Dataset Information

Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.

ABSTRACT: Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.

SUBMITTER: Landier W

PROVIDER: S-EPMC5455766 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.

Landier Wendy W Hageman Lindsey L Chen Yanjun Y Kornegay Nancy N Evans William E WE Bostrom Bruce C BC Casillas Jacqueline J Dickens David S DS Angiolillo Anne L AL Lew Glen G Maloney Kelly W KW Mascarenhas Leo L Ritchey A Kim AK Termuhlen Amanda M AM Carroll William L WL Relling Mary V MV Wong F Lennie FL Bhatia Smita S

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20170324 15

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using ...[more]

PMID: 28339328

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Project description:ImportanceVariability 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.ObjectiveTo determine the effect of high intra-individual variability of 6MP systemic exposure on relapse risk in children with ALL.Design, setting, and participantsWe 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 measuresDaily 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.ResultsAdjusting 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 relevanceThese findings emphasize the need to maximize 6MP regimen adherence and maintain steady thiopurine exposure to minimize relapse in children with ALL.

Project description:PAPER 1:"Identification of novel subgroups of high-risk pediatric precursor B acute lymphoblastic leukemia (B-ALL) by unsupervised microarray analysis: clinical correlates and therapeutic implications. A Children's Oncology Group (COG) study." ABSTRACT We examined gene expression profiles of pre-treatment specimens from 207 patients from the COG P9906 study to identify signatures of children with high risk B-precursor acute lymphoblastic leukemia (ALL) and to determine whether the resulting clusters are associated with either specific clinical features or treatment response characteristics. Four unsupervised clustering methods were utilized to classify patients into similar groups. The different clustering algorithms showed significant overlap in cluster membership. Two clusters contained all cases with either t(1;19)(q23;p13) translocations or MLL rearrangements. The other six clusters were novel and had no recurring chromosomal abnormalities or distinctive clinical features. Members of two of these novel clusters had significant survival differences when compared to the overall 4-year relapse-free survival (RFS) of 61%. These included clusters of patients with either significantly better (94.7%) or worse (21.0%) RFS at 4 years. Children of Hispanic/Latino ethnicity were disproportionately present in the poor outcome cluster. The poor outcome cluster represents a novel biologically distinctive subset of B-precursor ALL that may occur at least as frequently as BCR/ABL. Further molecular characterization of this cluster may lead to the discovery of genomic abnormalities that can be targeted to improve the currently dismal outcome for children with this gene signature. The Sample data have also been used in another study: PAPER 2: "Gene expression classifiers for minimal residual disease and relapse free survival improve outcome prediction and risk classification in children with high risk acute lymphoblastic leukemia. A Children's Oncology Group study". ABSTRACT Background. Nearly 25% of children with B-precursor ALL present with "high-risk" disease (HR-ALL) that is resistant to current therapies. Gene expression profiling may yield molecular classifiers for outcome prediction that can be used to improve risk classification and therapeutic targeting. Methods. Expression profiles were obtained in pre-treatment leukemic samples from 207 uniformly treated children with HR-ALL. Relapse free survival (RFS) was 61% at 4 years and flow cytometric measures of minimal residual disease (MRD) at the end of induction (day 29) were predictive of outcome (P<0.001). Molecular classifiers predictive of RFS and MRD were developed using extensive cross-validation procedures. Results. A 38 gene molecular risk classifier predictive of RFS (MRC-RFS) distinguished two groups in HR-ALL with different relapse risks: low (4 yr RFS: 81%, n=109) vs. high (4 yr RFS: 50%, n=98) (P<0.0001). In multivariate analysis, the best predictor combined MRC-RFS and day 29 flow MRD data, classifying children into low (87% RFS), intermediate (62% RFS), or high risk (29% RFS) groups (P<0.0001). A 21 gene molecular classifier predictive of MRD could effectively substitute for day 29 flow MRD, yielding a combined classifier that similarly distinguished three risk groups at pre-treatment (low: 82% RFS; intermediate: 63% RFS; and high risk: 45% RFS) (P<0.0001). This combined molecular classifier was further validated on an independent cohort of 84 children with HR-ALL (P = 0.006). Conclusions. Molecular classifiers predictive of RFS and MRD can be used to distinguish distinct prognostic groups within HR-ALL, significantly improving risk classification schemes and the ability to prospectively identify children at diagnosis who will respond to or fail current treatment regimens. NOTE: Due to Children's Oncology Group (COG) restrictions, outcome and MRD data cannot be provided as part of the covariate data for this dataset at the present time. If you would like to arrange individual access to this data, please contact COG or the PI of this study, Dr. Cheryl Willman, at the University of New Mexico Cancer Center (cwillman@unm.edu) to arrange a collaboration.

Project description:BACKGROUND:Nucleotide Excision Repair (NER) is a major pathway of mammalian DNA repair that is associated with drug resistance and has not been well characterized in acute lymphoblastic leukemia (ALL). The objective of this study was to explore the role of NER in relapsed ALL patients. We hypothesized that increased expression of NER genes was associated with drug resistance and relapse in ALL. METHODS:We performed secondary data analysis on two sets of pediatric ALL patients that all ultimately relapsed, and who had matched diagnosis-relapse gene expression microarray data (GSE28460 and GSE18497). GSE28460 included 49 precursor-B-ALL patients, and GSE18497 included 27 precursor-B-ALL and 14 T-ALL patients. Microarray data were processed using the Plier 16 algorithm and the 20 canonical NER genes were extracted. Comparisons were made between time of diagnosis and relapse, and between early and late relapsing subgroups. The Chi-square test was used to evaluate whether NER gene expression was altered at the level of the entire pathway and individual gene expression was compared using t-tests. RESULTS:We found that gene expression of the NER pathway was significantly increased upon relapse in patients that took 3 years or greater to relapse (late relapsers, P?=?.007), whereas no such change was evident in patients that relapsed in less than 3 years (early relapsers, P?= .180). Moreover, at diagnosis, the NER gene expression of the early relapsing subpopulation was already significantly elevated over that of the late relapsing group (P?<?.001). This pattern was validated by an 'NER score' established by averaging the relative expression of the 20 canonical NER genes. The NER score at diagnosis was found to be significantly associated with disease-free survival in precursor-B-ALL (P <?.001). CONCLUSION:Patients are over two times more likely to undergo early relapse if they have a high NER score at diagnosis, hazard ratio 2.008, 95% CI (1.256-3.211). The NER score may provide a underlying mechanism for "time to remission", a known prognostic factor in ALL, and a rationale for differential treatment.

Dataset Information

Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.

Publications

Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.

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