Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

Stork, Linda C.; Matloub, Yousif; Broxson, Emmett; La, Marzano; Yanofsky, Rochelle; Sather, Harland N.; Hutchinson, Ray; Heerema, Nyla A.; Sorrell, April; Masterson, Margaret; Bleyer, Archie; Gaynon, Paul S.

doi:10.1182/blood-2009-07-230656

Cited by 84 publications

(85 citation statements)

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“…This finding is similar to that found in the predecessor study (CCG-1952) in which patients with CNS-2 disease at diagnosis had an inferior outcome to those with CNS-1 status; 5-year EFS and overall survival were 74.0% Ϯ 4.3% and 89.4% Ϯ 3.1% versus 82.5 Ϯ 0.9% and 93.5 Ϯ 0.6%, respectively (P ϭ .001 for EFS; P ϭ .20 for overall survival). 26,27 However, patients with CNS-2 status on CCG-1991 had a better outcome than the similar cohort on CCG-1952, perhaps reflecting the beneficial effect of dexamethasone or the use of escalating IV MTX during IM or both in half the patients. Notably, the incidence of isolated CNS relapses in patients with CNS-2 status randomly assigned to the IV MTX regimens was less than a third the rate for patients randomly assigned to the PO MTX-containing regimens (2 of 35 vs 7 of 32).…”

Section: Discussionmentioning

confidence: 98%

“…24,25 EFS was inferior for boys on CCG-1891 and CCG-1952, whereas EFS was similar for both sexes on CCG-1922. 6,13,26 The 2 former protocols used prednisone as the steroid backbone, whereas in CCG-1922 one-half the patients received dexamethasone. Perhaps the equivalent outcome of males and females on CCG-1991 reflects use of dexamethasone throughout treatment.…”

Section: Discussionmentioning

confidence: 99%

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Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Matloub

Bostrom

Hunger

et al. 2011

Blood

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Matloub

Bostrom

Hunger

et al. 2011

Blood

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125

123

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“…85 Thioguanine is more potent than mercaptopurine, but its prolonged use at a dose more than 40 mg/m 2 has been associated with profound thrombocytopenia, an increased risk of death, and an unacceptable rate of hepatic veno-occlusive disease (ϳ 20%). 86,87 Hence, thioguanine is no longer used for continuation treatment; however, whether its short-term use can improve outcome, especially in terms of CNS control, without causing undue toxicity remains to be determined. Notably, thiopurine methyltransferase also has a significant impact on the pharmacokinetics of thioguanine, and patients with the enzyme deficiency are at an increased risk of developing hepatic veno-occlusive disease.…”

Section: Pharmacogenomics-guided Continuation (Maintenance) Treatmentmentioning

confidence: 99%

Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

Pui

Mullighan

Evans

et al. 2012

Blood

442

339

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Improved supportive care, more precise risk stratification, and personalized chemotherapy based on the characteristics of leukemic cells and hosts (eg, pharmacokinetics and pharmacogenetics) have pushed the cure rate of childhood acute lymphoblastic leukemia to near 90%. Further increase in cure rate can be expected from the discovery of additional recurrent molecular lesions, coupled with the development of novel targeted treatment through high-throughput genomics and innovative drug-screening systems. We discuss specific areas of research that promise to further refine current treatment and to improve the cure rate and quality of life of the patients. (Blood. 2012;120(6):1165-1174) IntroductionOptimal use of existing antileukemic agents and improved supportive care in contemporary clinical trials have improved the 5-year survival rate of childhood acute lymphoblastic leukemia (ALL) above 85% in developed countries (Table 1). [1][2][3][4][5][6][7][8] Further advances in survival and quality of life will require a better understanding of ALL pathobiology, the mechanisms of drug resistance, and drug disposition in the host, together with the development of innovative therapeutics. To this end, the advent of high-resolution genomewide analyses of gene expression, DNA copy number alterations, and epigenetic changes, and more recently, next-generation wholegenome and transcriptome sequencing have provided new insights into leukemogenesis, drug resistance, and host pharmacogenomics, identified novel subtypes of leukemia, and suggested potential targets for therapy. 9,10 Paralleling these advances has been the development of novel monoclonal antibodies, small molecule inhibitors, chemotherapeutics, and cell-based treatment strategies. 9 Here we discuss some of the current challenges and future directions in pediatric ALL research. Emerging leukemia subtypesTraditionally, ALL has been classified into precursor T (or T-cell), precursor B, and B-cell (Burkitt) phenotypes, which are then further subdivided according to recurrent karyotypic abnormalities, including aneuploidy and translocations. 9,11 Detailed profiling of submicroscopic alterations and mutational analyses have allowed refinement of these classification schema, identification of genetic alterations that coexist and cooperate with chromosomal alterations in leukemogenesis, and discovery of new ALL subtypes that lack alterations on cytogenetic analysis. Like acute myeloid leukemia, 12 many ALL subtypes are characterized by genetic alterations that perturb multiple key cellular pathways, including hematopoietic development, signaling or proliferation, and epigenetic regulation. Recent studies have identified a novel high-risk immature T-cell subtype, termed "early T-cell precursor" ALL, which is characterized by immunologic markers and a gene expression profile reminiscent of double-negative 1 thymocytes that retain the ability to differentiate into both T-cell and myeloid, but not B-cell, lineages. 13 Whole genome sequencing showed that the mutational spectru...

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“…17 In addition, a review of his laboratory values during maintenance showed that he had chronic elevation of his liver enzymes, although they remained below the 20Â threshold for stopping MP per protocol. 2 To minimize further hepatotoxicity, combination therapy of allopurinol with 6-MP was offered.…”

Section: Casementioning

confidence: 99%

Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity

Giamanco

Cunningham

Klein

et al. 2016

Journal of Pediatric Hematology/Oncology

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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.

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Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

Cited by 84 publications

References 47 publications

Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity

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