Systemic Exposure to Mercaptopurine as a Prognostic Factor in Acute Lymphocytic Leukemia in Children

Koren, Gideon; Ferrazini, Gianmario; Sulh, Hassan; Langevin, Anne-Marie; Kapelushnik, Joseph; Klein, Julia; Giesbrecht, Esther; Soldin, S J; Greenberg, Mark

doi:10.1056/nejm199007053230104

Cited by 131 publications

(77 citation statements)

References 14 publications

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“…Previous studies have shown that low systemic exposure to oral 6MP during maintenance therapy adversely affects prognosis. 40 It is speculated that genetic differences in metabolism and bioavailability of those drugs might explain the ethnic influence on treatment outcome. Genetic differences in metabolism of 6MP and methotrexate have been shown.…”

Section: Discussionmentioning

confidence: 99%

Racial and ethnic differences in survival of children with acute lymphoblastic leukemia

Bhatia

Sather

Heerema

et al. 2002

Blood

251

218

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Black children with acute lymphoblastic leukemia (ALL) have poor outcomes, but limited information is available for children from other racial and ethnic backgrounds, such as Hispanic and Asian. We undertook a retrospective cohort study of children with ALL treated on Children's Cancer Group therapeutic protocols to determine outcomes by racial and ethnic backgrounds of patients treated with contemporary risk-based therapy. In total, 8447 children (white, n ‫؍‬ 6703; Hispanic, n ‫؍‬ 1071; black, n ‫؍‬ 506; and Asian, n ‫؍‬ 167) with newly diagnosed ALL between 1983 and 1995 were observed for a median of 6.5 years. Analysis of disease outcome was measured as overall survival (OS) and event-free survival (EFS) and was adjusted for known predictors of outcome including clinical features, disease biology, socioeconomic status, and treatment era (1983-1989 vs 1989-1995). There was a statistically significant difference in survival by ethnicity (P < .001). Five-year EFS rates were: Asian, 75.1% ؎ 3.5%; white, 72.8% ؎ 0.6%; Hispanic, 65.9% ؎ 1.5%; and black, 61.5% ؎ 2.2%. Multivariate analysis revealed that when compared with white children, black and Hispanic children had worse outcomes and Asian children had better outcomes after adjusting for known risk factors. The poorer outcomes among black children were most apparent among patients with standard-risk features (relative risk [RR], 2.0; 95% confidence interval [CI], 1.6-2.5), whereas poorer outcomes in Hispanic children (RR, 1.4; 95% CI, 1.2-1.6) were most evident among patients with high-risk features. Asian children had better outcomes than all racial and ethnic groups among high-risk patients, particularly in the recent era (5-year EFS, 90.9% ؎ 6.1%). Racial and ethnic differences in OS and EFS persist among children with ALL who receive contemporary risk-based therapy. Future studies should focus on reasons-perhaps compliance or pharmacogeneticsfor those differences. (Blood. 2002;100: 1957-1964

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Section: Discussionmentioning

confidence: 99%

Racial and ethnic differences in survival of children with acute lymphoblastic leukemia

Bhatia

Sather

Heerema

et al. 2002

Blood

251

218

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“…[1][2][3][4]26 Peak plasma 6MP concentrations range from 0.01 to 1 mM, and several studies have shown that systemic exposure to 6MP during maintenance predicts the probability of relapse. [26][27][28] The two ALL cell lines were incubated with varying concentrations of 6MP for 72 h and then assayed for apoptosis and clonogenic growth. Following the incubations, the cells were washed to remove the drug to ensure that any loss of colony formation represented the clonogenic potential at the end of incubation rather than a direct antiproliferative effect of drug during the subsequent clonogenic assay.…”

Section: Mp and Mtx Inhibit All And Apl Cell Lines Clonogenicity Witmentioning

confidence: 99%

Induction of acute lymphocytic leukemia differentiation by maintenance therapy

et al. 2007

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Despite extensive study in many malignancies, maintenance therapy has clinically benefited only two diseases: acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL). ALL maintenance therapy utilizes low-dose 6-mercaptopurine (6MP) and methotrexate (MTX), while maintenance in APL primarily consists of all-trans-retinoic acid (ATRA). 6MP and MTX as used in ALL are also now usually added to maintenance ATRA for APL, based on data suggesting an improved disease-free survival. Although the mechanism of action of MTX and 6MP as maintenance is unknown, low-dose cytotoxic agents are potent inducers of differentiation in vitro. Thus, we studied whether maintenance therapy in ALL, like ATRA in APL, may be inducing terminal differentiation of ALL progenitors. The APL cell line NB4, the ALL cell lines REH and RS4;11, and patients' ALL blasts were incubated with ATRA, 6MP, and MTX in vitro. All three drugs inhibited the clonogenic growth of the APL and ALL cell lines without inducing immediate apoptosis, but associated with induction of phenotypic differentiation. The three drugs similarly upregulated lymphoid antigen expression, while decreasing CD34 expression, on patients' ALL blasts. These data suggest that induction of leukemia progenitor differentiation plays an important role in the mechanism of action of maintenance therapy in ALL.

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“…1 Prior studies of adherence to oral 6MP in children with ALL have reported adherence rates ranging from 70% to 95% by using a variety of subjective and objective measures. [2][3][4][5][6][7][8][9] We have previously shown that inadequate systemic exposure to 6MP because of poor 6MP adherence (,95% adherence rate, objectively measured by the Medication Event Monitoring System [MEMS; WestRock Healthcare, Sion, Switzerland]) is associated with increased risk of relapse.…”

Section: Introductionmentioning

confidence: 99%

Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children’s Oncology Group study

Landier

Chen

Hageman

et al. 2017

Blood

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• Self-report overestimated electronically monitored 6MP adherence at least some of the time in a large majority of patients (84.4%).• Nonadherers were more likely to overreport 6MP intake (47%) compared with adherent patients (8%).Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ‡5 days/month for ‡50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, TPMT genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, P 5 .02; Asian, OR, 3.1, P 5 .02; African American, P < .001; paternal education less than college (OR, 1.4, P 5 .05);

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Systemic Exposure to Mercaptopurine as a Prognostic Factor in Acute Lymphocytic Leukemia in Children

Cited by 131 publications

References 14 publications

Racial and ethnic differences in survival of children with acute lymphoblastic leukemia

Racial and ethnic differences in survival of children with acute lymphoblastic leukemia

Induction of acute lymphocytic leukemia differentiation by maintenance therapy

Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children’s Oncology Group study

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