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Early, empiric high-dose leucovorin rescue in lymphoma patients treated with sequential doses of high-dose methotrexate

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Abstract

Background

In patients exposed to high-dose methotrexate (HDMTX; >1g/m2) with a history of elevated methotrexate (MTX) concentrations during previous doses, it is unclear whether prescribing high-dose leucovorin (HDLV) rescue limits future high levels or reduces the likelihood of acute kidney injury (AKI).

Methods

This retrospective, single-center study longitudinally followed adult lymphoma patients treated with HDMTX between 1/1/2011 and 10/31/2017 from diagnosis until 30 days after the last HDMTX dose. Endpoints included elevated MTX concentrations at 48 h (>1.0 μmol/L) and incident AKI after each HDMTX dose.

Results

The 321 included patients had a median (IQR) age of 65 (57, 72) years, 190 (59%) were male, and 293 (91%) were Caucasian. There were 1558 HDMTX doses [median (IQR) 3 (2, 6) doses per patient] prescribed with 265 (83%) patients receiving more than one MTX dose. Those receiving HDLV rescue were more likely to have an elevated MTX concentration after that dose (OR = 2.69, 95% CI: 1.75-4.11, p < 0.001). Receiving HDLV rescue was associated with a greater likelihood of AKI after MTX (OR = 2.18, 95% CI: 1.38-3.43, p < 0.001). Hospital LOS was longer in those prescribed empiric HDLV rescue after MTX than those prescribed standard leucovorin with an estimated difference of 1.1 days, (95% CI: 0.5-1.7, p < 0.001).

Conclusion

Sequential HDMTX doses are associated with a significant incidence of elevated MTX levels and AKI during lymphoma management. HDLV rescue prescribed during subsequent MTX doses in patients with a previously elevated level was not associated with improved safety outcomes. The optimal supportive care strategy following HDMTX administration requires further investigation.

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References

  1. Freeman AI, Weinberg V, Brecher ML, Jones B, Glicksman AS, Sinks LF, Weil M, Pleuss H, Hananian J, Burgert EO Jr, Gilchrist GS, Necheles T, Harris M, Kung F, Patterson RB, Maurer H, Leventhal B, Chevalier L, Forman E, Holland JF (1983) Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med 308:477–484

    Article  CAS  PubMed  Google Scholar 

  2. Ginsberg SJ, Anderson JR, Gottlieb AJ et al (1987) A randomized trial of high-dose methotrexate versus standard-dose methotrexate following cyclophosphamide, doxorubicin (adriamycin), vincristine, and prednisone with or without bleomycin in the therapy of diffuse large cell lymphoma: preliminary report of Cancer and Leukemia Group B Study 7851. NCI Monogr:77–80

  3. Delepine N, Delepine G, Cornille H, Brion F, Arnaud P, Desbois JC (1995) Dose escalation with pharmacokinetics monitoring in methotrexate chemotherapy of osteosarcoma. Anticancer Res 15:489–494

    CAS  PubMed  Google Scholar 

  4. Isacoff WH, Townsend CM, Eiber FR, Forster T, Morton DL, Block JB (1976) High dose methotrexate therapy of solid tumors: observations relating to clinical toxicity. Med Pediatr Oncol 2:319–325

    Article  CAS  PubMed  Google Scholar 

  5. Holmboe L, Andersen AM, Morkrid L, Slordal L, Hall KS (2012) High dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients. Br J Clin Pharmacol 73:106–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rubenstein JL, Gupta NK, Mannis GN, Lamarre AK, Treseler P (2013) How I treat CNS lymphomas. Blood 122:2318–2330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kansara R (2018) Central nervous system prophylaxis strategies in diffuse large B cell lymphoma. Curr Treat Options in Oncol 19:52

    Article  Google Scholar 

  8. Glantz MJ, Cole BF, Recht L, Akerley W, Mills P, Saris S, Hochberg F, Calabresi P, Egorin MJ (1998) High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16:1561–1567

    Article  CAS  PubMed  Google Scholar 

  9. Skarin AT, Zuckerman KS, Pitman SW, Rosenthal DS, Moloney W, Frei E 3rd, Canellos GP (1977) High-dose methotrexate with folinic acid in the treatment of advanced non-Hodgkin lymphoma including CNS involvement. Blood 50:1039–1047

    CAS  PubMed  Google Scholar 

  10. Batchelor T, Carson K, O’Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R (2003) Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 21:1044–1049

    Article  CAS  PubMed  Google Scholar 

  11. Ferreri AJ, Reni M, Foppoli M et al (2009) High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 374:1512–1520

    Article  CAS  PubMed  Google Scholar 

  12. Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD (2013) Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 31:3061–3068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Abramson JS, Hellmann M, Barnes JA, Hammerman P, Toomey C, Takvorian T, Muzikansky A, Hochberg EP (2010) Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer 116:4283–4290

    Article  PubMed  Google Scholar 

  14. Bertino JR (1963) The mechanism of action of the folate antagonists in man. Cancer Res 23:1286–1306

    CAS  PubMed  Google Scholar 

  15. Bleyer WA (1977) Methotrexate: clinical pharmacology, current status and therapeutic guidelines. Cancer Treat Rev 4:87–101

    Article  CAS  PubMed  Google Scholar 

  16. Pinedo HM, Chabner BA (1977) Role of drug concentration, duration of exposure, and endogenous metabolites in determining methotrexate cytotoxicity. Cancer Treat Rep 61:709–715

    CAS  PubMed  Google Scholar 

  17. Joerger M, Huitema AD, Illerhaus G, Ferreri AJ (2012) Rational administration schedule for high-dose methotrexate in patients with primary central nervous system lymphoma. Leuk Lymphoma 53:1867–1875

    Article  CAS  PubMed  Google Scholar 

  18. Levitt M, Mosher MB, DeConti RC, Farber LR, Skeel RT, Marsh JC, Mitchell MS, Papac RJ, Thomas ED, Bertino JR (1973) Improved therapeutic index of methotrexate with “leucovorin rescue”. Cancer Res 33:1729–1734

    CAS  PubMed  Google Scholar 

  19. Zhu JJ, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, Hochberg FH, Betensky RA, Batchelor TT (2009) High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro-Oncology 11:211–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. May J, Carson KR, Butler S, Liu W, Bartlett NL, Wagner-Johnston ND (2014) High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis. Leuk Lymphoma 55:1345–1349

    Article  CAS  PubMed  Google Scholar 

  21. Green MR, Chamberlain MC (2009) Renal dysfunction during and after high-dose methotrexate. Cancer Chemother Pharmacol 63:599–604

    Article  CAS  PubMed  Google Scholar 

  22. Frei E 3rd, Jaffe NJ, Pitman S (1975) Letter: Limitations of methotrexate and citrovorum-factor treatments. N Engl J Med 292:107–108

    Article  PubMed  Google Scholar 

  23. Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA (1977) Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med 297:630–634

    Article  CAS  PubMed  Google Scholar 

  24. Abelson HT, Fosburg MT, Beardsley GP, Goorin AM, Gorka C, Link M, Link D (1983) Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine. J Clin Oncol 1:208–216

    Article  CAS  PubMed  Google Scholar 

  25. Stoller RG, Kaplan HG, Cummings FJ, Calabresi P (1979) A clinical and pharmacological study of high-dose methotrexate with minimal leucovorin rescue. Cancer Res 39:908–912

    CAS  PubMed  Google Scholar 

  26. Cohen IJ (2004) Defining the appropriate dosage of folinic acid after high-dose methotrexate for childhood acute lymphatic leukemia that will prevent neurotoxicity without rescuing malignant cells in the central nervous system. J Pediatr Hematol Oncol 26:156–163

    Article  PubMed  Google Scholar 

  27. Cohen IJ (2017) Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue. Cancer Chemother Pharmacol 79:1057–1065

    Article  CAS  PubMed  Google Scholar 

  28. Du Bois D, Du Bois EF (1916) Clinical calorimetry: tenth paper a formula to estimate the approximate surface area if height and weight be known. Arch Intern Med XVII:863–871

    Article  Google Scholar 

  29. Glass J, Gruber ML, Cher L, Hochberg FH (1994) Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg 81:188–195

    Article  CAS  PubMed  Google Scholar 

  30. Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA, Goldstein SL et al (2012) Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney disease: Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2(2):1–138

    Google Scholar 

  31. Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD (2016) Preventing and managing toxicities of high-dose methotrexate. Oncologist 21:1471–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dalia S, Price S, Forsyth P, Sokol L, Jaglal M (2015) What is the optimal dose of high-dose methotrexate in the initial treatment of primary central nervous system lymphoma? Leuk Lymphoma 56:500–502

    Article  PubMed  Google Scholar 

  33. Chabner BA, Young RC (1973) Threshold methotrexate concentration for in vivo inhibition of DNA synthesis in normal and tumorous target tissues. J Clin Invest 52:1804–1811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Thomasova D, Anders HJ (2015) Cell cycle control in the kidney. Nephrol Dial Transplant 30:1622–1630

    Article  CAS  PubMed  Google Scholar 

  35. Pannu AK (2019) Methotrexate overdose in clinical practice. Curr Drug Metab 20:714–719

    Article  CAS  PubMed  Google Scholar 

  36. Shank BR, Seung AH, Kinsman K, Newman MJ, Donehower RC, Burton B (2017) Effects of the leucovorin shortage: pilot study investigating cost, efficacy, and toxicity comparison of low fixed-dose versus body surface area-adjusted leucovorin dosing in patients with resectable colon or metastatic colorectal cancer. J Oncol Pharm Pract 23:163–172

    Article  CAS  PubMed  Google Scholar 

  37. Cohen IJ (2013) Challenging the clinical relevance of folinic acid over rescue after high dose methotrexate (HDMTX). Med Hypotheses 81:942–947

    Article  CAS  PubMed  Google Scholar 

  38. Safadi S, Hommos MS, Enders FT, Lieske JC, Kashani KB (2020) Risk factors for acute kidney injury in hospitalized non-critically ill patients: a population-based study. Mayo Clin Proc 95:459–467

    Article  PubMed  Google Scholar 

  39. Cheng YC, Nie S, Li L, Li Y, Liu D, Xiong M, Wang L, Ge S, Xu G, on behalf of the EACH study investigators (2019) Epidemiology and outcomes of acute kidney injury in hospitalized cancer patients in China. Int J Cancer 144:2644–2650

    Article  CAS  PubMed  Google Scholar 

  40. Na SY, Sung JY, Chang JH, Kim S, Lee HH, Park YH, Chung W, Oh KH, Jung JY (2011) Chronic kidney disease in cancer patients: an independent predictor of cancer-specific mortality. Am J Nephrol 33:121–130

    Article  PubMed  Google Scholar 

  41. Ubukata M, Hara M, Nishizawa Y, Fujii T, Nitta K, Ohta A (2018) Prevalence and mortality of chronic kidney disease in lymphoma patients: a large retrospective cohort study. Medicine 97:e9615

    Article  PubMed  PubMed Central  Google Scholar 

  42. Demiralp B, Koenig L, Kala J, Feng C, Hamlett EG, Steele-Adjognon M, Ward S (2019) Length of stay, mortality, and readmissions among Medicare cancer patients treated with glucarpidase and conventional care: a retrospective study. Clinicoecon Outcomes Res 11:129–144

    Article  PubMed  PubMed Central  Google Scholar 

  43. Nirenberg A, Mosende C, Mehta BM, Gisolfi AL, Rosen G (1977) High-dose methotrexate with citrovorum factor rescue: predictive value of serum methotrexate concentrations and corrective measures to avert toxicity. Cancer Treat Rep 61:779–783

    CAS  PubMed  Google Scholar 

  44. Levey AS, Inker LA (2017) Assessment of glomerular filtration rate in health and disease: a state of the art review. Clin Pharmacol Ther 102:405–419

    Article  CAS  PubMed  Google Scholar 

  45. Lameire N, Van Biesen W, Vanholder R (2008) Acute renal problems in the critically ill cancer patient. Curr Opin Crit Care 14:635–646

    Article  PubMed  Google Scholar 

  46. Barreto JN, McClanahan AL, Rule AD, Thompson CA, Frazee E (2018) Incorporating cystatin C to predict methotrexate elimination in patients with CNS lymphoma and suspicious renal function. Case Rep Hematol 2018:7169897

    PubMed  PubMed Central  Google Scholar 

  47. Kashani K, Al-Khafaji A, Ardiles T et al (2013) Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 17:R25

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hoste EA, McCullough PA, Kashani K, Chawla LS, Joannidis M, Shaw AD, Feldkamp T, Uettwiller-Geiger DL, McCarthy P, Shi J, Walker MG, Kellum JA, Sapphire Investigators (2014) Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers. Nephrol Dial Transplant 29:2054–2061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bihorac A, Chawla LS, Shaw AD, al-Khafaji A, Davison DL, DeMuth GE, Fitzgerald R, Gong MN, Graham DD, Gunnerson K, Heung M, Jortani S, Kleerup E, Koyner JL, Krell K, LeTourneau J, Lissauer M, Miner J, Nguyen HB, Ortega LM, Self WH, Sellman R, Shi J, Straseski J, Szalados JE, Wilber ST, Walker MG, Wilson J, Wunderink R, Zimmerman J, Kellum JA (2014) Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med 189:932–939

    Article  CAS  PubMed  Google Scholar 

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The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Funding

This project was supported in part by CTSA Grant Number TL1 TR002380 from the National Center for Advancing Translational Science (NCATS) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number K23AI143882 (PI - E.F.B.).

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Authors and Affiliations

  1. Department of Pharmacy, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Jason N. Barreto

  2. Department of Pharmacy, Duke University Medical Center, 2301 Erwin Road, Durham, NC, 27710, USA

    Kristen T. Peterson

  3. Department of Pharmacy, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Erin F. Barreto

  4. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Kristin C. Mara & Ross A. Dierkhising

  5. Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Nelson Leung

  6. Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Thomas E. Witzig & Carrie A. Thompson

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Contributions

Conceptualization and methodology: JNB, KTP, EFB, KCM, RAD, NL, TEW, and CAT.

Data curation, formal analysis, and interpretation: JNB, KTP, EFB, KCM, and RAD.

Writing—original draft: JNB, KTP, EFB, KCM, RAD, NL, TEW, and CAT

Writing—review and editing: JNB, KTP, EFB, KCM, RAD, NL, TEW, and CAT

Corresponding author

Correspondence to Jason N. Barreto.

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Ethics approval

This retrospective chart review was approved by the Mayo Clinic Institutional Review Board and performed in accordance with the ethical standards of the 1964 Declaration of Helsinki with adherence to all relevant regulations of the US health insurance portability and accountability act (HIPAA), IRB No. 17-008432, Approved 11 October 2017.

Consent to participate

All patients provided written informed consent or had consent provided for them by their legal power of attorney and were verified through Minnesota Research Authorization prior to data collection.

Competing interests

E.F.B. provides consultation for FAST Biomedical, unrelated to this work. All other authors declare no potential personal, financial, or ethical conflicts of interest regarding the contents of this manuscript.

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Abstract information

The material found in this work was presented as a poster at the 61st Annual Meeting and Exposition, December 7-10, 2019, in Orlando, FL.

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Barreto, J.N., Peterson, K.T., Barreto, E.F. et al. Early, empiric high-dose leucovorin rescue in lymphoma patients treated with sequential doses of high-dose methotrexate. Support Care Cancer 29, 5293–5301 (2021). https://doi.org/10.1007/s00520-021-06106-y

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