scholarly journals Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

2020 ◽  
Vol 86 (2) ◽  
pp. 362-371
Author(s):  
John C. Panetta ◽  
Jessica K. Roberts ◽  
Jie Huang ◽  
Tong Lin ◽  
Vinay M. Daryani ◽  
...  
Keyword(s):  
Young Children ◽  
Brain Tumours ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Malignant Brain Tumours ◽  
Infants And Young Children

Newly diagnosed high-risk malignant brain tumors with leptomeningeal dissemination in young children: A final update on Head Start II Regimen A2 intensified with high-dose methotrexate

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9552-9552
Author(s):  
S. Chi ◽  
S. Gardner ◽  
L. Y. Ji ◽  
R. Sposto ◽  
G. Dhall ◽  
...  
Keyword(s):  
High Risk ◽  
Head Start ◽  
Young Children ◽  
Brain Tumors ◽  
Response Rate ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Leptomeningeal Dissemination ◽  
Newly Diagnosed ◽  
Dose Methotrexate

9552 Background: The prognosis for young children with newly diagnosed malignant brain tumors with leptomeningeal dissemination remains poor. From Jan 1997 to Mar 2003, “Head Start II” Regimen A2, intensified with high-dose methotrexate, was offered to this high-risk population. Methods: Eligibility: patients < 10 yrs of age; confirmed diagnosis of medulloblastoma (MB), primitive neuroectodermal tumor (PNET), ependymoma and choroid plexus carcinoma (CPC); and high-risk status as determined by neuroaxis dissemination. Patients with atypical teratoid/rhabdoid tumor (ATRT), regardless of stage, were also eligible. Treatment: 5 cycles of vincristine (0.05 mg/kg/week × 3 doses), cisplatin (3.5 mg/kg), etoposide (4 mg/kg/day × 2 days), cyclophosphamide (65 mg/kg/day × 2 days), and methotrexate (400 mg/kg) with leucovorin. Children without progressive disease (PD) by the end of induction underwent a single consolidation cycle (carboplatin, etoposide, thiotepa) with autologous stem cell rescue. Reduced dose RT (2340cGy CSI and focal boost) was reserved for any with residual disease at the end of induction or for the older patient (>6 yrs of age). Results: 40 patients were enrolled (MB, 22; PNET, 6; ependymoma, 5; AT/RT, 6; CPC, 1), med age at diagnosis 38 mos (range 5 to 119 mos). Significant toxicities of this intensified regimen included GI toxicities and infections. Among the entire cohort, there were 26 CR, 6 PR, 2 with stable disease and 4 with PD (and 2 toxic deaths), for a CR +PR response rate of 82%. For disseminated MB (4 M1; 2 M2; 16 M3), the CR rate alone is 77% (17/22). The 5-year EFS and OS for disseminated MB are 45% (95% CI, 24 % to 64%) and 54% (95% CI, 31% to 72%), respectively. Of note, 6/12 MB survivors (all M3) did not receive RT and all are NED >5 years from diagnosis. In addition, there are 3 AT/RT survivors, 12, 54 and 66 mos post-diagnosis who did not receive RT. Conclusions: This intensified regimen is feasible and tolerable. For patients with disseminated MB, the majority of whom had M3 disease at diagnosis, the impressive response rate and outcomes suggest that the addition of methotrexate is justified for future studies. Long- term neuropsychological outcomes are being studied at this time. No significant financial relationships to disclose.

CNS-directed therapy in young children with T-lineage acute lymphoblastic leukemia: High-dose methotrexate versus cranial irradiation

2003 ◽  
Vol 42 (1) ◽  
pp. 24-29 ◽  
Author(s):  
Paul C. Nathan ◽  
Ronnen Maze ◽  
Brenda Spiegler ◽  
Mark L. Greenberg ◽  
Sheila Weitzman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Young Children ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate

High-dose methotrexate-induced reversible grade 4 hyperbilirubinaemia and transaminitis in an adolescent with Burkitt Leukaemia

2021 ◽  
Vol 14 (1) ◽  
pp. e237512
Author(s):  
Sanjeev Khera ◽  
Randhir Ranjan ◽  
Sateesh Ramachandran ◽  
Ajay Beriwal
Keyword(s):  
Liver Injury ◽  
Clinical Significance ◽  
Short Latency ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Drug Induced ◽  
Common Cause ◽  
Drug Induced Liver Injury ◽  
Dose Methotrexate

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.

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

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.

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

BMC Cancer ◽  
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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