How much is too much? Folinic acid rescue dose in children with acute lymphoblastic leukaemia

Borsi, Joseph D.; Wesenberg, Finn; Stokland, Tore; Pj, Moe

doi:10.1016/0277-5379(91)90269-j

Cited by 48 publications

(28 citation statements)

References 8 publications

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“…The patient population analyzed appears to be representative of the whole population of patients diagnosed with ALL in Sweden, Denmark and Norway during the same period of time, as they had similar characteristics (Table 1) The present results agree well with previous studies in vivo on osteosarcoma 11 and ALL 8,12,13 and in vitro, 9,10 indicating that higher doses of LV may be related to higher risk for relapse, probably by rescuing malignant cells from the effect of MTX. In fact, already in 1948, Farber et al 17 described an 'acceleration phenomenon' in the leukemic process as seen in the marrow and viscera of children with ALL treated by injection of folic acid conjugates.…”

Section: Leucovorin Methotrexate and Relapse Risk In Childhood Allsupporting

confidence: 89%

“…In addition, the duration of MTX exposure above a critical threshold may be relevant as well. 7,8 In contrast, the clinical significance of LV dosage has received little attention, although both in vitro 9,10 and in vivo studies 8,[11][12][13] have indicated that higher doses of LV or earlier administration may be related to a higher risk of relapse probably by rescuing malignant cells from the effect of HDM.…”

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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Section: Leucovorin Methotrexate and Relapse Risk In Childhood Allsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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 found that plasma precourse folate concentration was the principal determinant of the magnitude of both peak MTX plasma concentrations and the extent of wholebody homocysteine accumulation in response to MTX administration, supporting the original folate overrescue concept first pointed out by Borsi et al in the early 1990s (36 ). Because differences in relapse rates in their study did not reach statistical significance, it remained largely unnoticed by the medical community.…”

Section: Discussionsupporting

confidence: 78%

Pretreatment Plasma Folate Modulates the Pharmacodynamic Effect of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma: “Folate Overrescue” Concept Revisited

et al. 2006

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Background:To evaluate the influence of pretreatment plasma folate concentrations on methotrexate exposure in children with acute lymphoblastic leukemia/non-Hodgkin lymphoma treated with high-dose methotrexate, we assessed time profiles of plasma homocysteine, folate, and vitamin B 12 concentrations in children treated with highdose methotrexate with leucovorin rescue. Methods: We analyzed 98 treatment courses. The study endpoints were to determine how methotrexate exposure is related to homocysteine accumulation and whether it is influenced by pretreatment plasma folate. Results: Peak concentrations of homocysteine increased from the start of the intravenous infusion through cessation of methotrexate therapy up to time point t 42 , when this trend was reversed by administration of folinic acid. The area under the curve (AUC) for plasma homocysteine showed decreasing course-to-course tendencies with a statistically significant decrease only between courses 1 and 2 (P <0.05), indicating decreased

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“…Importantly, AUCs rather than the ‘square meter-normalized drug dose’ [10] are the target parameters determining the exposure of a tumor to a drug level achievable within the context of a patient’s actual clinical condition. Furthermore, striking differences in pretreatment plasma folate levels may extend the debate on the ‘folate overrescue concept’ [11] with possible critical reappraisal of leucovorin/methotrexate dosage and/or timing of administration. Evidence on the relation of timing and dosage of leucovorin and methotrexate is rather scarce and inconsistent – a randomized study evaluating high-dose protocols with leucovorin rescue and Capizzi scheme with no leucovorin rescue is currently ongoing [12].…”

Section: Resultsmentioning

confidence: 99%

Severe Encephalopathy Induced by the First but Not the Second Course of High-Dose Methotrexate Mirrored by Plasma Homocysteine Elevations and Preceded by Extreme Differences in Pretreatment Plasma Folate

Valík¹,

Štěrba

Bajčiová

et al. 2005

Oncology

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Plasma homocysteine has recently been associated with the occurrence of methotrexate-related neurotoxicity. We observed extreme elevations of homocysteine in a 9-year-old boy presenting with leukemia treated with the ALL-BFM 95 protocol. Coma occurred at about the 71st hour from the first methotrexate administration, and lasted for 30 h but MRI and CT studies showed no intracranial pathology. The second course of high-dose methotrexate was administered with no complications. Homocysteine areas under the curve (AUC) were calculated as the sum of areas of rectangles during the 6-hour intervals from T₀ to T₇₂ hours (AUC_0–72) and methotrexate AUCs were evaluated using MW/PHARM3.3 software. The AUC of homocysteine during the first, toxic course was 5.2 times higher than AUC during the second administration, whereas AUC of methotrexate also differed by a factor of 5. Plasma concentrations of folate prior to the first and the second courses, respectively, were 4.4 versus 45 µmol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C677T mutation in the MTHFR gene. We suggest that plasma homocysteine, pretreatment plasma folate and possibly the presence of MTHFR mutations may be biomarkers of methotrexate toxicity and possibly its antifolate effect targeted towards the tumor as well.

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How much is too much? Folinic acid rescue dose in children with acute lymphoblastic leukaemia

Cited by 48 publications

References 8 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

Pretreatment Plasma Folate Modulates the Pharmacodynamic Effect of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma: “Folate Overrescue” Concept Revisited

Severe Encephalopathy Induced by the First but Not the Second Course of High-Dose Methotrexate Mirrored by Plasma Homocysteine Elevations and Preceded by Extreme Differences in Pretreatment Plasma Folate

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