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A prospective study of a simple algorithm to individually dose high-dose methotrexate for children with leukemia at risk for methotrexate toxicities

  • Jennifer H. Foster
  • Patrick A. Thompson
  • M. Brooke Bernhardt
  • Judith F. Margolin
  • Susan G. Hilsenbeck
  • Eunji Jo
  • Deborah A. Marquez-Do
  • Michael E. Scheurer
  • Eric S. Schafer
Original Article

Abstract

Purpose

High-dose methotrexate (HDMTX) is critical to the successful treatment of pediatric acute lymphoblastic leukemia (ALL) but can cause significant toxicities. This study prospectively evaluated the effectiveness of a fixed algorithm which requires no real-time pharmacokinetic modeling and no previous patient exposure to HDMTX, to individualize HDMTX dosing for at-risk patients with the aim of avoiding methotrexate-related toxicities.

Methods

We developed a simple algorithm to individualize HDMTX infusions with 0–2 rate adjustments based on methotrexate levels during the infusion. This was a prospective, open-label, study; eligible patients were identified and referred by their oncologist.

Results

Fifty-four evaluable cycles of HDMTX (5 g/m2 over 24 h) were administered to 22 patients. Blood samples were obtained in 21 patients to examine single nucleotide polymorphisms (SNPs) related to methotrexate disposition. Twelve (54.5%) subjects had a history of previous HDMTX toxicities including seven (31.8%) who previously required glucarpidase rescue and seven (31.8%) with an entry glomerular filtration rate < 80 ml/min/1.73 m2. 107/110 (97.2%) of methotrexate levels were drawn properly and 100% of algorithm dosing instructions were performed correctly at the bedside. Thirty-five (64.8%) of all cycles and 24 of 33 (72.7%) cycles that required a dose-adjustment had an end 24-h methotrexate level (Cpss) within our goal range of 65 ± 15 µM with only 3 (5.6%) resulting in Cpss higher than goal. Grade 3/4 toxicities were rare; no patients developed > Grade 1 acute kidney injury.

Conclusion

This algorithm is a simple, safe and effective method for individualizing HDMTX in pediatric patients with ALL.

Clinicaltrials.gov Registry

NCT02076997.

Keywords

Methotrexate Children Pharmacokinetics Toxicity Renal insufficiency 

Abbreviations

ABCC4

ATP-binding cassette sub-family C member 4

ALL

Acute lymphoblastic leukemia

AKI

Acute kidney injury

ALT

Alanine aminotransaminase

AST

Aspartate aminotransaminase

AUC

Area under the plasma concentration–time curve

BUN

Blood urea nitrogen

CBC

Complete blood count

CI

Confidence interval

COG

Children’s Oncology Group

Cpss

Concentration in plasma at steady state

CTCAE

National Cancer Institute common terminology criteria for adverse events

FDA

US Food and Drug Administration

GFR

Glomerular filtration rate

GPDG2

Carboxypeptidase G2

HDMTX

High-dose methotrexate

IQR

Interquartile range

MAF

Minor allele frequency

MTHFR

Methylenetetrahydrofolate reductase

MTRR

Methionine synthase reductase

NSAIDS

Non-steroidal anti-inflammatory drugs

PdL

Ponte di Legno consensus criteria

PK

Pharmacokinetics

SD

Standard deviation

SNP

Single nucleotide polymorphism

SLCO1B1

Solute carrier organic anion transporter family member 1B1

Notes

Acknowledgements

This study was supported by grants from Alex’s Lemonade Stand Developmental Therapeutics Center of Excellence Program (JHF), NCI Grant CA125123 (SGH) and the Killian Owen Curing Kids’ Cancer Fellowship in Developmental Therapeutics (ESS).

Author contributions

JHF: PCR, DR, AD, WP, EP; PAT: DR, EP; MBB: AD, EP; JFM: EP, PS; SGH: AD, EP; EJ: AD, EP; DAM: PBR; MES: PBR, DR, AD, EP; ESS: PCR, DR, AD, WP, EP, PS. PCR: performed clinical research; PBR: performed basic research; DR: designed research; AD: analyzed data; WP: wrote paper; EP: edited paper; PS: provided subjects.

Compliance with ethical standards

Conflict of interest

No authors have any conflicts of interest to report.

Supplementary material

280_2018_3733_MOESM1_ESM.docx (421 kb)
Supplementary material 1 (DOCX 421 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jennifer H. Foster
    • 1
  • Patrick A. Thompson
    • 2
  • M. Brooke Bernhardt
    • 1
  • Judith F. Margolin
    • 1
  • Susan G. Hilsenbeck
    • 3
  • Eunji Jo
    • 3
  • Deborah A. Marquez-Do
    • 1
  • Michael E. Scheurer
    • 1
  • Eric S. Schafer
    • 1
  1. 1.Division of Pediatric Hematology and Oncology, Department of PediatricsBaylor College of MedicineHoustonUSA
  2. 2.Department of PediatricsUniversity of North CarolinaChapel HillUSA
  3. 3.Dan L. Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonUSA

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