Intensification of Mercaptopurine/Methotrexate Maintenance Chemotherapy May Increase the Risk of Relapse for Some Children With Acute Lymphoblastic Leukemia

Schmiegelow, Kjeld; Björk, Olle; Glomstein, Anders; Gustafsson, Göran; Keiding, Niels; Kristinsson, Jakob; Mäkipernaa, Anne; Rosthøj, Susanne; Szumlanski, Carol L.; Sørensen, Tine Møller; Weinshilboum, Richard M.

doi:10.1200/jco.2003.04.039

Cited by 107 publications

(138 citation statements)

References 44 publications

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“…6 For both sexes, patients with an average neutrophil count during maintenance therapy of o2.0 Â 10 9 /l (median of all patients) had an EFS superior to that of patients with higher average neutrophil counts (boys: 0.87 vs 0.75, P ¼ 0.02, girls: 0.94 vs 0.83, P ¼ 0.01). 6 Furthermore, the risk of relapse was higher for the patients who received MTX/6MP maintenance therapy and had normal TPMT activity compared with those with reduced TPMT activity (18 vs 7%, respectively P ¼ 0.03).…”

Section: Protocol-specific Treatment Outcomementioning

confidence: 99%

“…The study showed the feasibility of reduced use of cranial irradiation, 4 emphasized that host pharmacogenetics influence the cure rate, 5 confirmed the importance of myelosuppression during maintenance therapy, 6 showed that MTX/6MP maintenance therapy is important for high-risk (HR) ALL, 7 and allowed mapping of the epidemiological and clinical characteristics of several cytogenetically defined subsets of ALL. [8][9][10][11][12][13][14] The goals of the subsequent common NOPHO ALL-2000 protocol were to examine the efficacy of Vincristine (VCR)/Dexamethasone reinductions during maintenance therapy and to examine the feasibility of non-centralized minimal residual disease (MRD) monitoring by flow cytometry and PCR.…”

Section: Introductionmentioning

confidence: 98%

“…It examined the prognostic effect of pharmacologically guided dose adjustments of oral 6MP/MTX maintenance therapy by a combination of a target degree of leukopenia and the erythrocyte levels of 6-Thioguanine nucleotides (cytotoxic metabolites of 6MP) and MTX-polyglutamates (the cytotoxic metabolites of MTX). 6 …”

Section: Nopho All-92 Risk Groupingmentioning

confidence: 99%

“…4,6,22 The risk group assignment was based on age and white blood cell count (WBC) at diagnosis (standard risk (SR): age 2.0-9.9 years and WBC o10.0 Â 10 9 /l; intermediate risk (IR): age 1.0-1.9 or X10.0 years and/or WBC 10-49.9 Â 10 9 /l; higher risk (that is, HR or very high risk (VHR)): WBCX50.0 Â 10 9 /l) and the presence of higher risk features: Tlineage ALL, the presence of CNS or testicular involvement, translocations t(9;22)(q34;q11) or t(4;11)(q21;q23), lymphomatous leukemia or mediastinal lymphoma, and/or a poor treatment response (M3 BM at day 15 or M2/M3 at day 29). 4 Patients who had higher risk features were assigned to the VHR treatment arm, if they were at least 5 years of age at diagnosis (because of the use of cranial irradiation in that protocol arm) and in addition had (i) T-cell disease with one or more additional HR-features, (ii) CNS leukemia, (iii) lymphomatous leukemia and/or (iv) higher risk ALL at diagnosis and a day 15 M3 or a day 29 M2/M3 bone marrow.…”

Section: Nopho All-92 Risk Groupingmentioning

confidence: 99%

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Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

et al. 2009

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Analysis of 2668 children with acute lymphoblastic leukemia (ALL) treated in two successive Nordic clinical trials (Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 and ALL-2000) showed that 75% of all patients are cured by first-line therapy, and 83% are long-term survivors. Improvements in systemic and intrathecal chemotherapy have reduced the use of central nervous system (CNS) irradiation to o10% of the patients and provided a 5-year risk of isolated CNS relapse of 2.6%. Improved risk stratification and chemotherapy have eliminated the previous independent prognostic significance of gender, CNS leukemia and translocation t(1;19)(q23;p13), whereas the post-induction level of minimal residual disease (MRD) has emerged as a new risk grouping feature. Infant leukemia, high leukocyte count, T-lineage immunophenotype, translocation t(4;11)(q21;q23) and hypodiploidy persist to be associated with lower cure rates. To reduce the overall toxicity of the treatment, including the risk of therapy-related second malignant neoplasms, the current NOPHO ALL-2008 protocol does not include CNS irradiation in first remission, the dose of 6-mercaptopurine is reduced for patients with low thiopurine methyltransferase activity, and the protocol restricts the use of hematopoietic stem cell transplantation in first remission to patients without morphological remission after induction therapy or with high levels of MRD after 3 months of therapy.

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Section: Protocol-specific Treatment Outcomementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Nopho All-92 Risk Groupingmentioning

confidence: 99%

Section: Nopho All-92 Risk Groupingmentioning

confidence: 99%

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Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

et al. 2009

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“…MTX and its active metabolites have made a significant impact on the treatment of a wide range of diseases such as neoplasms, rheumatoid arthritis and psoriasis as well as being used as immunosuppressive agents in organ transplantation [11][12][13][14][15][16][17][18] . The administered dose of the drug is the differential in a given treatment.…”

Section: Introductionmentioning

confidence: 99%

Facial symmetry evaluation after experimentally displaced condylar process fracture in methotrexate treated rats

Cavalcanti¹,

Corrêa

Luz³

2012

Acta Cir. Bras.

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PURPOSE: To investigate the facial symmetry of high and low dose methotrexate (MTX) treated rats submitted to experimentally displaced mandibular condyle fracture through the recording of cephalometric measurements. METHODS: One hundred male Wistar rats underwent surgery using an experimental model of right condylar fracture. Animals were divided into four groups: A - saline solution (1mL/week); B - dexamethasone (DEX) (0,15mg/Kg); C - MTX low dose (3 mg/Kg/week); D - MTX high dose (30 mg/Kg). Animals were sacrificed at 1, 7, 15, 30 and 90 days postoperatively (n=5). Body weight was recorded. Specimens were submitted to axial radiographic incidence, and cephalometric mensurations were made using a computer system. Linear measurements of skull and mandible, as well as angular measurements of mandibular deviation were taken. Data were subjected to statistical analyses among the groups, periods of sacrifice and between the sides in each group (α=0.05). RESULTS: Animals regained body weight over time, except in group D. There was reduction in the mandibular length and also changes in the maxilla as well as progressive deviation in the mandible in relation to the skull basis in group D. CONCLUSION: Treatment with high dose methotrexate had deleterious effect on facial symmetry of rats submitted to experimentally displaced condylar process fracture.

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Mortality Among Pediatric Patients With Acute Lymphoblastic Leukemia in Sweden From 1988 to 2017

et al. 2022

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ImportanceAcute lymphoblastic leukemia (ALL) constitutes 20% to 30% of all pediatric cancers. The 5-year overall survival among pediatric patients with ALL in high-income countries such as Sweden is currently more than 90%, but long-term unselected nationwide mortality data and mortality data in relation to the general population are lacking.ObjectiveTo compare mortality between pediatric patients with ALL and the general population during a 30-year period in Sweden and to assess the incidence of ALL in Sweden.Design, Setting, and ParticipantsThis cohort study included pediatric patients (aged &lt;18 years) with a morphologically verified ALL diagnosis in the Swedish Cancer Register and/or at least 2 ALL diagnoses in the Swedish National Patient Register between January 1, 1988, and December 31, 2017. Data were cross-linked to the Swedish Cause of Death Register. Data were analyzed from May 2019 to January 2022.Main Outcomes and MeasuresThe main outcomes were mortality among patients with ALL compared with that in the general population and mortality in different subgroups within the cohort. Standardized mortality ratios (SMRs) were calculated using the general Swedish population as a reference. Within-cohort survival analyses were performed.ResultsA total of 2397 patients (1354 [56%] male; mean [SD] age at diagnosis, 6.1 [4.7] years) were included in the study. The mean (SD) incidence of pediatric ALL during the study period was 4.11 (0.60) cases per 100 000 persons per year (females, 3.68 [0.65] cases per 100 000 persons per year; males, 4.52 [0.81] cases per 100 000 persons per year; P &lt; .001). The observed number of deaths among pediatric patients with ALL was 409 vs the 9.5 deaths expected in the general population, resulting in an overall SMR of 43.1 (95% CI, 39.0-47.5); females had a higher SMR than males (57.8 [95% CI, 49.5-67.2] vs 34.5 [95% CI, 32.0-41.4]; P &lt; .001). Analysis within the cohort showed a continued decrease in survival throughout the 30-year follow-up. The association between calendar year of ALL diagnosis, corresponding with different ALL treatment protocols, and mortality showed the lowest survival for the 1988-1991 group and the highest for the 2008-2017 group (χ2 = 20.3; P &lt; .001).Conclusions and RelevanceIn this cohort study, a consistently high SMR was seen among pediatric patients with ALL. Within the ALL cohort, survival evolved to a similar extent as in the young general population of Sweden. Furthermore, survival among patients with ALL decreased throughout the whole follow-up period without any trend difference after the 5-year follow-up time point. The changes in ALL treatment protocols were associated with overall improved absolute survival over time.

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Intensification of Mercaptopurine/Methotrexate Maintenance Chemotherapy May Increase the Risk of Relapse for Some Children With Acute Lymphoblastic Leukemia

Abstract: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

Cited by 107 publications

References 44 publications

Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

Facial symmetry evaluation after experimentally displaced condylar process fracture in methotrexate treated rats

Mortality Among Pediatric Patients With Acute Lymphoblastic Leukemia in Sweden From 1988 to 2017

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