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"An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia." (MeSH 2013)

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Web Resources: Mercaptopurine
Latest Research Publications

Web Resources: Mercaptopurine (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Kimura S, Hasegawa D, Yoshimoto Y, et al.
Severe 6-mercaptopurine-induced hematotoxicity in childhood an ALL patient with homozygous NUDT15 missence variants.
Rinsho Ketsueki. 2016; 57(6):748-53 [PubMed] Related Publications
Thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are considered to be genes responsible for severe myelotoxicity induced by 6-mercaptopurine (6MP). We report a 4-year-old girl with acute lymphoblastic leukemia, who developed the complication of severe 6MP-induced myelotoxicity due to homozygous NUDT15 variant alleles. In early consolidation therapy containing 6MP, her course was complicated by severe neutropenia (Grade 4) and chemotherapy had to be discontinued for 33 days. The 6MP dose was subsequently adjusted based on the white blood cell count. The ratios of the prescribed 6MP dose over the protocol dose in early consolidation, central nervous system (CNS) prophylaxis, re-induction, interim maintenance and maintenance therapy were 63%, 27%, 4%, 26% and 7%, respectively. Suspension of therapy was required during early consolidation, CNS prophylaxis and interim maintenance therapy. We investigated candidate genes for 6MP-associated myelotoxicity and found homozygous NUDT15 variant alleles and a heterozygous inosine triphosphate pyrophosphatase (ITPA) variant allele. In patients with homozygous NUDT15 variants, drastic reduction (less than 10%) of the 6MP dose from the protocol dose might be required not only during maintenance therapy, but also during other treatment courses containing 6MP. Screening of candidate genes at diagnosis is recommended in order to avoid serious adverse events.

Moriyama T, Nishii R, Perez-Andreu V, et al.
NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.
Nat Genet. 2016; 48(4):367-73 [PubMed] Free Access to Full Article Related Publications
Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile and p.Val18_Val19insGlyVal) that resulted in 74.4-100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across the three cohorts (P = 0.021, 2.1 × 10(-5) and 0.0054, respectively; meta-analysis P = 4.45 × 10(-8), allelic effect size = -11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased thiopurine cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. Taken together, these results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.

Zerra P, Bergsagel J, Keller FG, et al.
Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis.
Pediatr Blood Cancer. 2016; 63(4):712-5 [PubMed] Related Publications
Mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.

Chen G, Crispin P, Cherian M, et al.
Placental involvement by non-Hodgkin lymphoma in a Crohn disease patient on long-term thiopurine therapy.
Intern Med J. 2016; 46(1):102-5 [PubMed] Related Publications
We report the first published case of aggressive diffuse large B-cell (non-Hodgkin) lymphoma in a 35-year-old pregnant woman who had Crohn disease and was taking long-term thiopurine therapy: the patient developed placental insufficiency, and there was intrauterine fetal death.

Giamanco NM, Cunningham BS, Klein LS, et al.
Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity.
J Pediatr Hematol Oncol. 2016; 38(2):147-51 [PubMed] Related Publications
6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

Vandenbulcke H, Borgies P, Dubois A, et al.
Crohn's Disease treated with azathioprine and basal cell carcinoma : three cases and literature review.
Acta Gastroenterol Belg. 2015; 78(4):436-8 [PubMed] Related Publications
Three cases of basal cell carcinoma in Crohn's disease patients treated with azathioprine are described. A review of the literature is conducted concerning this association between the occurrence of basal cell carcinoma and the use of azathioprine. Recently, practical advice on screening and follow-up of these situations have been proposed but there are no validated dermatological recommendations.

Tiphaine Ade B, Hjalgrim LL, Nersting J, et al.
Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children.
Eur J Pharm Sci. 2016; 83:1-7 [PubMed] Related Publications
BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.
METHODS: The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.
RESULTS: The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.
CONCLUSION: Pharmacokinetic, palatability and safety data support the use of Loulla in children.

Peiris-Pagès M, Smith DL, Győrffy B, et al.
Proteomic identification of prognostic tumour biomarkers, using chemotherapy-induced cancer-associated fibroblasts.
Aging (Albany NY). 2015; 7(10):816-38 [PubMed] Free Access to Full Article Related Publications
Cancer cells grow in highly complex stromal microenvironments, which through metabolic remodelling, catabolism, autophagy and inflammation nurture them and are able to facilitate metastasis and resistance to therapy. However, these changes in the metabolic profile of stromal cancer-associated fibroblasts and their impact on cancer initiation, progression and metastasis are not well-known. This is the first study to provide a comprehensive proteomic portrait of the azathioprine and taxol-induced catabolic state on human stromal fibroblasts, which comprises changes in the expression of metabolic enzymes, myofibroblastic differentiation markers, antioxidants, proteins involved in autophagy, senescence, vesicle trafficking and protein degradation, and inducers of inflammation. Interestingly, many of these features are major contributors to the aging process. A catabolic stroma signature, generated with proteins found differentially up-regulated in taxol-treated fibroblasts, strikingly correlates with recurrence, metastasis and poor patient survival in several solid malignancies. We therefore suggest the inhibition of the catabolic state in healthy cells as a novel approach to improve current chemotherapy efficacies and possibly avoid future carcinogenic processes.

McGurgan IJ, McGuigan C
Nonmelanoma skin cancer risk awareness in azathioprine-treated myasthenia gravis patients.
Brain Behav. 2015; 5(10):e00396 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Increased rates of NMSC (nonmelanoma skin cancer) have recently been reported in people with MG (myasthenia gravis) receiving azathioprine treatment. Guidelines on azathioprine for patients with dermatological and gastrointestinal disorders stress the importance of NMSC risk awareness and prevention. The aim of this study is to assess whether MG patients are being informed of this risk.
METHODS: Clinical records of patients with MG attending a university hospital neurology clinic were reviewed. Data on patient demographics, clinical presentation, diagnostic tests, azathioprine treatment, development of NMSC, and counseling regarding NMSC risk were recorded.
RESULTS: Sixty-nine MG cases were identified, median age 58 years (range 20-90). Forty-two (60.9%) had received azathioprine at some point with a mean cumulative dose of 235.5 g (range 9.1-972.8 g). Skin cancer risk and prevention advice provision was documented in 3 (7.1%) azathioprine-treated patients. Five patients developed histologically confirmed NMSC of whom all were treated with azathioprine (incidence rate of 24.9 per 1000, 16 times higher than expected). Documented advice on other safety issues such as regular blood test monitoring was found in 33 (78.8%) azathioprine-treated cases.
CONCLUSIONS: Preventative measures such as daily sunscreen use have been shown to reduce the incidence of NMSC in the general population. The results of this study demonstrate a very low rate of advice provision about NMSC risk in azathioprine-treated MG patients and the need for increased awareness among treating neurologists and patients.

Kremeike K, Juergens C, Alz H, Reinhardt D
Patients' Adherence in the Maintenance Therapy of Children and Adolescents with Acute Lymphoblastic Leukemia.
Klin Padiatr. 2015; 227(6-7):329-34 [PubMed] Related Publications
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common form of paediatric cancer. Maintenance therapy as last treatment phase includes oral chemotherapy with methotrexate (MTX) and mercaptopurine (6-MP), self- or parent-administered at home, given for about 1 ½ years, and qualified as decisive for an optimum therapy outcome. The aim of our study was to analyze factors influencing the adherence of patients with ALL undergoing maintenance therapy and their families.
METHODS: A multi-method study was undertaken between 11/2011 and 10/2014 with patients surveyed by the Hannover Medical School outpatient clinic, including a questionnaire survey and qualitative interviews with parents as well as blood samples of the patients.
RESULTS: 33 questionnaires, 27 interviews and blood samples of 26 patients could be analyzed. Only one third of the blood samples showed concentrations of the 6-MP active metabolite within the therapeutic reference range. Parents named the clinical doctor as their main advisor on medication intake. 36% (12/33) of the participants stated that medication intake has not always occurred the way medication was prescribed. Drug formulation and drug intake information could be identified as determinants of adherence. Parents' problems to obtain information are partly caused by different study results concerning the correct timing of the drug intake and drug interactions with milk products.
CONCLUSION: Parents' information on drug therapy should be more consistent and the pharmaceutical formulations have to be adapted to patients' needs to improve adherence and thereby the chance of long-term remission.

Choi YW, Jeong SH, Ahn MS, et al.
Oral Maintenance Chemotherapy with 6-Mercaptopurine and Methotrexate in Patients with Acute Myeloid Leukemia Ineligible for Transplantation.
J Korean Med Sci. 2015; 30(10):1416-22 [PubMed] Free Access to Full Article Related Publications
For decades, maintenance chemotherapy has failed to improve the cure rate or prolong the survival of patients with acute myeloid leukemia (AML), other than those with acute promyelocytic leukemia. Immediately after the first complete remission following consolidation therapy was obtained, oral maintenance chemotherapy (daily 6-mercaptopurine and weekly methotrexate) was given and continued for two years in transplant-ineligible AML patients. Leukemia-free survival (LFS) and overall survival (OS) were studied and compared between these patients and the historical control group who did not receive maintenance therapy. Consecutive 52 transplant-ineligible AML patients were analyzed. Among these patients, 27 received oral maintenance chemotherapy. No significant difference was found in the patients' characteristics between the maintenance and the control groups. The median OS was 43 (95% CI, 19-67) and 19 (95% CI, 8-30) months in the maintenance and the control groups, respectively (P = 0.202). In the multivariate analysis, the presence of maintenance therapy was an independent prognostic factor for better OS (P = 0.021) and LFS (P = 0.024). Clinical benefit from maintenance chemotherapy was remarkable in older patients (≥ 60 yr) (P = 0.035), those with intermediate or unfavorable cytogenetics (P = 0.006), those with initial low blast count in peripheral blood (P = 0.044), and those receiving less than two cycles of consolidation therapy (P = 0.017). Maintenance oral chemotherapy as a post-remission therapy can prolong the survival of patients with AML who are not eligible for transplantation, particularly older patients, those with intermediate or unfavorable cytogenetics, those with initial low blast count, and those receiving less than two cycles of consolidation therapy.

Gordillo J, Cabré E, Garcia-Planella E, et al.
Thiopurine Therapy Reduces the Incidence of Colorectal Neoplasia in Patients with Ulcerative Colitis. Data from the ENEIDA Registry.
J Crohns Colitis. 2015; 9(12):1063-70 [PubMed] Related Publications
BACKGROUND AND AIMS: Patients with ulcerative colitis (UC) are at increased risk of developing colorectal cancer (CRC), but recent studies suggest a lower risk than previously reported. The aim was to evaluate the incidence of dysplasia, CRC and related risk factors in UC patients from a Spanish nationwide database.
METHODS: All UC patients were identified and retrospectively reviewed. Clinical-epidemiological data and the finding of dysplasia and/or CRC were collected.
RESULTS: A total of 831 UC patients were included. Twenty-six cases of CRC in 26 patients and 29 cases of high-grade dysplasia (HGD) in 24 patients were found, accounting for 55 diagnoses of advanced neoplasia (AN = CRC and/or HGD) in 45 patients (33% of them within the first 8 years after UC diagnosis). The cumulative risk of AN was 2, 5.3 and 14.7% at 10, 20 and 30 years, respectively. Concomitant primary sclerosing cholangitis (odds ratio [OR] 10.90; 95% confidence interval [CI] 3.75-31.76, p < 0.001), extensive UC (OR 2.10, 95% CI 1.01-4.38, p = 0.048), UC diagnosis at an older age (OR 2.23, 95% CI 1.03-4.83, p = 0.043) and appendectomy prior to UC diagnosis (OR 2.66, 95% CI 1.06-6.71, p = 0.038) were independent risk factors for AN. Use of thiopurines (OR 0.21, 95% CI 0.06-0.74, p = 0.015) and being in a surveillance colonoscopy programme (OR 0.33; 95% CI 0.16-0.67; p = 0.002) were independent protective factors for AN.
CONCLUSIONS: The risk of AN among UC patients is lower than previously reported but steadily increases from the time of UC diagnosis. The widespread use of thiopurines may have influenced this reduced incidence of UC-related neoplasias.

Bodo S, Svrcek M, Sourrouille I, et al.
Azathioprine induction of tumors with microsatellite instability: risk evaluation using a mouse model.
Oncotarget. 2015; 6(28):24969-77 [PubMed] Free Access to Full Article Related Publications
Mismatch-repair (MMR)-deficient cells show increased in vitro tolerance to thiopurines because they escape apoptosis resulting from MMR-dependent signaling of drug-induced DNA damage. Prolonged treatment with immunosuppressants including azathioprine (Aza), a thiopurine prodrug, has been suggested as a risk factor for the development of late onset leukemias/lymphomas displaying a microsatellite instability (MSI) phenotype, the hallmark of a defective MMR system. We performed a dose effect study in mice to investigate the development of MSI lymphomas associated with long term Aza treatment. Over two years, Aza was administered to mice that were wild type, null or heterozygous for the MMR gene Msh2. Ciclosporin A, an immunosuppressant with an MMR-independent signaling, was also administered to Msh2(wt) mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2(+/-) mice were found more tolerant than Msh2(wt) mice to the cytotoxicity of Aza. In Msh2(+/-) mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2(wt) mice, a substantial lifespan was only observed at the lowest Aza dose. It was associated with the development of lymphomas, one of which displayed the MSI phenotype, unlike the CsA-induced lymphomas. Our findings define Aza as a risk factor for an MSI-driven lymphomagenesis process.

Kellet CV, Navarrete RA, Bombardieri SG, Manriquez J
Azathioprine-induced accelerated cutaneous and pulmonary nodulosis in a patient with rheumatoid arthritis.
An Bras Dermatol. 2015 May-Jun; 90(3 Suppl 1):162-4 [PubMed] Free Access to Full Article Related Publications
We report the case of a 42-year-old female with a 5-year history of rheumatoid arthritis treated with Rituximab and Azathioprine. Three months after the initiation of Azathioprine, the patient started with dry cough and noted the rapid development of multiple subcutaneous nodules on her right leg. CT scan of the chest demonstrates pulmonary nodulosis. Skin biopsy was compatible with rheumatoid nodule. A diagnosis of "accelerated cutaneous and pulmonary nodulosis" was considered. Azathioprine was discontinued and Rituximab was restarted. Two months later, most of the subcutaneous nodules had disappeared. This is the second case report of accelerated rheumatoid nodulosis in association with Azathioprine treatment.

Azimi F, Mortazavi Y, Alavi S, et al.
Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects.
Leuk Res. 2015; 39(10):1048-54 [PubMed] Related Publications
6-Mercaptopurine (6-MP) plays an important role in treatment of childhood acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphohydrolase (ITPA) is an enzyme involved in 6-MP metabolic pathway that convert the inosine triphosphate (ITP) to inosine monophosphate (IMP) and prevents the accumulation of the toxic metabolite ITP. Our objective was to evaluate the ITPA 94C>A, IVS2+21A>C polymorphisms in patients with ALL treated with 6-MP and prediction of its clinical outcomes. Our study population consisted of 70 patients diagnosed with ALL in the Division of Hematology-Oncology of Tehran Mofid Hospital. PCR was carried out to amplify exon 2, exon 3, intron 2, and intron 3 of ITPA gene then, all the amplified fragments were subjected to directional sequencing and then association between genotype and 6-MP toxicity was studied. In this study two exonic variants including 94C>A and 138G>A showed a prevalence of 8.5% and 36.4%, respectively. Two intronic variants, IVS2+21A>C and IVS3+101G>A were found in 13.5% and 7% of the samples, respectively. The rate of myelosuppression in the presence of mutant homozygote and heterozygous alleles (94C>A, 138G>A, IVS2+21A>C and IVS3+101G>A) was higher than that of wild type alleles during the use of 6-MP. Hepatotoxicity in patients with mutant homozygous and heterozygous 94C>A and IVS3+101G>A during the treatment 6-MP was higher than before treatment with 6-MP. Our results showed that patients with aberrant ITPase genotype (mutant homozygous or heterozygous), more likely to be myelosuppressed and show liver toxicity after treatment with 6-MP. Our results suggest that pre-therapeutic screening of patients for ITPA 94C>A, IVS2+21A>C and IVS3+101G>A can help in minimizing the adverse effects of 6-MP in ALL patients.

Hareedy MS, El Desoky ES, Woillard JB, et al.
Genetic variants in 6-mercaptopurine pathway as potential factors of hematological toxicity in acute lymphoblastic leukemia patients.
Pharmacogenomics. 2015; 16(10):1119-34 [PubMed] Related Publications
AIM: We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia.
MATERIALS & METHODS: Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were investigated using a Cox proportional hazard model in 70 acute lymphoblastic leukemia patients from upper Egypt.
RESULTS: We found significant associations between ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3 and ABCC4 SNPs and one or more of the hematological toxicity manifestations (neutropenia, agranulocytosis and leukopenia); age was significantly related to relapse.
CONCLUSION: Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Jayachandran D, Laínez-Aguirre J, Rundell A, et al.
Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization.
PLoS One. 2015; 10(7):e0133244 [PubMed] Free Access to Full Article Related Publications
6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype) plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient's ability to metabolize the drug instead of the traditional standard-dose-for-all approach.

Bhatia S, Landier W, Hageman L, et al.
Systemic Exposure to Thiopurines and Risk of Relapse in Children With Acute Lymphoblastic Leukemia: A Children's Oncology Group Study.
JAMA Oncol. 2015; 1(3):287-95 [PubMed] Free Access to Full Article Related Publications
IMPORTANCE: Variability in prescribed doses of 6-mercaptopurine (6MP) and lack of adherence to a 6MP treatment regimen could result in intra-individual variability in systemic exposure to 6MP (measured as erythrocyte thioguanine nucleotide [TGN] levels) in children with acute lymphoblastic leukemia (ALL). The effect on relapse risk of this variability is unknown.
OBJECTIVE: To determine the effect of high intra-individual variability of 6MP systemic exposure on relapse risk in children with ALL.
DESIGN, SETTING, AND PARTICIPANTS: We used a prospective longitudinal design (Children's Oncology Group study [COG-AALL03N1]) to monitor 6MP and disease relapse in 742 children with ALL in ambulatory care settings of 94 participating institutions from May 30, 2005, to September 9, 2011. All participants met the following eligibility criteria: (1) diagnosis of ALL at 21 years or younger; (2) first continuous remission in progress at the time of study entry; (3) receiving self-, parent-, or caregiver-administered oral 6MP during maintenance therapy; and (4) completion of at least 6 months of maintenance therapy at the time of study enrollment. The median patient age at diagnosis was 5 years; 68% were boys; and 43% had National Cancer Institute-based high-risk disease.
MAIN OUTCOMES AND MEASURES: Daily 6MP regimen adherence was measured over 68 716 person-days using an electronic system that recorded the date and time of each 6MP bottle opening; adherence rate was defined as the ratio of days that a 6MP bottle was opened to days thata 6MP bottle was prescribed. Average monthly 6MP dose intensity was measured over 120 439 person-days by dividing the number of 6MP doses actually prescribed by the number of planned protocol doses (75 mg/m2/d). Monthly erythrocyte TGN levels (pmol/8 × 108 erythrocytes) were measured over 6 consecutive months per patient (n = 3944 measurements). Using intra-individual coefficients of variation (CV%), patients were classified as having stable (CV% <85th percentile) vs varying (CV% ≥85th percentile) indices. Median follow-up time was 6.7 years from the time of diagnosis.
RESULTS: Adjusting for clinical prognosticators, we found that patients with 6MP nonadherence (mean adherence rate <95%) were at a 2.7-fold increased risk of relapse (95% CI, 1.3-5.6; P = .01) compared with patients with a mean adherence rate of 95% or greater. Among adherers, high intra-individual variability in TGN levels contributed to increased relapse risk (hazard ratio, 4.4; 95% CI, 1.2-15.7; P = .02). Furthermore, adherers with varying TGN levels had varying 6MP dose intensity (odds ratio [OR], 4.5; 95% CI, 1.5-13.4; P = .01) and 6MP drug interruptions (OR, 10.2; 95% CI, 2.2-48.3; P = .003).
CONCLUSIONS AND RELEVANCE: These findings emphasize the need to maximize 6MP regimen adherence and maintain steady thiopurine exposure to minimize relapse in children with ALL.

Senol S, Ucar M, İmamoğlu H, Yildirim A
Neuro-Behçet's disease mimicking a cranial tumour.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
Behçet's disease affects many systems and has been described as a multisystem disorder. In Behçet's disease, neurological involvement is responsible for morbidity and mortality, and can sometimes mimic other neurological disorders. We present a case of neuro-Behçet's disease that mimicked a cranial tumour.

Tanaka Y, Kato M, Hasegawa D, et al.
Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia.
Br J Haematol. 2015; 171(1):109-15 [PubMed] Related Publications
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.

Razidlo GL, Magnine C, Sletten AC, et al.
Targeting Pancreatic Cancer Metastasis by Inhibition of Vav1, a Driver of Tumor Cell Invasion.
Cancer Res. 2015; 75(14):2907-15 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. Although many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in more than half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its proinvasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Furthermore, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48(Cre/+), Kras(G12D/+), p53(F/+) mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent antimetastatic agents for Vav1-positive pancreatic tumors.

Goldberg R, Irving PM
Toxicity and response to thiopurines in patients with inflammatory bowel disease.
Expert Rev Gastroenterol Hepatol. 2015; 9(7):891-900 [PubMed] Related Publications
The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.

Vang SI, Schmiegelow K, Frandsen T, et al.
Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia.
Cancer Chemother Pharmacol. 2015; 75(5):1089-93 [PubMed] Related Publications
High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression.

Yang JJ, Landier W, Yang W, et al.
Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.
J Clin Oncol. 2015; 33(11):1235-42 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.
PATIENTS AND METHODS: The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.
RESULTS: MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.
CONCLUSION: We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

Fong SC, Blaker PA, Arenas-Hernandez M, et al.
Getting the best out of thiopurine therapy: thiopurine S-methyltransferase and beyond.
Biomark Med. 2015; 9(1):51-65 [PubMed] Related Publications
Thiopurines are the cornerstone of treatment for a wide variety of medical disorders, ranging from pediatric leukemia to inflammatory bowel disease. Because of their complex metabolism and potential toxicities, the use of biomarkers to predict risk and response is paramount. Thiopurine S-methyltransferase and thiopurine metabolite levels have emerged as companion diagnostics with crucial roles in facilitating safe and effective treatment. This review serves to update the reader on how these tools are being developed and implemented in clinical practice. A useful paradigm in thiopurine therapeutic strategy is presented, along with fresh insights into the mechanisms underlying these approaches. We elaborate on potential future developments in the optimization of thiopurine therapy.

Termsarasab P, Katirji B
Brainstem lymphoma in a myasthenia gravis patient on azathioprine.
J Clin Neurosci. 2015; 22(2):415-8 [PubMed] Related Publications
Azathioprine is used for immunosuppression in myasthenia gravis (MG). We report a patient with seropositive MG who developed a brainstem lymphoma 4 years after being treated with azathioprine and review the literature on the occurrence of lymphoma in this patient population. An 82-year-old man with ocular MG who had been on azathioprine for 4 years developed subacute worsening of bulbar symptoms including diplopia, dysarthria and dysphagia mimicking MG exacerbation. Neuroimaging followed by biopsy showed brainstem diffuse large B-cell lymphoma (DLBCL). To our knowledge this is the first reported patient with brainstem DLBCL after azathioprine treatment in MG. Lymphoma has been reported in MG patients treated with azathioprine, although the incidence is unknown. We suggest reduction of azathioprine dose and subsequent discontinuation, if possible, in MG patients who are in remission. Special caution should be taken with elderly patients and Epstein-Barr virus serology prior to initiation may be useful in this population, but this requires further study.

Tanaka Y, Manabe A, Fukushima H, et al.
Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia.
Pharmacogenomics J. 2015; 15(4):380-4 [PubMed] Related Publications
Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30-50 mg m(-2) in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m(-2), P=0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

Guillevin L, Pagnoux C, Karras A, et al.
Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.
N Engl J Med. 2014; 371(19):1771-80 [PubMed] Related Publications
BACKGROUND: The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission.
METHODS: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both).
RESULTS: The 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer).
CONCLUSIONS: More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. (Funded by the French Ministry of Health; MAINRITSAN ClinicalTrials.gov number, NCT00748644; EudraCT number, 2008-002846-51.).

Levinsen M, Rosthøj S, Nygaard U, et al.
Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity.
Cancer Chemother Pharmacol. 2015; 75(1):59-66 [PubMed] Free Access to Full Article Related Publications
PURPOSE: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSION: 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.

Rehman SU, Zubair H, Sarwar T, et al.
Redox cycling of Cu(II) by 6-mercaptopurine leads to ROS generation and DNA breakage: possible mechanism of anticancer activity.
Tumour Biol. 2015; 36(2):1237-44 [PubMed] Related Publications
6-Mercaptopurine (6MP) is a well-known purine antimetabolite used to treat childhood acute lymphoblastic leukemia and other diseases. Cancer cells as compared to normal cells are under increased oxidative stress and show high copper level. These differences between cancer cells and normal cells can be targeted to develop effective cancer therapy. Pro-oxidant property of 6MP in the presence of metal ions is not well documented. Redox cycling of Cu(II) to Cu(I) was found to be efficiently mediated by 6MP. We have performed a series of in vitro experiments to demonstrate the pro-oxidant property of 6MP in the presence of Cu(II). Studies on human lymphocytes confirmed the DNA damaging ability of 6MP in the presence of Cu(II). Since 6MP possesses DNA damaging ability by producing reactive oxygen species (ROS) in the presence of Cu(II), it may also possess apoptosis-inducing activity by involving endogenous copper ions. Essentially, this would be an alternative and copper-dependent pathway for anticancer activity of 6MP.

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