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01-02-2019 | Original Article

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

Authors: 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

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2019

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 (Cp_ss) within our goal range of 65 ± 15 µM with only 3 (5.6%) resulting in Cp_ss 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.

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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. https://doi.org/10.1016/j.ejca.2014.04.014 CrossRefPubMed

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. https://doi.org/10.1182/blood-2010-06-292615 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1200/JCO.2015.62.4544 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1002/pbc.10392 CrossRefPubMed

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):2514–2519PubMed

Bleyer WA (1978) The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 41(1):36–51CrossRefPubMed

Schmiegelow K (2009) Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol 146(5):489–503. https://doi.org/10.1111/j.1365-2141.2009.07765.x CrossRefPubMed

Widemann BC, Adamson PC (2006) Understanding and managing methotrexate nephrotoxicity. The Oncologist 11(6):694–703. https://doi.org/10.1634/theoncologist.11-6-694 CrossRefPubMed

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. https://doi.org/10.1634/theoncologist.2015-0164 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1002/pbc.24623 CrossRefPubMed

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. https://doi.org/10.1002/cncr.20255 CrossRefPubMed

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. https://doi.org/10.1093/ndt/gfw456 CrossRef

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):884–888CrossRefPubMed

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. https://doi.org/10.1186/cc8172 CrossRefPubMedPubMedCentral

15.

VORAXAZE(R) (glucarpidase) [package insert] (2017) BTG International, Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125327lbl.pdf. Accessed Jul 2018

16.

Patterson DM, Lee SM (2010) Glucarpidase following high-dose methotrexate: update on development. Expert Opin Biol Ther 10(1):105–111. https://doi.org/10.1517/14712590903468677 CrossRefPubMed

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. https://doi.org/10.1200/JCO.2009.25.4540 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1002/pbc.25395 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1002/ajh.24969 CrossRefPubMed

20.

Chan H, Evans WE, Pratt CB (1977) Recovery from toxicity associated with high-dose methotrexate: prognostic factors. Cancer Treat Rep 61(5):797–804PubMed

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. https://doi.org/10.1200/JCO.1994.12.8.1667 CrossRefPubMed

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. https://doi.org/10.1056/NEJM198602203140803 CrossRefPubMed

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. https://doi.org/10.1002/pbc.23074 CrossRefPubMed

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. https://doi.org/10.1007/s00280-013-2206-x CrossRefPubMedPubMedCentral

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):221–225CrossRefPubMed

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. https://doi.org/10.2165/00003088-200645120-00007 CrossRef

27.

Common terminology criteria for adverse events v4.03 NIH publication # 09-7473. http://ctep.cancer.gov

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. https://doi.org/10.1097/MPH.0000000000000696 CrossRefPubMed

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 62–64

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. https://doi.org/10.1016/S1470-2045(16)30035-3 CrossRefPubMed

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. https://doi.org/10.1038/ki.2013.444 CrossRefPubMed

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. https://doi.org/10.1038/sj.ki.5002231 CrossRefPubMed

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. https://doi.org/10.1002/cncr.27378 CrossRefPubMedPubMedCentral

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 5:81–85

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. https://doi.org/10.1097/MPH.0b013e31820ee239 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1056/NEJM199802193380803 CrossRefPubMed

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. https://doi.org/10.1111/j.1600-0609.2008.01128.x CrossRefPubMed

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. https://doi.org/10.1002/pbc.25850 CrossRefPubMed

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. https://doi.org/10.1200/JCO.2013.53.0808 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1002/pbc.26395 CrossRefPubMed

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. https://doi.org/10.1038/ng0595-111 CrossRef

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. https://doi.org/10.17219/acem/69802 CrossRefPubMed

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. https://doi.org/10.1038/tpj.2012.44 CrossRefPubMed

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. https://doi.org/10.1080/10428190902893819 CrossRefPubMed

Title: A prospective study of a simple algorithm to individually dose high-dose methotrexate for children with leukemia at risk for methotrexate toxicities
Authors: 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
Publication date: 01-02-2019
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-018-3733-2

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