Predictors Associated with Delayed Methotrexate Clearance among Patients with Haematological Malignancies
Article Sidebar
Main Article Content
Abstract
Introduction: High dose methotrexate is commonly utilised in haematological malignancies; however, the prevalence of delayed clearance is not well-defined. The study aimed to determine the prevalence of delayed clearance of methotrexate, to analyse correlation between rate of methotrexate infusions and its concentrations, and to identify the predictors associated with delayed clearance. Method: A crosssectional study was conducted among adult patients with haematological malignancies who received high-dose methotrexate. Spearman’s correlation was utilised to analyse correlation between the rates of methotrexate infusions with its concentrations at 48 and 72 hours. Multiple logistic regression was used to identify factors associated with delayed clearance. Results: A total of 63 patients with 159 methotrexate infusions were included, with a mean age of 42.2 years (±18.06) and a median body mass index of 23.36 kg/m2 (19.91-26.14). Delayed methotrexate clearance was observed in 29 (46%) patients, which affected 41 (25.6%) methotrexate infusions. A poor negative correlation was found between the rate of methotrexate infusion and 48-hour concentration (r=-0.206, p=0.009). Older age (odds ratio (OR) 1.06, 95% confidence interval (CI) 1.03-1.10, p<0.001) and dose of methotrexate >3000 mg/m2 (OR 3.33, 95% CI 6.45-120.88, p<0.001) were identified as the predictors of delayed methotrexate clearance. Conclusion: Almost half of the patients experienced delayed methotrexate clearance. A slower rate of infusion was found to correlate with higher 48-hour concentrations. Older age and higher doses of methotrexate were identified as predictors for delayed clearance. Prospective study is needed with larger sample size to ensure generalisability of the outcomes.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Journal of Pharmacy at https://journals.iium.edu.my/ktn/index.php/jp is licensed under a Creative Commons Attribution 4.0 International License.
References
Ackland, S. P., & Schilsky, R. L. (1987). High-dose methotrexate: a critical reappraisal. J Clin Oncol, 5(12), 2017-2031. https://doi.org/10.1200/jco.1987.5.12.2017
Allen, P. B., & Lechowicz, M. J. (2019). Management of NK/T-Cell Lymphoma, Nasal Type. Journal of Oncology Practice, 15(10), 513-520. https://doi.org/10.1200/jop.18.00719
Bacci, G., Loro, L., Longhi, A., Bertoni, F., Bacchini, P., Versari, M., Picci, P., & Serra, M. (2006). No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma. Anticancer Drugs, 17(4), 411-415. https://doi.org/10.1097/01.cad.0000203379.14738.d9
Barreto, J. N., Reid, J. M., Thompson, C. A., Mara, K. C., Rule, A. D., Kashani, K. B., Leung, N., Larson, T. R., McGovern, R. M., Witzig, T. E., & Barreto, E. F. (2021). Prospective evaluation of high-dose methotrexate pharmacokinetics in adult patients with lymphoma using novel determinants of kidney function. Clin Transl Sci. https://doi.org/10.1111/cts.13125
Bursac, Z., Gauss, C. H., Williams, D. K., & Hosmer, D. W. (2008). Purposeful selection of variables in logistic regression. Source Code for Biology and Medicine, 3(1), 17. https://doi.org/10.1186/1751-0473-3-17
Campbell, J. M., Bateman, E., Stephenson, M. D., Bowen, J. M., Keefe, D. M., & Peters, M. D. (2016). Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chemother Pharmacol, 78(1), 27-39. https://doi.org/10.1007/s00280-016-3043-5
Cano, J. P., Aubert, C., Rigault, J. P., Gilli, R., Coassolo, P., Monjanel, S., Seitz, J. F., & Carcassone, Y. (1981). Advantages and limitations of pharmacokinetic studies in the rationalization of anticancer therapy: methotrexate and 5-FU. Cancer Treat Rep, 65 Suppl 3, 33-42.
Chan, Y. H. (2003). Biostatistics 104: correlational analysis. Singapore Med J, 44(12), 614-619.
Dhand N. K., Khatkar M. S. (n.d.). Statulator: An online statistical calculator. Sample Size Calculator for Estimating a Single Proportion. Accessed 24 January 2025, http://statulator.com/SampleSize/ss1P.html
Dhanushkodi, M. (2021). High-dose Methotrexate. Indian Journal of Medical and Paediatric Oncology, 40(03), 424-426. https://doi.org/10.4103/ijmpo.ijmpo_157_19
Goh, T. S., Wong, K. Y., Lampkin, B., O'Leary, J., & Gnarra, D. (1979). Evaluation of 24-hour infusion of high-dose methotrexate--pharmacokinetics and toxicity. Cancer Chemother Pharmacol, 3(3), 177-180. https://doi.org/10.1007/bf00262419
Gökbuget, N., Hoelzer, D., Arnold, R., Böhme, A., Bartram, C. R., Freund, M., Ganser, A., Kneba, M., Langer, W., Lipp, T., Ludwig, W. D., Maschmeyer, G., Rieder, H., Thiel, E., Weiss, A., & Messerer, D. (2000). Treatment of Adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL). Hematol Oncol Clin North Am, 14(6), 1307-1325, ix. https://doi.org/10.1016/s0889-8588(05)70188-x
Goldie, J. H., Price, L. A., & Harrap, K. R. (1972). Methotrexate toxicity: Correlation with duration of administration, plasma levels, dose and excretion pattern. European Journal of Cancer, 8(4), 409-414. https://doi.org/10.1016/0014-2964(72)90125-9
Grommes, C., & DeAngelis, L. M. (2017). Primary CNS Lymphoma. J Clin Oncol, 35(21), 2410-2418. https://doi.org/10.1200/jco.2017.72.7602
Gupta, S., Pole, J. D., Baxter, N. N., Sutradhar, R., Lau, C., Nagamuthu, C., & Nathan, P. C. (2019). The effect of adopting pediatric protocols in adolescents and young adults with acute lymphoblastic leukemia in pediatric vs adult centers: An IMPACT Cohort study. Cancer Med, 8(5), 2095-2103. https://doi.org/10.1002/cam4.2096
Hanbali, A., Kotb, A., Fakih, R. E., Alfraih, F., Ahmed, S. O., Shaheen, M., Alhayli, S., Alahmari, A., Alotaibi, A., Alshaibani, A., Riash, M. A., Deeba, F., Asif, M., Rasheed, W., Alzahrani, H., Alsharif, F., Chaudhri, N., Almohareb, F., & Aljurf, M. (2021). Improved survival in adolescents and young adults (AYA) patients aged 14-55 years with acute lymphoblastic leukemia using pediatric-inspired protocol - a retrospective analysis of a real-world experience in 79 of patients treated at a national tertiary care referral center. Leuk Res Rep, 16, 100270. https://doi.org/10.1016/j.lrr.2021.100270
Howard, S. C., McCormick, J., Pui, C. H., Buddington, R. K., & Harvey, R. D. (2016). Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist, 21(12), 1471-1482. https://doi.org/10.1634/theoncologist.2015-0164
Kawakatsu, S., Nikanjam, M., Lin, M., Le, S., Saunders, I., Kuo, D. J., & Capparelli, E. V. (2019). Population pharmacokinetic analysis of high-dose methotrexate in pediatric and adult oncology patients. Cancer Chemother Pharmacol, 84(6), 1339-1348. https://doi.org/10.1007/s00280-019-03966-4
Kowalski, A., Jaszczur, S. M., Nadeau-Nguyen, M., & Merl, M. Y. (2021). Assessment of High-Dose Methotrexate Management Guideline in Adults with Cancer at an Academic Medical Center [Article]. Journal of Hematology Oncology Pharmacy, 11(2), 69-73.
Li, X., Cui, Y., Sun, Z., Zhang, L., Li, L., Wang, X., Wu, J., Fu, X., Ma, W., Zhang, X., Chang, Y., Nan, F., Li, W., Su, L., Wang, J., Xue, H., & Zhang, M. (2016). DDGP versus SMILE in Newly Diagnosed Advanced Natural Killer/T-Cell Lymphoma: A Randomized Controlled, Multicenter, Open-label Study in China. Clin Cancer Res, 22(21), 5223-5228. https://doi.org/10.1158/1078-0432.CCR-16-0153
Li, X., Sui, Z., Jing, F., Xu, W., Li, X., Guo, Q., Sun, S., & Bi, X. (2019). Identifying risk factors for high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia. Cancer Manag Res, 11, 6265-6274. https://doi.org/10.2147/CMAR.S207959
Lin, F., Juan, Y., Zheng, S. E., Shen, Z., Tang, L. N., Zhao, H., & Yao, Y. (2009). Relationship of serum methotrexate concentration in high-dose methotrexate chemotherapy to prognosis and tolerability: A prospective cohort study in chinese adults with osteosarcoma. Curr Ther Res Clin Exp, 70(2), 150-160. https://doi.org/10.1016/j.curtheres.2009.04.005
May, J., Carson, K. R., Butler, S., Liu, W., Bartlett, N. L., & Wagner-Johnston, N. D. (2014). High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis. Leuk Lymphoma, 55(6), 1345-1349. https://doi.org/10.3109/10428194.2013.840780
Misaka, K. O., Suga, Y., Staub, Y., Tsubata, A., Shimada, T., Sai, Y., & Matsushita, R. (2020). Risk Factors for Delayed Elimination of Methotrexate in Children, Adolescents and Young Adults with Osteosarcoma. In Vivo, 34(6), 3459-3465. https://doi.org/10.21873/invivo.12185
Moricke, A., Reiter, A., Zimmermann, M., Gadner, H., Stanulla, M., Dordelmann, M., Loning, L., Beier, R., Ludwig, W. D., Ratei, R., Harbott, J., Boos, J., Mann, G., Niggli, F., Feldges, A., Henze, G., Welte, K., Beck, J. D., Klingebiel, T., Niemeyer, C., Zintl, F., Bode, U., Urban, C., Wehinger, H., Niethammer, D., Riehm, H., Schrappe, M., & German-Austrian-Swiss, A. L. L. B. F. M. S. G. (2008). Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood, 111(9), 4477-4489. https://doi.org/10.1182/blood-2007-09-112920
Mosleh, E., Snyder, S., Wu, N., Willis, D. N., Malone, R., & Hayashi, R. J. (2023). Factors influencing delayed clearance of high dose methotrexate (HDMTX) in pediatric, adolescent, and young adult oncology patients. Front Oncol, 13, 1280587. https://doi.org/10.3389/fonc.2023.1280587
Nakano, T., Kobayashi, R., Matsushima, S., Hori, D., Yanagi, M., Suzuki, D., & Kobayashi, K. (2021). Risk factors for delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia and lymphoma. Int J Hematol, 113(5), 744-750. https://doi.org/10.1007/s12185-020-03071-w
National Cancer Institute (U.S.). (2006). Closing the gap: research and care imperatives for adolescents and young adults with cancer. U.S. Dept. of Health and Human Services, National Institutes of Health (NIH), National Cancer Institute (NCI). https://www.cancer.gov/types/aya/research/ayao-august-2006.pdf
National Cancer Institute (U.S.). (2017). Common terminology criteria for adverse events (CTCAE) v5.0 (Rev. ed.). U.S. Dept. of Health and Human Services, National Institutes of Health, National Cancer Institute.
Ng, H. Y., Ong, P. S., Loy, X. M., Chen, Y., & Goh, Y. T. (2016). Predictors of Delayed Clearance and Toxicities from High Dose Methotrexate in Patients Receiving Hypercvad Regimen for Treatment of Lymphoid Malignancies. Blood, 128(22), 1630-1630. https://doi.org/10.1182/blood.V128.22.1630.1630
Perazella, M. A., & Moeckel, G. W. (2010). Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy. Semin Nephrol, 30(6), 570-581. https://doi.org/10.1016/j.semnephrol.2010.09.005
Proudfoot, A. T., Krenzelok, E. P., & Vale, J. A. (2004). Position Paper on urine alkalinization. J Toxicol Clin Toxicol, 42(1), 1-26. https://doi.org/10.1081/clt-120028740
Razali, R. H., Noorizhab, M. N. F., Jamari, H., James, R. J., Teh, K. H., Ibrahim, H. M., Teh, L. K., & Salleh, M. Z. (2020). Association of ABCC2 with levels and toxicity of methotrexate in Malaysian Childhood Acute Lymphoblastic Leukemia (ALL). Pediatr Hematol Oncol, 37(3), 185-197. https://doi.org/10.1080/08880018.2019.1705949
Ribera, J. M., Ribera, J., & Genesca, E. (2014). Treatment of adolescent and young adults with acute lymphoblastic leukemia. Mediterr J Hematol Infect Dis, 6(1), e2014052. https://doi.org/10.4084/MJHID.2014.052
Shi, Z.-y., Liu, Y.-o., Gu, H.-y., Xu, X.-q., Yan, C., Yang, X.-y., & Yan, D. (2020). Population pharmacokinetics of high-dose methotrexate in Chinese pediatric patients with medulloblastoma. Biopharmaceutics & Drug Disposition, 41(3), 101-110. https://doi.org/https://doi.org/10.1002/bdd.2221
Stock, W., Luger, S. M., Advani, A. S., Yin, J., Harvey, R. C., Mullighan, C. G., Willman, C. L., Fulton, N., Laumann, K. M., Malnassy, G., Paietta, E., Parker, E., Geyer, S., Mrózek, K., Bloomfield, C. D., Sanford, B., Marcucci, G., Liedtke, M., Claxton, D. F., Foster, M. C., Bogart, J. A., Grecula, J. C., Appelbaum, F. R., Erba, H., Litzow, M. R., Tallman, M. S., Stone, R. M., & Larson, R. A. (2019). A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood, 133(14), 1548-1559. https://doi.org/10.1182/blood-2018-10-881961
Stoller, R. G., Hande, K. R., Jacobs, S. A., Rosenberg, S. A., & Chabner, B. A. (1977). Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med, 297(12), 630-634. https://doi.org/10.1056/nejm197709222971203
Valade, S., Mariotte, E., Azoulay, E., & Darmon, M. (2020). High-dose methotrexate in ICU patients: a retrospective study. Ann Intensive Care, 10(1), 81. https://doi.org/10.1186/s13613-020-00693-5
Weber, B. L., Tanyer, G., Poplack, D. G., Reaman, G. H., Feusner, J. H., Miser, J. S., & Bleyer, W. A. (1987). Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood. NCI Monogr(5), 207-212.
Widemann, B. C., & Adamson, P. C. (2006). Understanding and managing methotrexate nephrotoxicity. Oncologist, 11(6), 694-703. https://doi.org/10.1634/theoncologist.11-6-694
Winter, S. S., Dunsmore, K. P., Devidas, M., Wood, B. L., Esiashvili, N., Chen, Z., Eisenberg, N., Briegel, N., Hayashi, R. J., Gastier-Foster, J. M., Carroll, A. J., Heerema, N. A., Asselin, B. L., Gaynon, P. S., Borowitz, M. J., Loh, M. L., Rabin, K. R., Raetz, E. A., Zweidler-Mckay, P. A., Winick, N. J., Carroll, W. L., & Hunger, S. P. (2018). Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results from the Children's Oncology Group AALL0434 Methotrexate Randomization. J Clin Oncol, 36(29), 2926-2934. https://doi.org/10.1200/jco.2018.77.7250
Young, E. P., Cheng, W. S., Bernhardt, M. B., Wang, L. L., Rainusso, N., & Foster, J. H. (2020). Risk factors associated with delayed methotrexate clearance and increased toxicity in pediatric patients with osteosarcoma. Pediatr Blood Cancer, 67(4), e28123. https://doi.org/10.1002/pbc.28123
Zhang, W., Zhang, Q., Zheng, T. T., Zhen, J. C., & Niu, X. H. (2016). Delayed High-dose Methotrexate Excretion and Influencing Factors in Osteosarcoma Patients. Chin Med J (Engl), 129(21), 2530-2534. https://doi.org/10.4103/0366-6999.192781