Ratio of Methotrexate to Folate Uptake by Lymphoblasts in Children With B-Lineage Acute Lymphoblastic Leukemia: A Pilot Study

Mantadakis, Elpis; Smith, Angela K.; Kamen, Barton A.

doi:10.1097/00043426-200005000-00007

Cited by 13 publications

(20 citation statements)

References 23 publications

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“…Furthermore, there was a pronounced intraindividual variability for both LV dose and MTX 23 . For MTX 23 , the median within-patient s.d.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, there was a pronounced intraindividual variability for both LV dose and MTX 23 . For MTX 23 , the median within-patient s.d. was about 30% of the respective individual geometric mean value in the SR, IR and HR groups, whereas it was 10% in the VHR group.…”

Section: Resultsmentioning

confidence: 99%

“…Although considerable efforts were made to obtain a more complete material, a substantial amount of data could not be retrieved; for example, in the various risk groups, 12-17% of the data on MTX 23 was missing. Furthermore, there was a pronounced intraindividual variability for both LV dose and MTX 23 .…”

Section: Resultsmentioning

confidence: 99%

“…There was a slight correlation between patient log LV dose and log MTX 23 In Figures 3 and 4, median LV dose and MTX 23 , respectively, are plotted vs course number for relapsed and non-relapsed Table 3 Median (lower-upper quartile) and number of patients for which the examined parameters were obtained in relation to SR, IR, HR and VHR groups and relapse Tables 4 and 5. As can be seen in Figure 3, the median LV dose in the relapsed patients is higher than in the relapse-free patients in all courses in both the HR and IR groups.…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we have explored the relation between relapse rates obtained from the Nordic Society of Paediatric Haematology and Oncology (NOPHO) database and end of infusion serum MTX (S-MTX) concentrations (MTX 23 ), and LV dosage for patients treated with 5 or 8 g MTX/m 2 /24 h according to the NOPHO 92 ALL protocol. We have also examined the relation between relapse rates and S-MTX concentrations 36 h (MTX 36 ) and 42 h (MTX 42 ) after infusion start and duration of MTX exposure.…”

Section: Introductionmentioning

confidence: 99%

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High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia

et al. 2006

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We explored the relationship between time to relapse and different exposure variables (serum methotrexate (S-MTX) 23, 36 and 42 h after start of administration, MTX elimination time and leucovorin (LV) dose) during high-dose MTX (HDM) treatment of 445 children with acute lymphoblastic leukemia. MTX was infused at 5 g/m 2 (non-high risk) or 8 g/m 2 (high risk) over 24 h, 2-9 times per patient. LV rescue dose was adjusted according to the S-MTX concentration. Time from end of the last HDM to relapse was analyzed by Cox regression analysis with the logarithms of S-MTX and LV dose as exposures. The combined results from all risk groups suggest that high LV dose is related to higher risk for relapse. Doubling of the LV dose increased the relapse risk by 22% (95% confidence interval 1-49%, P ¼ 0.037). High LV doses correlated with high MTX levels at 23, 36 and 42 h and longer elimination time. The results suggest that high doses of LV increase the risk for relapse despite the fact that they were correlated with high MTX levels and longer MTX elimination time. The choice of MTX and LV doses may be regarded as an intricate balance between effect and counter-effect.

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“…Furthermore, there was a pronounced intraindividual variability for both LV dose and MTX 23 . For MTX 23 , the median within-patient s.d.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia

et al. 2006

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Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia

Kaufman

Drori

Cole

et al. 2004

Cancer

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BACKGROUND Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with combination chemotherapy containing methotrexate (MTX), drug resistance contributes to treatment failure for a substantial fraction of patients. The primary transporter for folates and MTX is the reduced folate carrier (RFC). Impaired drug transport is a documented mechanism of MTX resistance in patients with ALL; however, to the authors' knowledge it is not known whether inactivating RFC mutations are a contributing factor. METHODS The authors devised a genomic polymerase chain reaction‐single strand conformational polymorphism assay followed by sequencing and screened the entire RFC coding region for sequence alterations in DNA from 246 leukemia specimens from patients with diverse ethnic variation, 24 at the time of recurrence and the rest at the time of diagnosis. This cohort was comprised of 203 B‐precursor ALL specimens (82.5%), 32 T‐lineage ALL specimens (13%), and 11 acute myeloblastic leukemia specimens (4.5%). RESULTS Of 246 DNA samples, only 3 diagnosis B‐precursor ALL specimens (1.2%) were found to harbor alterations in the RFC gene, including heterozygous single nucleotide changes resulting in D56H and D522N substitutions in the first extracellular loop and the C‐terminus of this transporter, respectively. The third sample had a sequence alteration in exon 3 that could not be identified because of the lack of availability of DNA. CONCLUSIONS Whereas inactivating RFC mutations are a frequent mechanism of MTX resistance in human leukemia cell lines and in patients with osteosarcoma, they are not common and do not appear to play any significant role in intrinsic or acquired resistance to MTX in childhood leukemia. This is the first study of RFC mutations in multiple pediatric leukemia specimens. Cancer 2004;100:773–82. © 2003 American Cancer Society.

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High‐dose methotrexate therapy of childhood acute lymphoblastic leukemia: Lack of relation between serum methotrexate concentration and creatinine clearance

Joannon

Oviedo

Campbell

et al. 2004

Pediatric Blood & Cancer

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Ratio of Methotrexate to Folate Uptake by Lymphoblasts in Children With B-Lineage Acute Lymphoblastic Leukemia: A Pilot Study

Abstract: The uptake of [3H]MTX in relation to 5CH3[3H]THF by leukemic lymphoblasts in vitro may correlate positively with treatment outcome in children with B-lineage ALL. A larger study of homogeneously treated patients is necessary to confirm these results.

Cited by 13 publications

References 23 publications

High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia

High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia

Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia

High‐dose methotrexate therapy of childhood acute lymphoblastic leukemia: Lack of relation between serum methotrexate concentration and creatinine clearance

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