel disease on 6-mercaptopurine or azathioprine. 2. For 6-thioguanine levels, there is a fair amount of overlap, but maximal differentiation between responders and non-responders is seen at levels > 260 pmol/8 x 10(8) RBC. 3. Relative leukopenia does not correlate well with clinical response.

Topics: Adult; Antirheumatic Agents; Azathioprine; Dose-Response Relationship, Drug; Endpoint Determination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Treatment Outcome

The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype.. Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype.. Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy.. 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Leukopenia; Liver; Male; Mercaptopurine; Mesalamine; Methyltransferases; Prospective Studies; Thioguanine; Treatment Outcome

Topics: Adolescent; Anemia, Aplastic; Bone Marrow; Bone Marrow Cells; Child; Child, Preschool; Clinical Trials as Topic; Digestive System; Drug Combinations; Female; Humans; Leukemia, Myeloid, Acute; Leukopenia; Male; Mercaptopurine; Remission, Spontaneous; Triazines; Vincristine

Topics: Adenocarcinoma; Anemia; Bone Marrow Diseases; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Colonic Neoplasms; Humans; Leukopenia; Lung Neoplasms; Mercaptopurine; Nausea; Neoplasms; Rectal Neoplasms; Stomach Neoplasms; Thrombocytopenia; Vomiting

Topics: Alopecia; Antibody Formation; Bone Marrow; Bone Marrow Cells; Child; Child, Preschool; Chromosome Aberrations; Daunorubicin; Drug Hypersensitivity; Heart; Humans; Immunosuppressive Agents; Inflammation; Intestinal Mucosa; Leukemia; Leukocytes; Leukopenia; Lymphocyte Activation; Mercaptopurine

Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity.. To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study.. The ITPA c.94c > a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c > a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c > a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c > a only, 42.9% for NUDT15 polymorphism (s) only, and 80.0% for both polymorphisms.. All cases of leukopenia were associated with ITPA c.94c > a and/or polymorphism of NUDT15 and the risk of developing leukopenia was synergistically increased by ITPA and NUDT15 gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.

Topics: Azathioprine; East Asian People; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine; Pyrophosphatases

Thiopurines, such as 6-mercaptopurine (6-MP), are widely used as cytotoxic agents and immunosuppressants for leukemia and autoimmune or inflammatory diseases. A nonsynonymous single nucleotide polymorphism (p.Arg139Cys; R139C) of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene causes the loss of thiopurine detoxification, inducing myelosuppression. To understand such hematotoxicity, we investigate the effects of NUDT15 R139C on hematopoietic stem cells (HSCs) upon thiopurine administration. Using previously established Nudt15

Topics: Animals; DNA Damage; Hematopoietic Stem Cells; Immunosuppressive Agents; Leukopenia; Mercaptopurine; Mice; Pyrophosphatases

Several genetic variants of thiopurine metabolic pathway are associated with 6-thiopurine-mediated leucopenia. A population-based evaluation of these variants lays the foundation for Pharmacogenetic-guided thiopurine therapy.. A total of 2000 subjects were screened for the pharmacogenetic determinants using the infinium global screening array (GSA). The functional relevance of these variants was deduced using SNAP2, SIFT, Provean, Mutalyzer, Mutation Taster, Phyre2, SwissDock, AGGRESCAN, and CUPSAT.. The minor allele frequencies of NUDT15*3, NUDT15*5, TPMT*3C, TPMT*3B variant alleles were 6.78%, 0.11%, 1.98% and 0.69%, respectively. TPMT*3A genotype was observed in 0.35% subjects. No gender-based differences were observed in the incidence of these variants. Data from studies of the Indian population showed that 92.86% subjects heterozygous for NUDT15*3 and 60% subjects heterozygous for TPMT*3C exhibit thiopurine-mediated hematological toxicity. NUDT15 variants have no impact on the binding of 'dGTP' to the NUDT protein. NUDT15*3 variant increases aggregation 'hot spot' region and induces unfavourable torsion in the protein. NUDT15*5 destabilizes the protein and impairs Mg/Mn binding. TPMT*3A, TPMT*3B and TPMT*3C variants lower binding affinity to 6-mercaptopurine compared to the wild protein. TPMT*3C variant destabilizes the TPMT protein in the thermal experiment. Compared to the data of European and African/African American populations, NUDT15*3 frequency is higher and TPMT*3C frequency is lower in our population.. TPMT variants were less frequent in Indian population, while NUDT15*3 is more frequent compared to European and African/African American populations. NUDT15*3 increases aggregation 'hot spot' and induces unfavourable torsion in the protein. NUDT15*5 and TPMT*3C destabilize the respective proteins. TPMT*3A, TPMT*3B and TPMT*3C are associated with a lower binding affinity towards 6-mercaptopurine.

Topics: Antimetabolites, Antineoplastic; Asian People; Black People; Cohort Studies; Computational Biology; Female; Gene Frequency; Genotype; Humans; Incidence; India; Leukopenia; Male; Mercaptopurine; Metabolic Networks and Pathways; Methyltransferases; Molecular Structure; Pharmacogenetics; Pyrophosphatases; White People

Xanthine oxidase (XO) competes with thiopurine S-methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6-mercaptopurine (6-MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine-induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6-MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu-like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu-like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine-induced toxicity.

Topics: Adolescent; Adult; Aged; Asian People; Azathioprine; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Xanthine Oxidase; Young Adult

Thiopurines are widely used as antileukemia agents and immunosuppressants. Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys (NUDT15

Topics: Animals; DNA Repair; Female; Flow Cytometry; Gene Knock-In Techniques; Genotype; Hematopoietic Stem Cells; Humans; Leukemia; Leukopenia; Male; Mercaptopurine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Polymorphism, Genetic; Pyrophosphatases

Thiopurines are used in the treatment of inflammatory bowel disease (IBD) but remain clinically challenging to manage due to wide interpatient variability in clinical outcomes and adverse events. Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results. To clarify the role of FTO variants in a multiethnic Asian IBD cohort, we recruited 149 patients on thiopurine-based therapy and genotyped two FTO variants p.Ala134Thr (rs79206939) and rs16952570 T > C using Sanger sequencing. FTO p.Ala134Thr (rs79206939) was non-polymorphic and absent whereas intronic rs16952570 T > C was equally prevalent in Chinese (22%) and Indians (18%) and higher in Malays (28%). Higher nadir white blood cell (WBC) and absolute neutrophil count (ANC) levels were observed in patients harboring FTO rs16952570 CC genotypes compared with TT carriers at 4, 8, and 12 weeks after start of thiopurine therapy (P < 0.05). A similar trend was observed in patients carrying the previously well-characterized NUDT15 rs116855232 wild-type CC genotypes. Further in silico analysis suggests that FTO variants linked to rs16952570, particularly rs74018601, may play a regulatory role in altering the FTO expression. The findings from this study indicate a novel protective association with the FTO variant rs16952570 CC genotype and hematological parameters.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Asian People; Azathioprine; Female; Genetic Variation; Humans; Inflammatory Bowel Diseases; Introns; Leukopenia; Male; Mercaptopurine; Middle Aged; Neutropenia; Retrospective Studies; Young Adult

Topics: Azathioprine; Humans; Leukopenia; Mercaptopurine

The rationale of the current study was to develop 6-mercaptopurine (6-MP)-mediated hematological toxicity prediction model for acute lymphoblastic leukemia (ALL) therapeutic management.. A total of 96 children with ALL undergoing therapy with MCP-841 protocol were screened for all the ten exons of TPMT, exon 2, exon 3 and intron 2 of ITPA using bidirectional sequencing. This dataset was used to construct prediction models of leucopenia grade by constructing classification and regression trees (CART) followed by smart pruning.. The developed CART model indicated TPMT*12 and TPMT*3C as the key determinants of toxicity. TPMT int3, int4 and int7 polymorphisms exert toxicity when co-segregated with one mutated allele of TPMT*12 or TPMT*3C or ITPA exon 3. The developed CART model exhibited 93.6% accuracy in predicting the toxicity. The area under the receiver operating characteristic curve was 0.9649.. TPMT *3C and TPMT*12 are the key determinants of 6-MP-mediated hematological toxicity while other variants of TPMT (int3, int4 and int7) and ITPA ex2 interact synergistically with TPMT*3C or TPMT*12 variant alleles to enhance the toxicity. TPMT and ITPA variants cumulatively are excellent predictors of 6-MP-mediated toxicity.

Topics: Adolescent; Alleles; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Regression Analysis

A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration.. We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation.. The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months.. NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Erythrocyte Indices; Female; Gastrointestinal Agents; Genetic Predisposition to Disease; Heterozygote; Humans; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Middle Aged; Mutation, Missense; Pyrophosphatases; Retrospective Studies; Risk Factors; Time Factors; Tokyo; Treatment Outcome; Young Adult

6-Mercaptopurine (6-MP) is a main component of childhood acute lymphoblastic leukemia (ALL) treatment. Some candidate gene variants are associated with its toxicities, but the major variants and effects of combined variants remain unclear. We used Cox regression analysis to evaluate the time-dependent association between candidate variants and the cumulative incidence of 6-MP intolerability in 95 Japanese patients. The major risk factors for severe leukopenia were ABCC4 rs3765534, NUDT15 rs116855232 and rs186364861 in multi-covariate analysis (P<0.05). NUDT15 intermediate activity variant, that is, heterozygous rs116855232 or rs186364861 variant, and the ABCC4 rs3765534 variant showed leukopenia more frequently than either variant alone. All patients with both the intermediate activity NUDT15 variant and the ABCC4 rs3765534 variant suffered from leukopenia, and 57.1% patients required 50% protocol dose by day 168. These data indicate that NUDT15 and ABCC4 are major factors for 6-MP intolerability and that the interaction between these variants enhances intolerability to 6-MP.

Topics: Adolescent; Antimetabolites, Antineoplastic; Asian People; Child; Child, Preschool; Female; Humans; Infant; Japan; Leukopenia; Male; Mercaptopurine; Multidrug Resistance-Associated Proteins; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

The single nucleotide polymorphism (SNP) c.415C>T in exon 3 of. Ninety-six Japanese patients with IBD were enrolled. Genotyping for the. Genetic variants of exon 1 and exon 3 of. Mutations in exon 1 of

Topics: Adolescent; Adult; Aged; Asian People; Child; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Erythrocyte Indices; Exons; Female; Genetic Predisposition to Disease; Heterozygote; Humans; Immunosuppressive Agents; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Nudix Hydrolases; Polymorphism, Single Nucleotide; Prednisolone; Pyrophosphatases; Retrospective Studies; Risk Factors; Young Adult

Topics: Adolescent; Child; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Leukopenia; Mercaptopurine; Methyltransferases; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases

Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.. Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.. We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r. Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

Topics: Alopecia; Antibodies, Monoclonal; Azathioprine; Biomarkers, Pharmacological; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomic Structural Variation; Haplotypes; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Japan; Leukopenia; Logistic Models; Mercaptopurine; Mesalamine; Pharmacogenetics; Pyrophosphatases; Retrospective Studies; Risk; ROC Curve; Sulfasalazine

Thiopurine drugs, such as thioguanine, mercaptopurine and azathioprine, are used for treating inflammatory bowel disease, such as ulcerative colitis. One must be aware of the serious side effects these drugs can have (e.g. bone marrow depression). A 56-year-old man with ulcerative colitis was treated with mercaptopurine. He developed leukopenia as a result. Thioguanine was started ten months later, resulting in life-threatening pancytopenia. Thiopurine methyltransferase (TPMT) genotyping proved that the patient was a poor metaboliser of thioguanine (TPMT3A*/3A*). Dose reduction is recommended for patients with reduced or absent TPMT activity. This life-threatening side effect could have been prevented by taking a number of relatively simple precautions.

Topics: Colitis, Ulcerative; Humans; Leukopenia; Male; Mercaptopurine; Middle Aged; Pancytopenia; Thioguanine

NUDT15 c.415C>T was a novel genetic marker confirmed in our center for thiopurine-induced leukopenia in Chinese inflammatory bowel disease (IBD). For validation, a large cohort study is needed. Meanwhile, the newly discovered NUDT15 coding variants (c.36_37insGGAGTC and c.52 G>A) have not been studied in patients with IBD. We aimed to further confirm the influence of 3 NUDT15 variants (c.415C>T, c.36_37insGGAGTC, and c.52G>A) on thiopurine-induced leukopenia in Chinese patients with IBD.. Patients prescribed on thiopurines for at least 2 weeks were recruited from 4 tertiary hospitals. Clinical data were collected. NUDT15 genotypes were determined with polymerase chain reaction-RFLP and sequencing. The interactions between variants and leukopenia were analyzed.. A total of 732 patients were included, 177 (24.3%) of whom developed leukopenia. There were strong associations of NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A with thiopurine-induced leukopenia (P = 1.81 × 10, P = 4.74 × 10 and P = 0.04, respectively), whereas there was no relevance for thiopurine S-methyltransferase genotypes (P = 0.25). The predictive sensitivity of NUDT15 c.415C>T was 49.2%, whereas it increased to 55.4% when combined analysis with c.36_37insGGAGTC and c.52G>A. Notably, not only the homozygotes with NUDT15 c.415C>T but also the heterozygotes both carrying c.415C>T and c.52G>A developed early leukopenia. The median dosage for NUDT15 c.415C>T carriers was significantly lower than that for wild-type (P < 0.001).. We confirmed that NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A variants were risk factors for thiopurine-induced leukopenia. Combined detection of the 3 variants could increase the predictive sensitivity of thiopurine-induced leukopenia and help to distinguish early leukopenia in heterozygote of c.415C>T in Chinese patients with IBD. Treatment monitoring by NUDT15 variants may be promising in individualized therapy.

Topics: Adolescent; Adult; Aged; Asian People; Azathioprine; Child; Child, Preschool; China; Cohort Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Pyrophosphatases; Risk Factors; Young Adult

Interindividual variation seen in the thiopurine metabolism is attributed to the genetic variant in thiopurine methyltransferase (TPMT) gene leading to myelosuppression. In Asians, the thiopurine-induced toxicity is not completely explained by TPMT variants. Literature indicates that a newer genetic variant in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene is associated with thiopurine intolerance. We aimed to determine the risk allele frequency of NUDT15 genetic variant and its association with thiopurine-induced toxicity in Indian patients.. In this pilot study, 69 patients on thiopurine therapy were analyzed. The frequencies of thiopurine-induced leukopenia were recorded. NUDT15 (C415T) and TPMT (*2, *3A, *3B, and *3C) genotyping was performed using amplification refractory mutation system-polymerase chain reaction and restriction fragment length polymorphism technique. Results were validated by DNA sequencing.. The NUDT15 CC, CT, and TT genotypes were found to be 86.9%, 11.5%, and 1.5%, respectively, whereas TPMT genetic variants were absent. Of 60 patients without NUDT15 variant, none developed leukopenia, whereas of nine patients with NUDT15 variant, six developed leukopenia (P-value < 0.0001). The mean thiopurine dose of 1.01 and 0.73 mg/kg/day for patients with wild and mutant NUDT15 alleles, respectively, was statistically significant (P < 0.01). The sensitivity and specificity for NUDT15 variant were 100% and 95.2%, respectively.. The NUDT15 risk allele frequency was 7.2%. There are 6/69 (8.7%) patients who developed leukopenia and harbored NUDT15 variant, thus showing a strong association for thiopurine-induced toxicity. Hence, NUDT15 genotyping may be considered before thiopurine therapy in Indian patients.

Topics: Aged; Asian People; Azathioprine; Female; Gene Frequency; Genetic Association Studies; Genetic Variation; Genotype; Humans; India; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Pyrophosphatases; Risk

Myelosuppression is a life-threatening complication of thiopurine therapy, and the incidence of thiopurine-induced myelosuppression is higher in East Asians than in Europeans. We investigated genetic factors associated with thiopurine-induced leukopenia in patients with IBD.. A genome-wide association study (GWAS) was conducted in thiopurine-treated patients with IBD, followed by high-throughput sequencing of genes identified as significant in the GWAS or those involved in thiopurine metabolism (n=331). Significant loci associated with thiopurine-induced leukopenia were validated in two additional replication cohorts (n=437 and n=330). Functional consequences of. The GWAS identified two loci associated with thiopurine-induced leukopenia (rs16957920,. The results suggest that the hypomorphic

Topics: Adolescent; Adult; Aged; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Azathioprine; Case-Control Studies; Cohort Studies; Female; Genetic Markers; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Mice; Mice, Knockout; Middle Aged; Polymorphism, Single Nucleotide; Republic of Korea; Sequence Analysis, DNA; Young Adult

The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with t

Topics: Adult; Alopecia; Anti-Inflammatory Agents; Asian People; Azathioprine; Chi-Square Distribution; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Female; Gastrointestinal Agents; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Japan; Kaplan-Meier Estimate; Leukopenia; Logistic Models; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Odds Ratio; Phenotype; Pyrophosphatases; Risk Factors; Severity of Illness Index; Treatment Outcome; Young Adult

NUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6-TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD).. Two hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled. Genotyping for NUDT15 R139C was performed using Custom TaqMan® SNP genotyping assays.. The NUDT15 C/C, C/T, and T/T genotypes were 80.7, 18.2, and 1.1 %, respectively. The allelic frequency was 10.2 %. Among 161 IBD patients, there was no significant difference in 6-TGN levels among the NUDT15 genotypes. Forty-five patients (27.9 %) developed leukocytopenia (WBC <3000/μl), and the C/T and T/T genotypes were significantly associated with the development of leukocytopenia (P = 1.7 × 10(-5)). In these patients, 6-TGN levels were not significantly different between NUDT15 genotypes. NUDT15 R139C was significantly associated with early (<8 weeks) (P = 1.03 × 10(-4)) and late (>8 weeks) leukocytopenia (P = 4.3 × 10(-4)). The decrease in WBC count at 2 and 4 weeks was significantly higher in patients with the C/T or T/T genotypes as compared to the patients with the C/C genotype. All patients with the T/T genotype (n = 2) developed early severe hair loss and severe leukocytopenia (<1000/μl). The logistic regression analysis revealed that NUDT15 R139C was the sole genetic factor responsible for the thiopurine-induced leukocytopenia (P = 0.001).. These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism.

Topics: Adult; Alopecia; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Guanine Nucleotides; Humans; Inflammatory Bowel Diseases; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Middle Aged; Pyrophosphatases; Thionucleotides

The impact of genetic variation in the thiopurine S-methyltransferase (TPMT) gene on thiopurine-induced leukopenia has been well demonstrated. Although xanthine dehydrogenase (XDH) is the second major contributor to azathioprine breakdown, polymorphisms in XDH have rarely been studied in IBD patients. We aim to access association between XDH variants and thiopurine-induced leukopenia by gene-gene interaction in a Crohn's disease (CD) population.. A total of 964 CD patients treated with thiopurines were recruited from a tertiary referral center. The association between four XDH variants (p.Gly172Arg, p.Asn1109Thr, p.Arg149Cys, and p.Thr910Lys) and thiopurine-induced leukopenia was analyzed in cases with early leukopenia (n = 66), late leukopenia (n = 264), and in controls without leukopenia (n = 632). Three non-synonymous SNPs, which we previously reported association with thiopurine-induced leukopenia, NUDT15 (p.Arg139Cys), SUCLA2 (p.Ser199Thr), and TPMT *3C were selected for epistasis analysis with the XDH variants.. There was no significant association for two variants of XDH and thiopurine-induced leukopenia. In the epistasis analysis, only XDH (p.Asn1109Thr) * SUCLA2 (p.Ser199Thr) showed a statistically significant association with early leukopenia [odds ratio (OR) = 0.16; p = 0.03]. After genotype stratification, a positive association on the background of SUCLA2 wild-type (199Ser) between the XDH (p.Asn1109Thr) and early leukopenia (OR = 4.39; p = 0.01) was detected.. Genes associated with thiopurine-induced leukopenia can act in a complex interactive manner. Further studies are warranted to explore the mechanisms underlying the effects of the combination of XDH (p.Asn1109Thr) and SUCLA2 (199Ser) on thiopurine-induced leukopenia.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Child; Crohn Disease; Epistasis, Genetic; Female; Follow-Up Studies; Genetic Markers; Genotype; Humans; Immunosuppressive Agents; Leukopenia; Logistic Models; Male; Mercaptopurine; Middle Aged; Polymorphism, Single Nucleotide; Republic of Korea; Succinate-CoA Ligases; Treatment Outcome; Xanthine Dehydrogenase; Young Adult

Topics: Adult; Azathioprine; Child; Female; Hong Kong; Humans; Leukopenia; Male; Mercaptopurine; Middle Aged; Pyrophosphatases; Young Adult

A median of 22 (range 8-27) 6MP/MTX metabolite samples and 100 (range 25-130) blood counts during therapy and 10 (range 2-15) off therapy were collected in 50 children with ALL. Differences between off-therapy and on-therapy WBCs [including absolute neutrophil (ANC) and lymphocyte counts (ALC)] were used to retrospectively approximate the absolute myelosuppression (="delta-") and association with age, sex and 6MP/MTX doses explored. We applied linear mixed models to estimate on-therapy counts by 6MP/MTX metabolites: DNA-incorporated thioguanine nucleotides (DNA-TGN), erythrocyte thioguanine nucleotides (ery-TGN), erythrocyte-methylated 6MP metabolites (ery-MeMP) and erythrocyte MTX polyglutamates with 2-6 glutamate residues (ery-MTXpg. On-therapy WBC was correlated with ANC and ALC (r. Measurements of 6MP/MTX metabolites could supplement blood counts in assessing therapy intensity, but require prospective validation.

Topics: Adolescent; Aging; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Child; Child, Preschool; Female; Genotype; Humans; Leukocyte Count; Leukopenia; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; PTEN Phosphohydrolase; Risk Assessment

Few studies exist on the frequency of thiopurine methyltransferase (TPMT) mutation in patients from Southern Europe. We aimed to evaluate the frequency of TPMT mutation in a homogeneous Sicilian cohort of patients with inflammatory bowel disease (IBD), autoimmune and hematological disorders, the rate of thiopurine-related adverse events, and its association with the TPMT genotype.. Among 105 patients with IBD, 45 with autoimmune disease, and 34 with hematologic diseases, the homozygous TPMT variant genotype was found in one patient only (0.5%), while the heterozygous TPMT genotype was identified in 8 patients (4.3%). In patients with IBD, leukopenia was observed in ten patients: one had the homozygous TPMT genotype, one the heterozygous genotype, and the remaining eight the wild type genotype.. The frequency of TPMT mutation in a Mediterranean area was low. TPMT genotyping is not a sensitive tool for predicting thiopurine-induced leukopenia.

Topics: Adult; Autoimmune Diseases; Azathioprine; Female; Hematologic Diseases; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Italy; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Mutation; Phenotype; Polymorphism, Genetic

The thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine (6-MP) are well-established drugs for the treatment of inflammatory bowel disease (IBD). Although leukopenia is a well-recognized side effect of AZA/6-MP treatment, its association with therapeutic effects has yet to be determined. We therefore evaluated the influences of thiopurine-induced leukopenia on the long-term prognosis of IBD.. We included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn's disease (CD), and 83 with intestinal Behçet's disease (BD)] who were treated with AZA/6-MP and achieved remission between January 2006 and December 2012. We retrospectively analyzed patient characteristics, AZA/6-MP maintenance dose (mg/kg), the lowest white blood cell (WBC) count during AZA/6-MP treatment, duration of remission, and the occurrence of relapse. We compared the clinical variables between leukopenic (n = 120, WBC count <4,000/μL) and nonleukopenic (n = 76, WBC count ≥ 4,000/μL) patients.. The two groups were well matched for baseline clinical characteristics. The cumulative relapse-free survival rate was higher in the leukopenic group than the nonleukopenic group by Kaplan-Meier survival analysis (log-rank test, P < 0.001). On multivariate analysis, age, duration of AZA/6-MP treatment, presence of macrocytosis, and the presence of leukopenia were negatively associated with relapse (odds ratios 0.975, 0.988, 0.563, and 0.390, respectively). On subgroup analysis, the cumulative relapse-free survival rate was significantly higher in the leukopenic group than in the nonleukopenic group for all types of IBDs, including UC, CD, and intestinal BD (log-rank test, P = 0.032, 0.047, and 0.002, respectively).. Leukopenia during thiopurine maintenance therapy was associated with prolonged remission in patients with IBD and Behcet's disease.

Topics: Adolescent; Adult; Aged; Azathioprine; Behcet Syndrome; Colitis, Ulcerative; Comorbidity; Crohn Disease; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Leukopenia; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Prognosis; Remission Induction; Retrospective Studies; Young Adult

Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT.. Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy.. The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 10⁹/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10⁹/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses).. For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heterozygote; Humans; Leukopenia; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Methyltransferases; Myelopoiesis; Nucleic Acid Synthesis Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Risk; Scandinavian and Nordic Countries; Survival Analysis

Topics: Azathioprine; Behcet Syndrome; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Leukopenia; Male; Mercaptopurine

Topics: Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Gastrointestinal Agents; Genetic Variation; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Thrombocytopenia

Acute Lymphoblastic Leukemia, commonly known as ALL, is a predominant form of cancer during childhood. With the advent of modern healthcare support, the 5-year survival rate has been impressive in the recent past. However, long-term ALL survivors embattle several treatment-related medical and socio-economic complications due to excessive and inordinate chemotherapy doses received during treatment. In this work, we present a model-based approach to personalize 6-Mercaptopurine (6-MP) treatment for childhood ALL with a provision for incorporating the pharmacogenomic variations among patients. Semi-mechanistic mathematical models were developed and validated for i) 6-MP metabolism, ii) red blood cell mean corpuscular volume (MCV) dynamics, a surrogate marker for treatment efficacy, and iii) leukopenia, a major side-effect. With the constraint of getting limited data from clinics, a global sensitivity analysis based model reduction technique was employed to reduce the parameter space arising from semi-mechanistic models. The reduced, sensitive parameters were used to individualize the average patient model to a specific patient so as to minimize the model uncertainty. Models fit the data well and mimic diverse behavior observed among patients with minimum parameters. The model was validated with real patient data obtained from literature and Riley Hospital for Children in Indianapolis. Patient models were used to optimize the dose for an individual patient through nonlinear model predictive control. The implementation of our approach in clinical practice is realizable with routinely measured complete blood counts (CBC) and a few additional metabolite measurements. The proposed approach promises to achieve model-based individualized treatment to a specific patient, as opposed to a standard-dose-for-all, and to prescribe an optimal dose for a desired outcome with minimum side-effects.

Topics: Antimetabolites, Antineoplastic; Child; Erythrocyte Indices; Humans; Leukopenia; Mercaptopurine; Patient-Specific Modeling; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors

Few data on azathioprine (AZA) therapy for inflammatory bowel disease (IBD) exist for children. We evaluated whether the 6-thioguanine nucleotides (6-TGN) level predicts AZA refractoriness in children with IBD and whether children benefit an AZA dose escalation. Seventy-eight children with IBD initially treated with an AZA dose of 1.5-2.5 mg/kg/day were retrospectively included. The dose was adjusted based on the clinical status. The receiver operating characteristic curve and logistic regression were used to determine predictors for AZA resistance. Initially, 18 of 40 (45%) patients receiving a dose of <2 mg/kg/day and 11 of 38 (28.9%) patients receiving a dose of 2-2.5 mg/kg/day achieved remission. The 6-TGN level above 250 pmol/8.10(8) RBCs was associated with a higher remission rate, though non-significant. Among 35 patients with a dose escalation due to treatment failure, 12 (34.3%) achieved remission (the median 6-TGN level increased from 260 to 394 pmol/8.10(8) RBCs [P = .002]), 23 (67.6%) were AZA refractory. A 6-TGN level above 405 pmol/8.10(8) RBCs was the only predictor for AZA resistance (sensitivity 78.3%, specificity 75%, OR 10.8 [95% CI: 2.1-55.7, P = .004]). Serial metabolite monitoring is useful to identify children with IBD resistant to AZA. Children who cannot achieve remission despite a 6-TGN level above 405 pmol/8.10(8) RBCs should receive alternative therapies than dose increase.

Topics: Adolescent; Antimetabolites; Azathioprine; Child; Child, Preschool; Drug Resistance; Female; Humans; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Thioguanine

To assess the levels of red blood cell thiopurine methyltransferase (TPMT) in subjects with inflammatory bowel disease (IBD) and to determine how these levels impacted thiopurine dosing and leukopenia over the first six months of therapy.. A retrospective chart review was performed on all adult IBD patients (n=423, 88.2% Caucasian) who had TPMT levels measured by 11 participating gastroenterologists in Manitoba between 2008 and 2010. In addition to descriptive data, white blood cell count, dose and reason for discontinuation were analyzed for the first six months of therapy. Patients receiving ≥2.0 mg/kg of azathioprine (AZA) or ≥1.0 mg/kg of 6-mercapatopurine were considered to be 'substantially' dosed.. Of the 423 patients, 8.3% had intermediate levels and 93.4% had normal levels of TPMT. Only one subject had a low level. A total of 216 patients had sufficient data to be included for full analysis. Patients with intermediate TPMT levels were generally started at lower doses of thiopurine than patients with normal TPMT levels (mean [± SD] 1.0±0.6 mg/kg versus 1.8±0.5 mg/kg). Of the subjects with normal TPMT levels, only 37.8% were dosed with ≥2.0 mg/kg of AZA. Each month, approximately 5% of subjects were leukopenic. These subjects received a mean overall AZA dose of 1.9±0.3 mg/kg and had a mean white blood cell count of 3.8±0.4×10(9)/L.. Normal TPMT levels did not prevent the development of leukopenia, although life-threatening leukopenia was rare. Physicians are not using TPMT levels to substantially dose thiopurines at the outset, which may limit the speed at which adequate doses are reached to facilitate remission.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Leukopenia; Male; Manitoba; Mercaptopurine; Methyltransferases; Middle Aged; Retrospective Studies; Young Adult

Immunomodulator medications (IMM) play a vital role in the care of patients with inflammatory bowel disease (IBD). IBD practice guidelines recommend myelosuppression monitoring after initiation of IMM.. To identify adherence rates and predictors of myelosuppression monitoring after IMM initiation in a large practice setting.. We identified a national cohort of VA users with IBD for the fiscal years 2003-2009 using the Veterans Affairs administrative datasets. Subjects with filled prescriptions for IMM were included. The primary endpoint was the proportion of subjects who had a white blood cell (WBC) test completed within 90 days of the IMM index date. Determinants of myelosuppression monitoring were identified by univariate and multivariate analyses.. A total of 6045 unique IBD patients were identified with filled IMM prescriptions. Overall, only 57% of subjects completed a WBC test within 90 days of IMM index date. Monitoring rates increased over time, from 48% in 2003 to 75% in 2009. There was variability of monitoring rates by facility, ranging from 0 to 83%. In multivariate analyses, older age at IMM index date was associated with a lower rate of monitoring. Frequency of VA encounters and IMM index date were associated with increased rates of myelosuppression monitoring.. Monitoring for myelosuppression among veterans with inflammatory bowel disease after immunomodulator medications initiation is low with wide variability based on facility. This may reflect a low quality of care among veterans with IBD. Provider- and system-wide interventions are needed to improve adherence and reduce variability of immunomodulator medications monitoring across facilities.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Azathioprine; Delivery of Health Care; Drug Monitoring; Drug Prescriptions; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocyte Count; Leukopenia; Male; Medical Audit; Mercaptopurine; Methotrexate; Middle Aged; Practice Guidelines as Topic; Treatment Outcome; United States; United States Department of Veterans Affairs; Veterans

Not all of the adverse effects to thiopurine therapy can be explained by thiopurine methyltransferase (TPMT) polymorphisms. This study was intended to evaluate the value of TPMT genotype and phenotype measurement during the first year of thiopurine therapy.. Consecutive patients with inflammatory bowel disease (IBD) who were receiving azathioprine or 6-mercaptopurine were followed up for 12 months. TPMT genotypes and phenotypes were examined in patients with IBD before thiopurine therapy and in unrelated healthy volunteers by polymerase chain reaction and high-performance liquid chromatography.. A total of 199 patients and 300 healthy volunteers were included at 2 centers. Forty-seven of the 199 patients (23.62%) exhibited adverse effects during the entire course of thiopurine therapy. Two (1%) patients carrying TPMT*3C developed leucopenia at week 4 of azathioprine treatment. The TPMT*3C had a specificity of 100% (163/163) but a sensitivity of 5.56% (2/36) for predicting leucopenia. The calculated optimal cutoff activity for high TPMT activity and decreased TPMT activity was 4.75 U/mL red blood cells. The risk of leucopenia increased in the decreased TPMT group (odds ratio: 20.25; 95% confidence interval: 2.19-187.17; P = 0.004) and increased more during the initial 3 months of thiopurine therapy (odds ratio: 34.80; 95% confidence interval: 3.71-326.77; P = 0.001). Leucopenia occurred more frequently in the patients cotreated with 5-aminosalicylates than in those not cotreated (32.81% versus 11.11%, respectively, P < 0.001).. The results of this study suggest that the value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia, and that phenotyping is a more cost-effective tool that can be successfully used in patients. The coadministration of 5-aminosalicylates results in a high frequency of leucopenia in patients receiving azathioprine or 6-mercaptopurine.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; China; Drug Interactions; Drug Monitoring; Female; Follow-Up Studies; Genetic Association Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Mutation; Prospective Studies; Young Adult

Thiopurines are a common, effective means of maintaining remission in pediatric Crohn disease (CD). Methotrexate (MTX) may be considered for those intolerant of or unresponsive to thiopurines. The purpose of this study was to examine the effectiveness of MTX as maintenance therapy in patients previously treated with thiopurines.. All of the patients at Nationwide Children's Hospital from 1998 to 2007 with an International Classification of Diseases code indicative of CD were identified. Patients with a diagnosis of CD, a history of prior thiopurine use, no current infliximab therapy, and at least 6 months of follow-up after MTX initiation were included. The primary outcome was defined as steroid-/infliximab-free remission determined by the physician global assessment at 6 and 12 months. Secondary outcomes included subsequent treatment with infliximab and/or corticosteroids, rate of discontinuation of MTX, and adverse events (AEs).. Twenty-seven patients (17 boys, 63%) with a mean age at diagnosis of 12.3 ± 0.7 years and mean disease duration of 1.49 ± 0.3 years were identified. Indications for MTX included nonresponse to thiopurines, AE, and poor adherence to thiopurines. At 6 and 12 months, 13 of 27 patients (48.1%) and 9 of 27 patients (33.3%), respectively, were in steroid-/infliximab-free remission. A total of 10 patients (37.0%) required infliximab therapy during the 12-month period and 5 patients discontinued MTX. Nausea was the most commonly reported AE. Transient transaminase elevation occurred in 4 patients and transient leukopenia in 2 patients.. MTX can be effective as maintenance therapy for patients with pediatric CD previously intolerant of or unresponsive to thiopurines; however, greater than one third of this cohort required escalation to antitumor necrosis factor therapy within 12 months following MTX initiation. MTX was well tolerated.

Topics: Antibodies, Monoclonal; Child; Crohn Disease; Drug Tolerance; Female; Humans; Infliximab; Leukopenia; Male; Mercaptopurine; Methotrexate; Methyltransferases; Nausea; Outcome Assessment, Health Care; Patient Compliance; Remission Induction; Retrospective Studies; Transaminases

Thiopurines (azathioprine and 6-mercaptopurine) can induce life-threatening myelosuppression. This study determined the frequency, timing, and outcomes of mild and severe myelosuppression after initiation of thiopurine therapy.. This retrospective cohort study included patients with inflammatory bowel disease who were new users of thiopurines; those tested for thiopurine methyltransferase levels before therapy were excluded. Patients were followed from their first thiopurine prescription until the earliest of severe leukopenia (white blood cell count, <1.0 x 10(9)/L), severe thrombocytopenia (platelet level, <20 x 10(9)/L), the end of therapy, the first gap in therapy, disenrollment, or December 31, 2006.. Among 1997 new users, the incidence of severe leukopenia per 100 person-months was 0.16 (95% confidence interval [CI], 0.03-0.29; n = 6) in weeks 0 to 8, 0.00 in weeks 9 to 24, and 0.01 (95% CI, 0-0.03; n = 3) after week 26 of therapy. The incidence of severe neutropenia and severe thrombocytopenia per 100 person-months during the first 8 weeks of therapy was 0.51 (95% CI, 0.31-0.80; n = 19) and 0.08 (95% CI, 0.02-0.23; n = 3), respectively. During the first 8 weeks, the median duration from a normal white blood cell count to severe leukopenia was 13 days (range, 8-26 d) and to severe neutropenia was 14 days (range, 7-23 d).. The high incidence of severe myelosuppression justifies frequent monitoring during the first 8 weeks of therapy. Subsequently, the rate of severe myelosuppression and the proportion of patients who progress from mild to severe myelosuppression decrease, justifying less-frequent monitoring.

Topics: Adult; Aged; Antimetabolites; Azathioprine; Bone Marrow; Cohort Studies; Drug Monitoring; Female; Humans; Inflammatory Bowel Diseases; Leukopenia; Longitudinal Studies; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Thrombocytopenia; Time Factors; Treatment Outcome

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).. Medical records of the patients with IBD treated with AZA/6-MP at Severance hospital from June 1996 to September 2006 were retrospectively analyzed.. 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.. 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.

Topics: Adolescent; Adult; Azathioprine; Behcet Syndrome; Cohort Studies; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Time Factors

Topics: Antimetabolites, Antineoplastic; Azathioprine; Cohort Studies; Drug Therapy, Combination; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine

Azathioprine (AZA) and 6-mercaptopurine (6-MP) have recently been used in Japanese pediatric patients with ulcerative colitis. The aims of this study were to evaluate both the therapeutic efficacy and safety of AZA/6-MP in this group of patients.. Fourteen members of the Japanese Society for Pediatric Inflammatory Bowel Disease reported 35 retrospective cases that received AZA/6-MP and were evaluated for adverse drug effects. In those who tolerated AZA/6-MP, disease activity and corticosteroid doses before and during the first 6 months of therapy were assessed.. AZA or 6-MP was safely used in 21 of 35 patients (60%) without adverse drug effects. The disease activity began to decrease from the first month of therapy and the maximum effect was achieved after 3 months. The mean daily prednisolone dose was decreased from 26.9 to 11.6 mg and dose reduction was achieved in 58% of patients after 6 months of therapy. Fourteen of the 35 patients (40%) experienced adverse drug effects, including leukopenia (n = 11), aplastic anemia (n = 1), pancreatitis (n = 1) and liver dysfunction (n = 1).. The majority of Japanese children with ulcerative colitis tolerated AZA/6-MP and experienced favorable effects. However, 40% experienced adverse drug effects, mainly myelosuppression.

Topics: Adolescent; Algorithms; Azathioprine; Child; Colitis, Ulcerative; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Japan; Leukopenia; Male; Mercaptopurine; Prednisolone; Retrospective Studies

Measurement of thiopurine metabolite levels may be useful as a clinical tool to optimize thiopurine treatment of paediatric inflammatory bowel disease (IBD).. The authors evaluated correlations between 6-thioguanine nucleotide (6-TGN) and therapeutic response, metabolite levels and drug toxicity.. Fifty-six paediatric IBD patients treated with thiopurines had 326 metabolite level measurements and were retrospectively reviewed. Clinical status and laboratory parameters were compared with metabolite levels.. There was significant correlation between 6-TGN levels and therapeutic response, with higher median 6-TGN levels among patients with therapeutic response than those with non-therapeutic response (194 vs. 146 pmol/8 x 10(8) RBC; P = 0.0004). Patients with 6-TGN levels >235 pmol/8 x 10(8) RBC were more likely to achieve therapeutic response than those below the cut-off (odds ratio, 2.5; 95% CI, 1.5-4.1). Patients who developed leukopenia tended to have higher median 6-TGN levels than those without leukopenia (261 vs. 160 pmol/8 x 10(8) RBC) but the difference was not statistically significant. There was no correlation between 6-methylmercaptopurine levels and hepatotoxicity. Two patients developed acute pancreatitis. Metabolite level measurements were helpful in identifying non-compliance in nine patients.. Monitoring of thiopurine metabolite levels is useful to guide and optimize dosing, as an adjunct to clinical judgement, blood count and liver biochemistry measurements to minimize the risk of drug toxicity and to confirm non-compliance.

Topics: Adolescent; Azathioprine; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Pancreatitis; Retrospective Studies; Thioguanine; Thrombocytopenia; Treatment Refusal

Studies to date have not confirmed an association between neoplasms and inflammatory bowel disease (IBD) treated with 6-mercaptopurine (6-MP). We have observed the occurrence of some neoplasms in IBD patients who developed sustained leukopenia as a result of treatment with 6-MP. As a result, we sought to compare the incidence of neoplasms in patients who developed sustained leukopenia after taking 6-MP compared with patients treated with 6-MP without sustained leukopenia.. A database containing the medical records of more than 600 patients treated with 6-MP for IBD at 1 center between 1965 and 2002 was searched. The patients were divided into 2 groups. The study group consisted of patients who developed sustained leukopenia, defined as a white blood cell count of less than 4000 for 20 or more days. The control group patients matched those in the study group for age and sex. There were 3 matched controls for each patient in the study group.. Eighteen patients developed sustained leukopenia and, of these, 4 developed neoplasms (22%)-2 leukemias, 1 non-Hodgkin's lymphoma, and 1 breast cancer. Of the 54 patients in the control group, 4 developed neoplasms (7%) (P = .10). Post hoc analysis revealed a statistically significant difference in the number of hematologic malignancies in the group with sustained leukopenia (P = .014). There was no significant difference between the 2 groups for all confounding variables examined.. There was a trend toward a greater number of total malignancies in the sustained leukopenic patients. The data suggest that it is those patients who develop sustained leukopenia while taking 6-MP/azathioprine who are most at risk.

Topics: Adult; Aged; Case-Control Studies; Databases as Topic; Female; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Middle Aged; Neoplasms; Retrospective Studies

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Crohn Disease; Drug Therapy, Combination; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Inosine Triphosphatase; Leukopenia; Mercaptopurine; Pyrophosphatases

Topics: Adult; Crohn Disease; Female; Fever; Humans; Immunosuppressive Agents; Leukopenia; Male; Mercaptopurine; Remission Induction; Severity of Illness Index; Time Factors

Azathioprine induced profound myelosuppression linked to TPMT deficiency has now been documented in many patient groups, including those with Crohn's disease. At the start of azathioprine or mercaptopurine therapy, measurement of TPMT activity has a role in identifying the 1 in 300 patients who are at risk of severe myelosuppression when treated with standard thiopurine dosages. During the initial months of azathioprine therapy a knowledge of TPMT status warns of early bone marrow toxicity. In patients established on azathioprine these is no clear evidence to suggest that TPMT is predictive of clinical response or drug toxicity, indicating a role for TPMT in the prediction of early events rather than long term control. In patients with Crohn's disease on long term azathioprine therapy, it is clear that myelosuppression, particularly leucopenia, is caused by other factors in addition to variable TPMT activity and therefore monitoring of blood cell counts throughout treatment is essential.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Biomarkers; Crohn Disease; Drug Interactions; Humans; Immunosuppressive Agents; Leukopenia; Mercaptopurine; Methyltransferases; Risk Factors; Sulfasalazine; Time Factors

We evaluated the effect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine.. Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sulphasalazine 4 g/day, or balsalazide 6.75 g/day. The primary outcome measure was the occurrence of clinically important leucopenia during the study, defined separately as total leucocyte counts < 3.0 x 10(9)/l and < or = 3.5 x 10(9)/l. Whole blood 6-thioguanine nucleotide concentrations were determined.. Three patients could not be evaluated for the primary outcome measure. In the remaining 31 patients, the frequency of total leucocyte counts < 3.0 and < or = 3.5 were: 1/10 and 5/10 in the mesalamine group; 1/11 and 6/11 in the sulphasalazine group; and 0/10 and 2/10 in the balsalazide group. There were significant increases in mean whole blood 6-thioguanine nucleotide concentrations from baseline at most time points in the mesalamine and sulphasalazine groups but not in the balsalazide group.. In patients with Crohn's disease receiving azathioprine or 6-mercaptopurine, coadministration of mesalamine, sulphasalazine, and possibly balsalazide results in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leucopenia.

Topics: Adult; Aminosalicylic Acids; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Binomial Distribution; Chromatography, High Pressure Liquid; Confidence Intervals; Drug Interactions; Female; Humans; Immunosuppressive Agents; Leukopenia; Male; Mercaptopurine; Mesalamine; Methyltransferases; Phenylhydrazines; Sulfasalazine; Thioguanine

Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine.. We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease < 170, remission > or = 170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count.. Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (r(s) = -0.09, p = 0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8 x 10(8) red blood cells; p = 0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts.. In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6-thioguanine nucleotide concentrations is warranted.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Severity of Illness Index; Statistics, Nonparametric

Some authors suggest that efficacy of 6-mercaptopurine (6-MP) in patients with inflammatory bowel disease correlates with circulating 6-thioguanine (6-TG) levels more than 235 pmol/8 x 10(8) red blood cells. The authors evaluated the relation between 6-MP metabolite levels and disease activity in children and adolescents with inflammatory bowel disease.. Clinical status and hematologic and hepatic parameters were determined in 101 children with inflammatory bowel disease from a single center and compared with 6-MP metabolite levels.. There was a trend for higher 6-TG levels among patients in remission than among those with active disease (217 vs. 173); however the difference was not statistically significant ( P = 0.09). The likelihood of therapeutic response did not increase significantly at 6-TG levels greater than 235 pmol/8 x 10(8) red blood cells (odds ratio 1.7; P = 0.1). In the current study, 58% of patients in remission had 6-TG levels less than 235. However, serial measurements of 6-MP metabolite levels in 50 patients with active disease showed that increasing 6-TG levels correlated significantly with disease remission in patients followed up longitudinally ( P = 0.04). Leukopenia was significantly associated with high 6-TG levels ( P = 0.03) but not with clinical response ( P = 0.2).. These data suggest that the target range of 6-TG levels previously described by others did not apply to 58% of the pediatric patients with IBD in remission. However, serial monitoring of 6-MP metabolite levels in individual patients with active disease should allow dose escalation and induction of remission while minimizing the risk of toxicity.

Topics: Adolescent; Antimetabolites, Antineoplastic; Azathioprine; Child; Cross-Sectional Studies; Erythrocytes; Humans; Inflammatory Bowel Diseases; Leukocyte Count; Leukopenia; Liver; Male; Mercaptopurine; Odds Ratio; Retrospective Studies; Thioguanine; Treatment Outcome

Topics: Adult; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocytes; Leukopenia; Male; Mercaptopurine; Middle Aged

Azathioprine-induced myelosuppression is the most important side effect observed in kidney transplantation. We report a case of severe neutropenia after kidney transplantation due to a thiopurine methyltransferase deficiency. This cause of azathioprine-induced myelotoxicity is rare, but its infectious consequences may be severe. Thiopurine methyltransferase deficiency must therefore be suspected when early and severe leukopenia occurs during azathioprine therapy. Erythrocyte thiopurine methyltransferase activity measurement confirms the diagnosis. Azathioprine and 6-mercaptopurine must afterwards be definitively avoided.

Topics: Azathioprine; Contraindications; Female; Glomerulonephritis, Membranoproliferative; Graft Rejection; Homozygote; Humans; Kidney Failure, Chronic; Kidney Transplantation; Leukopenia; Mercaptopurine; Methyltransferases; Middle Aged; Postoperative Complications; Transplantation, Homologous

A feared complication of therapy with 6-mercaptopurine (6-MP) is myelosuppression. To evaluate whether rigorous blood count monitoring is necessary, we prospectively followed the hematologic profiles of 57 patients with inflammatory bowel disease who were treated with low-dose 6-MP. Most patients (97%) were treated initially with a single dose of 50 mg/day and 79% never used more than 50 mg/day. Blood counts were obtained at weekly intervals over the first month, every two weeks for the second month, and monthly thereafter in the first year. Sixteen (28%) developed mild leukopenia (white blood count < 4.5 x 10(3)/mm3). No patient had a white blood cell count < 2.8 x 10(3)/mm3 and no patient developed leukopenia prior to three months of treatment. In only five patients did the leukopenia prompt a change in 6-mercaptopurine dose. Very mild thrombocytopenia (platelet count of < 145 x 10(3)/mm3) developed in three (5%) and macrocytosis (mean cell volume > 101 fl) was seen in nine (16%). In conclusion, leukopenia was not uncommon in patients treated with low-dose 6-MP, but was not clinically significant. Leukopenia occurred no earlier than three months and as late as 42 months into therapy. Thrombocytopenia was uncommon, mild, and was not associated with apparent bleeding. Macrocytosis may occur in the absence of vitamin B12 and folate deficiencies. Patients can be spared from weekly blood count monitoring when using low-dose 6-mercaptopurine treatment.

Topics: Anemia, Macrocytic; Humans; Inflammatory Bowel Diseases; Leukopenia; Mercaptopurine; Monitoring, Physiologic; Prospective Studies; Thrombocytopenia

1) to determine the frequency of induced leukopenia in patients with refractory Crohn's disease treated with 6-Mercaptopurine (6-MP). 2) to determine the influence of 6-MP-induced leukopenia on achieving remission [including the three major specific goals of therapy: (a) elimination or reduction of steroids, (b) healing of abscesses and fistulas, and (c) elimination of recurrent intestinal obstruction] and the effect on the rate and percentage of improvement in the CCFA-IOIBD index of Crohn's disease activity after 3 months of 6-MP therapy. 3) to determine whether an improvement of leukopenia was accomplished by an increased risk of clinical bone marrow depression.. We reviewed the course of 98 consecutive patients with refractory Crohn's disease treated with 6-MP and compared the 51 who developed leukopenia and the 47 who did not, in regard to achievement of remission, length of time until remission, rate of recurrence, and time until recurrence.. 1) The mean time to remission was 8.8 wk for patients with leukopenia versus 14.3 wk for those without leukopenia. 2) A strong positive correlation exists between 6-MP induced leukopenia and the achievement and maintenance of remission in refractory Crohn's disease. This was evident in the analysis of response in specific goals and in the activity index. 3) There was no clinical evidence of bone marrow suppression in the 51 patients who developed 6-MP induced leukopenia.. 1) Increasing the dose of 6-MP in patients with refractory Crohn's disease who have not yet responded and who have not achieved leukopenia will very likely increase the efficacy of this drug. 2) Influenced by the results of this study, we have launched a double-blind prospective study to evaluate the relationship between the induction of leukopenia with 6-MP and the achievement of remission.

Topics: Adult; Crohn Disease; Dose-Response Relationship, Drug; Female; Humans; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Remission Induction; Time Factors

To investigate the physiologic role of macrophage colony-stimulating factor (M-CSF) in hematological recovery from bone marrow hypoplasia, we used an enzyme-linked immunosorbent assay to measure serial changes of the serum M-CSF level during 25 intensification chemotherapy courses given to seven patients with acute non-lymphocytic leukemia who were in complete remission. Three M-CSF peaks were observed during therapy: the first peak was during or just after chemotherapy, the second peak was around the leukocyte nadir, and the third peak coincided with a rapid increase in the monocyte count. We could find no significant correlation between the height of the second peak and the time from the initiation of therapy to hematological recovery. On the other hand, there was a significant positive correlation between the height of the second peak and the interval from the last day of chemotherapy to the peak (r = 0.62, p = 0.001), and there was a significant negative correlation between the peak height and the time from the peak until hematological recovery (defined as a neutrophil count of over 500/microliters (r = -0.63, p = 0.001) and a leukocyte count of over 1,000/microliters (r = 0.55, p = 0.008)). However, we found only a weak correlation between the peak height and monocyte recovery. These data suggest that increased M-CSF levels lead to the stimulation of granulocyte progenitors, and that we can predict the time of neutrophil recovery by monitoring the serum M-CSF level and finding its peak.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Enzyme-Linked Immunosorbent Assay; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Leukopenia; Macrophage Colony-Stimulating Factor; Male; Mercaptopurine; Middle Aged; Mitoxantrone; Predictive Value of Tests; Prednisone; Remission Induction; Vindesine

In the present study of 12 boys and 19 girls 2-16 years of age (median, 7 years) on oral 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy (MT) for non-B-cell acute lymphoblastic leukemia (ALL), we found that (a) during MT, 6-thioguanine nucleotides (6TGN) (the major cytotoxic metabolite of 6MP) accumulate in the erythrocytes (E-6TGN); (b) for patients receiving an unchanged dose of 6MP, no significant correlation could be demonstrated between the mean E-6TGN (mE-6TGN) and the dose of 6MP (r = -0.11, P = 0.28) (31 patients); (c) among 21 patients receiving 50-75 mg/m2 6MP, a variation of up to 3 orders of magnitude in mE-6TGN could be demonstrated, with the interindividual coefficient of variation (CV) in mE-6TGN for these patients being 0.31; (d) the median intraindividual CV in E-6TGN at an unchanged dose of 6MP was 0.11 (range, 0.04-0.18); and (e) the degree of myelodepression as measured by the mean white cell count was related to mE-6TGN (r = -0.55, P = 0.0006). These results indicate that E-6TGN could be a useful parameter for monitoring 6MP maintenance chemotherapy, although this needs to be explored in prospective studies.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythrocytes; Female; Guanine Nucleotides; Humans; Leukopenia; Male; Mercaptopurine; Methotrexate; Monitoring, Physiologic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thionucleotides

Advances in the management of gestational trophoblastic tumor have been made during the last three decades. Individualization of the therapy is one of the major advances. A number of risk factors has proved to predict accurately the prognosis of each patient. A few systems were currently in use, but difficult in putting them to practical use in the different geographical areas. At National Taiwan University Hospital from 1965 to 1979, 65 patients treated by chemotherapy were analyzed with respect of various prognostic factors. The score was assigned according to the mortality rate of each item to each prognostic factor, and thus established a scoring system which is suitable for the use in Taiwan. After establishment of our scoring system, 51 patients from 1980 to 1986 were treated according to the system and the appropriate therapeutic regimens. The outcome of these patients and toxicity of the different therapeutic regimens are presented.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Choriocarcinoma; Cyclophosphamide; Doxorubicin; Drug Evaluation; Etoposide; Female; Humans; Leucovorin; Leukopenia; Liver; Mercaptopurine; Methotrexate; Middle Aged; Pregnancy; Pregnancy Complications, Neoplastic; Prognosis; Remission Induction; Risk Factors; Taiwan; Trophoblastic Neoplasms; Uterine Neoplasms

Isoproterenol produces myocardial necrosis in rats. To investigate the possible role of oxygen free radicals generated by xanthine oxidase and neutrophils, we examined the effects of the xanthine oxidase inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG) combined and allopurinol, or of irradiation (to induce leukopenia) on isoproterenol-induced myocardial necrosis (ISOMN). The incidence and severity of ISOMN was significantly reduced by 6MP + 6TG but not by the specific inhibitor of xanthine oxidase, allopurinol, indicating that the protective effects of 6MP + 6TG may be due to its free radical scavenging activity rather than its xanthine oxidase inhibitory activity. Irradiation provided complete protection against ISOMN in all rats. Marked leukopenia or other radiation-induced protective factors could play a role in the mechanism of the protection.

Topics: Allopurinol; Animals; Heart Diseases; Isoproterenol; Leukocytes; Leukopenia; Male; Mercaptopurine; Myocardium; Necrosis; Radiation Injuries, Experimental; Rats; Rats, Inbred Strains; Thioguanine

Acute myelogenous leukemia (ALM) can be cured by chemotherapy. We have treated 121 adult AML cases for the past 9 years. With BHAC-DMP therapy starting in 1979, CR was obtained in 82% of 51 consecutive AML and the predicted 8-year continuing CR (CCR). Survival of CR cases was, 15 and 21%, respectively. Multivariate analysis of the prognostic factors revealed that % of blasts in the bone marrow at 2 weeks after the start of induction therapy was the most significant factor for CCR. Thus, we started BHAC-DMP (II) therapy with highly intensive induction therapy in 1983, but were forced to cancel this because of an intolerably high incidence of severe infections during the induction therapy. The CR rate was 76% in 29 consecutive patients, and the predicted 5-year CCR and survival of CR cases are 27 and 47%, respectively. Then we started M-85 protocol with intermediately intensive induction followed by 3 courses of highly intensive consolidation therapy using non-cross resistant drugs in 1985. The CR rate was 71% in 41 consecutive patients. Although 4 patients died of infections or myocardial infarction during the consolidation therapies, the predicted 2.5-year CCR and survival of CR cases are 76 and 74%, respectively, with a median follow-up of 28 months.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Daunorubicin; Drug Evaluation; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Leukopenia; Mercaptopurine; Prednisolone; Prognosis; Remission Induction

Topics: Adult; Crohn Disease; Female; Humans; Leukopenia; Mercaptopurine; Xanthine Oxidase

Six-MP and its palladium and platinum complexes of this compound were administered intraperitoneally to 28 day old Sprague-Dawley rats in dosages of 15 mg/kg, 26.85 mg/kg, respectively for 21 days. The leukopenia induction capacity of 6-MP was greater at the end of day 7 while the 6-MP-Pd complex evidenced a more drastic leukocyte reduction at the end of day 21. The platinum complex was less toxic, as demonstrated by greater weight gain, while treatment with the palladium complex resulted in approximately the same weight gain as that observed in rats treated with pure 6-MP.

Topics: Animals; Body Weight; Chelating Agents; Leukocyte Count; Leukopenia; Mercaptopurine; Palladium; Platinum; Rats; Time Factors

16 courses of an 8-drug regimen including daunomycin, vincristine, cytosinearabinoside, thioguanine, methotrexate, cyclophosphamide, prednisolone and hydroxyurea, and 12 courses of a 7-drug regimen including the same drugs minus hydroxyurea were administered in 16 otherwise therapy-resistant cases of acute myeloid leukaemia. In spite of a significant and rapid reduction of the leukaemic cell-mass in all the cases treated, only two brief minimal remissions were obtained. The main toxic effect was myelosuppression. However, the treatment was associated with a high frequency of mucosal ulcerations of the oesophagus and stomach, and it cannot be excluded that the latter complication may be drug-related.

Topics: Adolescent; Adult; Aged; Candidiasis; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Resistance; Drug Therapy, Combination; Esophagitis, Peptic; Female; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Stomach Ulcer; Thioguanine; Vincristine

Topics: Animals; Antineoplastic Agents; Blood Platelets; Bone Marrow; Bone Marrow Cells; Deoxyribonucleosides; Diarrhea; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Erythrocyte Count; Feeding and Eating Disorders; Female; Haplorhini; Hematocrit; Humans; Injections, Intravenous; Leukocyte Count; Leukopenia; Lymphocytes; Macaca; Male; Mercaptopurine; Neutrophils; Thrombocytopenia; Time Factors; Vomiting

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Child; Child, Preschool; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Leukopenia; Male; Mercaptopurine; Nausea; Prednisone; Radiography; Recurrence; Sulfasalazine; Time Factors; Vomiting

Topics: Adolescent; Adult; Age Factors; Aged; Blood Platelets; Blood Transfusion; Cytarabine; Daunorubicin; Female; Humans; Hydrazines; Hyperplasia; Leukemia, Myeloid; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Remission, Spontaneous; Thrombocytopenia; Time Factors

Topics: Adult; Anemia, Hemolytic, Autoimmune; Chromium Isotopes; Coombs Test; Cortisone; Female; Humans; Leukopenia; Male; Mercaptopurine; Middle Aged; Purpura, Thrombocytopenic; Splenectomy; Syndrome

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Child; Child, Preschool; Colitis, Ulcerative; Female; Humans; Leukopenia; Male; Mercaptopurine; Middle Aged; Nausea; Recurrence; Sigmoidoscopy; Sulfasalazine; Time Factors

Topics: Adolescent; Asparaginase; Diabetic Ketoacidosis; Humans; Hyperglycemia; Leukemia; Leukopenia; Male; Mercaptopurine; Prednisone; Remission, Spontaneous

Topics: Adrenal Cortex Hormones; Adult; Aged; Antimetabolites; Azathioprine; Dermatomyositis; Female; Follow-Up Studies; Hematuria; Humans; Hyperbilirubinemia; Leukopenia; Male; Mercaptopurine; Middle Aged; Prednisone; Retrospective Studies; Transaminases

Topics: Adolescent; Adult; Age Factors; Azathioprine; Biopsy; Chlorambucil; Cortisone; Cyclophosphamide; Female; Glomerulonephritis; Humans; Kidney; Leukopenia; Lupus Erythematosus, Systemic; Male; Mechlorethamine; Mercaptopurine; Prednisolone; Proteinuria; Racial Groups; Serum Albumin; Sex Factors; Thioguanine

Topics: Adolescent; Adult; Aged; Asparaginase; Azaserine; Burkitt Lymphoma; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Drug Hypersensitivity; Escherichia coli; Female; Humans; Leukemia, Lymphoid; Leukopenia; Lymphoma, Non-Hodgkin; Lymphopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms; Pancreatitis; Thrombocytopenia

Topics: Adrenal Glands; Adult; Cicatrix; Diabetes Insipidus; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Leukopenia; Male; Mercaptopurine; Metyrapone; Pituitary Gland, Posterior; Pituitary-Adrenal Function Tests; Sodium Chloride; Specific Gravity; Urine

Topics: Animals; Body Weight; Brain; Coxsackievirus Infections; Female; Herpes Simplex; Interferons; Leukocytes; Leukopenia; Liver; Male; Mercaptopurine; Mice; Vaccinia

Topics: Alopecia; Azathioprine; Child, Preschool; Cyclophosphamide; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Leukopenia; Mercaptopurine; Nephrosis, Lipoid; Nephrotic Syndrome

Topics: Anemia, Aplastic; Azathioprine; Hematopoiesis; Hematopoietic System; Humans; Immunosuppressive Agents; Leukopenia; Mechlorethamine; Mercaptopurine; Time Factors

Topics: Adolescent; Adult; Aged; Anemia; Blood Platelets; Blood Transfusion; Blood Urea Nitrogen; Bone Marrow Cells; Bone Marrow Examination; Chromosome Aberrations; Cytomegalovirus; Female; Fever; Hemorrhage; Humans; Jaundice; Leukemia, Myeloid; Leukocyte Count; Leukocytes; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Nocardia Infections; Pneumonia; Prednisone; Proteus Infections; Pseudomonas Infections; Sepsis; Thrombocytopenia; Vincristine

Topics: Animals; Busulfan; Chlorambucil; Cyclophosphamide; Dactinomycin; Drug-Related Side Effects and Adverse Reactions; Folic Acid Antagonists; Haplorhini; Hematologic Diseases; Hematopoiesis; Infections; Leukocyte Count; Leukopenia; Mechlorethamine; Mercaptopurine; Models, Biological; Pyrimidines; Thiotepa; Triethylenemelamine; Vinblastine; Vincristine

Topics: Adult; Afibrinogenemia; Aged; Anemia; Antineoplastic Agents; Child; Cytarabine; Daunorubicin; Humans; Hydroxyzine; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukopenia; Mercaptopurine; Methotrexate; Middle Aged; Polycythemia Vera; Prednisone; Primary Myelofibrosis; Splenomegaly; Vincristine

Topics: Adolescent; Adult; Female; Hepatitis; Humans; Leukopenia; Liver Cirrhosis; Male; Mercaptopurine; Middle Aged; Prednisolone; Thrombocytopenia

Topics: Absorption; Anemia; Animals; Bone Marrow; Cyclophosphamide; Depression, Chemical; Erythrocytes; Female; Hemagglutination; Hematocrit; Hematopoiesis; Lectins; Leukocyte Count; Leukopenia; Lymphocyte Activation; Male; Mercaptopurine; Mice; Rabbits; Radiation Injuries, Experimental; Radiation-Protective Agents; Rats; Time Factors

Topics: Analysis of Variance; Animals; Antiviral Agents; Body Weight; Chickens; Depression, Chemical; Immunosuppressive Agents; Leukocyte Count; Leukopenia; Mercaptopurine; Palladium

Topics: Animals; Antineoplastic Agents; Blood Cells; Cyclophosphamide; Dactinomycin; Guinea Pigs; Leukocytes; Leukopenia; Lymphocytes; Mercaptopurine; Phenylbutazone; Plants, Medicinal; Plants, Toxic; Podophyllum; Prednisolone; Triethylenemelamine; Vinblastine

Topics: Animals; Body Weight; Chickens; Leukocyte Count; Leukopenia; Mercaptopurine; Platinum

Topics: Abdomen; Animals; Axilla; Dogs; Leukocyte Count; Leukopenia; Lymph Nodes; Lymphocytes; Mercaptopurine; Neck; Radiation Effects; Regeneration; Skin Transplantation; Spleen; Thorax; Thymus Gland; Transplantation Immunology

Topics: Bone Marrow; Chloramphenicol; Female; Hematocrit; Hemoglobinometry; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Leukopenia; Lupus Erythematosus, Systemic; Mercaptopurine; Middle Aged; Pneumonia; Prednisone

Topics: Formates; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukocytes; Leukopenia; Mercaptopurine; Nucleic Acids; Purines; Thymine

Topics: Alkylating Agents; Carbamates; Chlorambucil; Fluorouracil; Humans; Leukocyte Count; Leukopenia; Mercaptopurine; Mitomycins; Neoplasms; Thrombocytopenia

Topics: Adult; Anti-Bacterial Agents; Culture Media; Cyclophosphamide; Fluorouracil; Germ-Free Life; Humans; Leukemia; Leukopenia; Male; Mercaptopurine; Methotrexate; Prednisolone; Teratoma; Vincristine

Topics: Adrenal Cortex Hormones; Adult; Aged; Anemia, Hemolytic, Autoimmune; Arthritis, Rheumatoid; Asthma; Azathioprine; Collagen Diseases; Female; Humans; Leukopenia; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Middle Aged; Polyarteritis Nodosa; Polymyalgia Rheumatica; Thyroiditis

Topics: Adolescent; Adult; Anemia, Aplastic; Biopsy; Child; Female; Humans; Kidney; Leukopenia; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Microscopy, Electron; Nephrotic Syndrome; Proteinuria; Thrombocytopenia

Topics: Antineoplastic Agents; Bone Marrow Examination; Erythrocyte Count; Hemorrhage; Humans; Leukemia; Leukocyte Count; Leukopenia; Mercaptopurine; Nucleosides; Thioinosine; Toxicology

Topics: Adrenal Cortex Hormones; Aminopterin; Androgens; Antimetabolites; Antineoplastic Agents; Blood Platelet Disorders; Chemotherapy, Cancer, Regional Perfusion; Chlorambucil; Cyclophosphamide; Dactinomycin; Estrogens; Fluorouracil; Geriatrics; Humans; Leukopenia; Mechlorethamine; Mercaptopurine; Neoplasms; Nitrogen Mustard Compounds; Surgical Procedures, Operative; Thiotepa; Toxicology; Vinblastine

Topics: Bone Marrow; Injections, Intravenous; Leukopenia; Mercaptopurine; Mice; Neoplasms; Nucleosides; Pharmacology; Purines; Pyrimidines; Research; Thioinosine; Thrombocytopenia; Toxicology

Topics: Agranulocytosis; Aminopterin; Animals; Azaguanine; Biopsy; Chloramphenicol; Connective Tissue; Cyclophosphamide; Dactinomycin; Fluorouracil; Glycosaminoglycans; Histocytochemistry; Inflammation; Leukopenia; Lymphocytes; Mercaptopurine; Mice; Neutrophils; Photomicrography; Puromycin; Rabbits; Research

Topics: Albuminuria; Drug Therapy; Humans; Kidney Diseases; Leukopenia; Lupus Erythematosus, Systemic; Lupus Nephritis; Mercaptopurine; Toxicology