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



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.


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.


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.


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



Methotrexate Children Pharmacokinetics Toxicity Renal insufficiency 



ATP-binding cassette sub-family C member 4


Acute lymphoblastic leukemia


Acute kidney injury


Alanine aminotransaminase


Aspartate aminotransaminase


Area under the plasma concentration–time curve


Blood urea nitrogen


Complete blood count


Confidence interval


Children’s Oncology Group


Concentration in plasma at steady state


National Cancer Institute common terminology criteria for adverse events


US Food and Drug Administration


Glomerular filtration rate


Carboxypeptidase G2


High-dose methotrexate


Interquartile range


Minor allele frequency


Methylenetetrahydrofolate reductase


Methionine synthase reductase


Non-steroidal anti-inflammatory drugs


Ponte di Legno consensus criteria




Standard deviation


Single nucleotide polymorphism


Solute carrier organic anion transporter family member 1B1



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)


  1. 1.
    Paci A, Veal G, Bardin C, Leveque D, Widmer N, Beijnen J, Astier A, Chatelut E (2014) Review of therapeutic drug monitoring of anticancer drugs part 1—cytotoxics. Eur J Cancer 50(12):2010–2019. CrossRefPubMedGoogle Scholar
  2. 2.
    Asselin BL, Devidas M, Wang C, Pullen J, Borowitz MJ, Hutchison R, Lipshultz SE, Camitta BM (2011) Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children’s Oncology Group (POG 9404). Blood 118(4):874–883. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL (2016) Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from children’s oncology group study AALL0232. J Clin Oncol 34(20):2380–2388. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Nathan PC, Maze R, Spiegler B, Greenberg ML, Weitzman S, Hitzler JK (2004) CNS-directed therapy in young children with T-lineage acute lymphoblastic leukemia: high-dose methotrexate versus cranial irradiation. Pediatr blood cancer 42(1):24–29. CrossRefPubMedGoogle Scholar
  5. 5.
    Niemeyer CM, Gelber RD, Tarbell NJ, Donnelly M, Clavell LA, Blattner SR, Donahue K, Cohen HJ, Sallan SE (1991) Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (protocol 81-01 update). Blood 78(10):2514–2519PubMedGoogle Scholar
  6. 6.
    Bleyer WA (1978) The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 41(1):36–51CrossRefGoogle Scholar
  7. 7.
    Schmiegelow K (2009) Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol 146(5):489–503. CrossRefPubMedGoogle Scholar
  8. 8.
    Widemann BC, Adamson PC (2006) Understanding and managing methotrexate nephrotoxicity. The Oncologist 11(6):694–703. CrossRefPubMedGoogle Scholar
  9. 9.
    Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD (2016) Preventing and managing toxicities of high-dose methotrexate. The Oncologist 21(12):1471–1482. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mikkelsen TS, Mamoudou AD, Tuckuviene R, Wehner PS, Schroeder H (2014) Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions: a prospectively randomized cross-over study. Pediatr Blood Cancer 61(2):297–301. CrossRefPubMedGoogle Scholar
  11. 11.
    Widemann BC, Balis FM, Kempf-Bielack B, Bielack S, Pratt CB, Ferrari S, Bacci G, Craft AW, Adamson PC (2004) High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma. Cancer 100(10):2222–2232. CrossRefPubMedGoogle Scholar
  12. 12.
    Bouchard J, Lavergne V, Roberts DM, Cormier M, Morissette G, Ghannoum M (2017) Availability and cost of extracorporeal treatments for poisonings and other emergency indications: a worldwide survey. Nephrol Dial Transp 32(4):699–706. CrossRefGoogle Scholar
  13. 13.
    Relling MV, Stapleton FB, Ochs J, Jones DP, Meyer W, Wainer IW, Crom WR, McKay CP, Evans WE (1988) Removal of methotrexate, leucovorin, and their metabolites by combined hemodialysis and hemoperfusion. Cancer 62(5):884–888CrossRefGoogle Scholar
  14. 14.
    Santiago MJ, Lopez-Herce J, Urbano J, Solana MJ, del Castillo J, Ballestero Y, Botran M, Bellon JM (2009) Complications of continuous renal replacement therapy in critically ill children: a prospective observational evaluation study. Crit Care 13(6):R184. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    VORAXAZE(R) (glucarpidase) [package insert] (2017) BTG International, Inc. Accessed Jul 2018
  16. 16.
    Patterson DM, Lee SM (2010) Glucarpidase following high-dose methotrexate: update on development. Expert Opin Biol Ther 10(1):105–111. CrossRefPubMedGoogle Scholar
  17. 17.
    Widemann BC, Balis FM, Kim A, Boron M, Jayaprakash N, Shalabi A, O’Brien M, Eby M, Cole DE, Murphy RF, Fox E, Ivy P, Adamson PC (2010) Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol 28(25):3979–3986. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Scott JR, Zhou Y, Cheng C, Ward DA, Swanson HD, Molinelli AR, Stewart CF, Navid F, Jeha S, Relling MV, Crews KR (2015) Comparable efficacy with varying dosages of glucarpidase in pediatric oncology patients. Pediatr Blood Cancer 62(9):1518–1522. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Schafer ES, Bernhardt MB, Reichert KE, Haworth TE, Shah MD (2018) Hispanic ethnicity as a risk factor for requiring glucarpidase rescue in pediatric patients receiving high-dose methotrexate. Am J Hematol 93(2):E40–E42. CrossRefPubMedGoogle Scholar
  20. 20.
    Chan H, Evans WE, Pratt CB (1977) Recovery from toxicity associated with high-dose methotrexate: prognostic factors. Cancer Treat Rep 61(5):797–804PubMedGoogle Scholar
  21. 21.
    Relling MV, Fairclough D, Ayers D, Crom WR, Rodman JH, Pui CH, Evans WE (1994) Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol 12(8):1667–1672. CrossRefPubMedGoogle Scholar
  22. 22.
    Evans WE, Crom WR, Abromowitch M, Dodge R, Look AT, Bowman WP, George SL, Pui CH (1986) Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl J Med 314(8):471–477. CrossRefPubMedGoogle Scholar
  23. 23.
    Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Pinan MA, Garcia-Miguel P, Navajas A, Garcia-Orad A (2011) Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 57(4):612–619. CrossRefPubMedGoogle Scholar
  24. 24.
    Pauley JL, Panetta JC, Crews KR, Pei D, Cheng C, McCormick J, Howard SC, Sandlund JT, Jeha S, Ribeiro R, Rubnitz J, Pui CH, Evans WE, Relling MV (2013) Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. Cancer Chemother Pharmacol 72(2):369–378. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wall AM, Gajjar A, Link A, Mahmoud H, Pui CH, Relling MV (2000) Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia. Leukemia 14(2):221–225CrossRefGoogle Scholar
  26. 26.
    Aumente D, Buelga DS, Lukas JC, Gomez P, Torres A, Garcia MJ (2006) Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia. Clin Pharmacokinetics 5(12):1227–1238. CrossRefGoogle Scholar
  27. 27.
    Common terminology criteria for adverse events v4.03 NIH publication # 09-7473.
  28. 28.
    Foster JH, Bernhardt MB, Thompson PA, Smith EO, Schafer ES (2017) Using a bedside algorithm to individually dose high-dose methotrexate for patients at risk for toxicity. J Pediatr Hematol Oncol 39(1):72–76. CrossRefPubMedGoogle Scholar
  29. 29.
    DiPiro J, Spruill W, Wade W, Blouin R, Pruemer J (2010) Concepts in clinical pharmacokinetics, 5th edn. American Society of Health-System Pharmacists, Bethesda, pp 62–64Google Scholar
  30. 30.
    Schmiegelow K, Attarbaschi A, Barzilai S, Escherich G, Frandsen TL, Halsey C, Hough R, Jeha S, Kato M, Liang DC, Mikkelsen TS, Moricke A, Niinimaki R, Piette C, Putti MC, Raetz E, Silverman LB, Skinner R, Tuckuviene R, van der Sluis I, Zapotocka E, Ponte di Legno toxicity working g (2016) Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. Lancet Oncol 17(6):e231–e239. CrossRefPubMedGoogle Scholar
  31. 31.
    Levin A, Stevens PE (2014) Summary of KDIGO 2012 CKD guideline: behind the scenes, need for guidance, and a framework for moving forward. Kidney Int 85(1):49–61. CrossRefPubMedGoogle Scholar
  32. 32.
    Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL (2007) Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 71(10):1028–1035. CrossRefPubMedGoogle Scholar
  33. 33.
    Christensen AM, Pauley JL, Molinelli AR, Panetta JC, Ward DA, Stewart CF, Hoffman JM, Howard SC, Pui CH, Pappo AS, Relling MV, Crews KR (2012) Resumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients. Cancer 118(17):4321–4330. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Evans WE, Abromowitch M, Crom WR, Relling MV, Bowman WP, Pui CH, Ochs J, Dodge R (1987) Clinical pharmacodynamic studies of high-dose methotrexate in acute lymphocytic leukemia. NCI Monogr 5:81–85Google Scholar
  35. 35.
    Salzer WL, Winick NJ, Wacker P, Lu X, Devidas M, Shuster JJ, Mahoney DH, Lauer SJ, Camitta BM (2012) Plasma methotrexate, red blood cell methotrexate, and red blood cell folate values and outcome in children with precursor B-acute lymphoblastic leukemia: a report from the Children’s Oncology Group. J Pediatr Hematol Oncol 34(1):e1–e7. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH (1998) Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 338(8):499–505. CrossRefPubMedGoogle Scholar
  37. 37.
    van Kooten Niekerk PB, Schmiegelow K, Schroeder H (2008) Influence of methylene tetrahydrofolate reductase polymorphisms and coadministration of antimetabolites on toxicity after high dose methotrexate. Eur J Haematol 81(5):391–398. CrossRefPubMedGoogle Scholar
  38. 38.
    Badke C, Fleming A, Iqbal A, Khilji O, Parhas S, Weinstein J, Morgan E, Hijiya N (2016) Rechallenging with intrathecal methotrexate after developing subacute neurotoxicity in children with hematologic malignancies. Pediatr Blood Cancer 63(4):723–726. CrossRefPubMedGoogle Scholar
  39. 39.
    Bhojwani D, Sabin ND, Pei D, Yang JJ, Khan RB, Panetta JC, Krull KR, Inaba H, Rubnitz JE, Metzger ML, Howard SC, Ribeiro RC, Cheng C, Reddick WE, Jeha S, Sandlund JT, Evans WE, Pui CH, Relling MV (2014) Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 32(9):949–959. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Svahn T, Mellgren K, Harila-Saari A, Asberg A, Kanerva J, Jonsson O, Vaitkeviciene G, Stamm Mikkelssen T, Schmiegelow K, Heldrup J (2017) Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia. Pediatr Blood Cancer. CrossRefPubMedGoogle Scholar
  41. 41.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113. CrossRefPubMedGoogle Scholar
  42. 42.
    Mahmoud LB, Mdhaffar M, Frikha R, Ghozzi H, Hakim A, Sahnoun Z, Elloumi M, Zeghal K (2018) Use of MTHFR C677T polymorphism and plasma pharmacokinetics to predict methotrexate toxicity in patients with acute lymphoblastic leukemia. Adv Clin Exp Med. CrossRefPubMedGoogle Scholar
  43. 43.
    Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Garcia-Orad A (2013) A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J 13(6):498–506. CrossRefPubMedGoogle Scholar
  44. 44.
    Kantar M, Kosova B, Cetingul N, Gumus S, Toroslu E, Zafer N, Topcuoglu N, Aksoylar S, Cinar M, Tetik A, Eroglu Z (2009) Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Leuk Lymphoma 50(6):912–917. CrossRefPubMedGoogle Scholar

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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