Selectivity of Very High Dose Methotrexate in MCF-7 and Normal Cells Using a Priming and Non-Toxic 5-Fluorouracil Dose

Symptomatic drug-induced liver injury (DILI) is an uncommon problem. Direct DILI is dose-related, predictable with short latency (hour to days) and is generally associated with transient and reversible transaminitis without jaundice. Antimetabolites including methotrexate are a common cause for direct DILI. Hepatotoxicity associated with high-dose methotrexate (HD-MTX) is generally transient and includes reversible elevation of transaminase in up to 60% and associated hyperbilirubinaemia (≤grade 2) in 25% of courses and therefore is of no clinical significance. Severe grades of DILI with HD-MTX (grade ≥4) are extremely rare. We describe an adolescent with Burkitt leukaemia who had reversible grade 4 DILI including hyperbilirubinaemia postfirst course of HD-MTX. Rechallenge with two-third dose of HD-MTX in subsequent chemotherapeutic cycle did not cause recurrence of DILI.

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Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

Supportive Care in Cancer ◽

10.1007/s00520-021-06395-3 ◽

2021 ◽

Author(s):

Riitta Niinimäki ◽

Henri Aarnivala ◽

Joanna Banerjee ◽

Tytti Pokka ◽

Kaisa Vepsäläinen ◽

...

Keyword(s):

Folinic Acid ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Optimal Dosage ◽

High Dose Methotrexate ◽

Reduced Dose ◽

Dose Methotrexate ◽

Antileukemic Effect ◽

Folinic Acid Rescue ◽

High Doses

Abstract Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

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Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients

BMC Cancer ◽

10.1186/s12885-021-08443-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Usman Arshad ◽

Max Taubert ◽

Tamina Seeger-Nukpezah ◽

Sami Ullah ◽

Kirsten C. Spindeldreier ◽

...

Keyword(s):

Plasma Concentration ◽

Surface Area ◽

Body Surface Area ◽

Body Surface ◽

Large Cohort ◽

Therapeutic Drug ◽

High Dose ◽

High Dose Methotrexate ◽

Concentration Data ◽

Dose Methotrexate

Abstract Background The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. Methods We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. Results Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. Conclusion A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

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Impact of High-Dose Methotrexate on the Outcome of Patients with Diffuse Large B-Cell Lymphoma and Skeletal Involvement

Cancers ◽

10.3390/cancers13122945 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2945

Author(s):

Mélanie Mercier ◽

Corentin Orvain ◽

Laurianne Drieu La Rochelle ◽

Tony Marchand ◽

Christopher Nunes Gomes ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Skeletal Involvement ◽

Large B Cell Lymphoma ◽

Dose Methotrexate ◽

The Impact ◽

Large B Cell

Diffuse large B-cell lymphoma (DLBCL) with extra nodal skeletal involvement is rare. It is currently unclear whether these lymphomas should be treated in the same manner as those without skeletal involvement. We retrospectively analyzed the impact of combining high-dose methotrexate (HD-MTX) with an anthracycline-based regimen and rituximab as first-line treatment in a cohort of 93 patients with DLBCL and skeletal involvement with long follow-up. Fifty patients (54%) received upfront HD-MTX for prophylaxis of CNS recurrence (high IPI score and/or epidural involvement) or because of skeletal involvement. After adjusting for age, ECOG, high LDH levels, and type of skeletal involvement, HD-MTX was associated with an improved PFS and OS (HR: 0.2, 95% CI: 0.1–0.3, p < 0.001 and HR: 0.1, 95% CI: 0.04–0.3, p < 0.001, respectively). Patients who received HD-MTX had significantly better 5-year PFS and OS (77% vs. 39%, p <0.001 and 83 vs. 58%, p < 0.001). Radiotherapy was associated with an improved 5-year PFS (74 vs. 48%, p = 0.02), whereas 5-year OS was not significantly different (79% vs. 66%, p = 0.09). A landmark analysis showed that autologous stem cell transplantation was not associated with improved PFS or OS. The combination of high-dose methotrexate and an anthracycline-based immunochemotherapy is associated with an improved outcome in patients with DLBCL and skeletal involvement and should be confirmed in prospective trials.

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