Document Type : Original Article(s)


1 Thalassemia Research Center (TRC), Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran

2 Department of Clinical Pharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

3 Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran



Background: Acute lymphoblastic leukemia (ALL) represents the predominant childhood cancer. High-dose methotrexate is integral to leukemia treatment protocols. This study aimed to explore the efficacy of glutamine in preventing mucositis among leukemia patients undergoing high-dose methotrexate therapy.
Method: This randomized clinical trial encompassed 45 patients (22 in the glutamine group and 23 in the placebo group). The intervention group was administered a glutamine mouthwash, while the control group received an identical placebo. Data analysis was performed using SPSS version 23, with a significance threshold set at P < 0.05.
Results: No significant difference emerged between the groups concerning the incidence of nausea and vomiting; however, both groups observed a notable reduction in nausea frequency from the first to the fourth days (P = 0.0001 and P = 0.040, respectively). Grades III and IV mucositis were absent in both groups on the third and seventh days post-treatment. Furthermore, no significant difference was detected in mucositis improvement between the groups (P = 0.848).
Conclusion: Glutamine mouthwash significantly reduced the incidence of nausea and vomiting, which are common chemotherapy complications. Moreover, up to 95% of patients were free from mucositis by the seventh-day post-chemotherapy.


Mohammad Naderisorki (PubMed)


Main Subjects

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination, and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.30476/mejc.2024.100100.1971

  1. Cooper SL, Brown PA. Treatment of pediatric acute lymphoblastic leukemia. Pediatr Clin North Am. 2015;62(1):61-73. doi: 10.1016/j.pcl.2014.09.006.
  2. Hunger SP, Raetz EA. How I treat relapsed acute lymphoblastic leukemia in the pediatric population. Blood. 2020;136(16):1803-12. doi: 10.1182/blood.2019004043.
  3. Bordbar M, Jam N, Karimi M, Shahriari M, Zareifar S, Zekavat OR, et al. The survival of childhood leukemia: An 8-year single-center experience. Cancer Rep (Hoboken). 2023;6(4):e1784. doi: 10.1002/cnr2.1784.
  4. Elgarten CW, Aplenc R. Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy. Curr Opin Pediatr. 2020;32(1):57-66. doi: 10.1097/MOP.0000000000000855.
  5. Goudarzi Pour K, Eshghi P, Naderisorki M. A comparison of two chemotherapeutic regimes in children with B-cell acute lymphoblastic leukemia. J Compr Ped. 2018;9(4):e64153. doi:10.5812/compreped.64153.
  6. Fish JD, Lipton JM, Lanzkowsky P. Lanzkowsky's manual of pediatric hematology and oncology. 6th ed. London, United Kingdom: Academic Press; 2016.
  7. Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020 Nov 11;105(11):2524.
  8. Mohammed AI, Celentano A, Paolini R, Low JT, McCullough MJ, O' Reilly LA, et al. Characterization of a novel dual murine model of chemotherapy-induced oral and intestinal mucositis. Sci Rep. 2023;13(1):1396. doi: 10.1038/s41598-023-28486-3.
  9. Daugėlaitė G, Užkuraitytė K, Jagelavičienė E, Filipauskas A. Prevention and treatment of chemotherapy and radiotherapy induced oral mucositis. Medicina. 2019;55(2):25. doi: 10.3390/medicina55020025
  10. Zobeck M, Bernhardt MB, Kamdar KY, Rabin KR, Lupo PJ, Scheurer ME. Novel and replicated clinical and genetic risk factors for toxicity from high-dose methotrexate in pediatric acute lymphoblastic leukemia. Pharmacotherapy. 2023;43(3):205-14. doi: 10.1002/phar.2779.
  11. Cluntun AA, Lukey MJ, Cerione RA, Locasale JW. Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer. 2017;3(3):169-80. doi: 10.1016/j.trecan.2017.01.005.
  12. Peng TR, Lin HH, Yang LJ, Wu TW. Effectiveness of glutamine in the management of oral mucositis in cancer patients: a meta-analysis of randomized controlled trials. Support Care Cancer. 2021;29(8):4885-92. doi: 10.1007/s00520-021-06060-9.
  13. Matés JM, Campos-Sandoval JA, Santos-Jiménez JL, Márquez J. Dysregulation of glutaminase and glutamine synthetase in cancer. Cancer Lett. 2019;467:29-39. doi: 10.1016/j.canlet.2019.09.011.
  14. Villa A, Vollemans M, De Moraes A, Sonis S. Concordance of the WHO, RTOG, and CTCAE v4.0 grading scales for the evaluation of oral mucositis associated with chemoradiation therapy for the treatment of oral and oropharyngeal cancers. Support Care Cancer. 2021;29(10):6061-8. doi: 10.1007/s00520-021-06177-x.
  15. Sayles C, Hickerson SC, Bhat RR, Hall J, Garey KW, Trivedi MV. Oral glutamine in preventing treatment-related mucositis in adult patients with cancer: a systematic review. Nutr Clin Pract. 2016;31(2):171-9. doi: 10.1177/0884533615611857.
  16. Cerchietti LC, Navigante AH, Lutteral MA, Castro MA, Kirchuk R, Bonomi M, et al. Double-blinded, placebo-controlled trial on intravenous L-alanyl-L-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2006;65(5):1330-7. doi: 10.1016/j.ijrobp.2006.03.042.
  17. Anderson PM, Lalla RV. Glutamine for amelioration of radiation and chemotherapy associated mucositis during cancer therapy. Nutrients. 2020;12(6):1675. doi: 10.3390/nu12061675.
  18. Huang CJ, Huang MY, Fang PT, Chen F, Wang YT, Chen CH, et al. Randomized double-blind, placebo-controlled trial evaluating oral glutamine on radiation-induced oral mucositis and dermatitis in head and neck cancer patients. Am J Clin Nutr. 2019;109(3):606-14. doi: 10.1093/ajcn/nqy329.
  19. Yokota T, Ogawa T, Takahashi S, Okami K, Fujii T, Tanaka K, et al. Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study. BMC Cancer. 2017;17(1):314. doi: 10.1186/s12885-017-3295-4.
  20. Tang G, Huang W, Zhang L, Wei Z. Role of glutamine in the management of oral mucositis in patients with cancer: a meta-analysis of randomized controlled trials. Nutr Cancer. 2022;74(2):482-95. doi: 10.1080/01635581.2021.1889623.
  21. Chang YH, Yu MS, Wu KH, Hsu MC, Chiou YH, Wu HP, et al. Effectiveness of parenteral glutamine on methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia. Nutr Cancer. 2017;69(5):746-51. doi: 10.1080/01635581.2017.1324995.
  22. Issaq SH, Mendoza A, Fox SD, Helman LJ. Glutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth. Oncogenesis. 2019;8(3):20. doi: 10.1038/s41389-019-0129-z.
  23. Lee P, Malik D, Perkons N, Huangyang P, Khare S, Rhoades S, et al. Targeting glutamine metabolism slows soft tissue sarcoma growth. Nat Commun. 2020;11(1):498. doi: 10.1038/s41467-020-14374-1.
  24. Choi YK, Park KG. Targeting glutamine metabolism for cancer treatment. Biomol Ther (Seoul). 2018;26(1):19-28. doi: 10.4062/biomolther.2017.178.
  25. Suardi C, Cazzaniga E, Graci S, Dongo D, Palestini P. Link between viral infections, immune system, inflammation and diet. Int J Environ Res Public Health. 2021;18(5):2455. doi: 10.3390/ijerph18052455.
  26. Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: metabolism and immune function, supplementation and clinical translation. Nutrients. 2018;10(11):1564. doi: 10.3390/nu10111564.
  27. Ramezani Ahmadi A, Rayyani E, Bahreini M, Mansoori A. The effect of glutamine supplementation on athletic performance, body composition, and immune function: A systematic review and a meta-analysis of clinical trials. Clin Nutr. 2019;38(3):1076-91. doi: 10.1016/j.clnu.2018.05.001.
  28. Newsholme P, Diniz VLS, Dodd GT, Cruzat V. Glutamine metabolism and optimal immune and CNS function. Proc Nutr Soc. 2023;82(1):22-31. doi: 10.1017/S0029665122002749.
  29. Perna S, Alalwan TA, Alaali Z, Alnashaba T, Gasparri C, Infantino V, et al. The role of glutamine in the complex interaction between gut microbiota and health: a narrative review. Int J Mol Sci. 2019;20(20):5232. doi: 10.3390/ijms20205232.
  30. Ward E, Smith M, Henderson M, Reid U, Lewis I, Kinsey S, et al. The effect of high-dose enteral glutamine on the incidence and severity of mucositis in paediatric oncology patients. Eur J Clin Nutr. 2009;63(1):134-40. doi: 10.1038/sj.ejcn.1602894.
  31. Yildirim ZK, Bidev D, Buyukavci M. Parenteral glutamine supplementation has no effect on chemotherapy-induced toxicity in children with non-Hodgkin lymphoma. J Pediatr Hematol Oncol. 2013;35(5):371-6. doi: 10.1097/MPH.0b013e318282daf4.
  32. Huang EY, Leung SW, Wang CJ, Chen HC, Sun LM, Fang FM, et al. Oral glutamine to alleviate radiation-induced oral mucositis: a pilot randomized trial. Int J Radiat Oncol Biol Phys. 2000;46(3):535-9. doi: 10.1016/s0360-3016(99)00402-2.
  33. Sornsuvit C, Komindr S, Chuncharunee S, Wanikiat P, Archararit N, Santanirand P. Pilot study: effects of parenteral glutamine dipeptide supplementation on neutrophil functions and prevention of chemotherapy-induced side-effects in acute myeloid leukaemia patients. J Int Med Res. 2008;36(6):1383-91. doi: 10.1177/147323000803600628.
  34. Choi K, Lee SS, Oh SJ, Lim SY, Lim SY, Jeon WK, et al. The effect of oral glutamine on 5-fluorouracil/leucovorin-induced mucositis/stomatitis assessed by intestinal permeability test. Clin Nutr. 2007;26(1):57-62. doi: 10.1016/j.clnu.2006.07.003.