Effectiveness of Probiotics for the Prevention of Gastrointestinal Toxicity in Children With Leukemia

Summary

Background: Acute lymphoblastic leukemia (ALL) is a common malignant neoplasm in children. Although chemotherapy achieves remission in over 70% of cases, it can cause gastrointestinal toxicity in up to 32.5%. Some studies suggest that administering probiotics reduces this risk, but the evidence remains inconsistent. Objective: To evaluate the effectiveness and safety of administering L. casei, L. rhamnosus or B. bifidum compared to a placebo for the prevention of gastrointestinal toxicity, decreased intestinal permeability, and changes in intestinal microbiota in pediatric patients diagnosed with acute lymphoblastic leukemia receiving chemotherapy. Methods: A total of 120 participants aged 6 to 17 years, diagnosed with ALL and receiving consolidation phase chemotherapy without gastrointestinal comorbidities, will be included. Participants will be administered daily 2 capsules containing either 1) L. casei, 2) L. rhamnosus, 3) B. bifidum or 4) placebo daily for 8 weeks. The clinical status of the participants will be evaluated weekly by the oncology service to determine the presence of gastrointestinal toxicity and adverse events. Changes in intestinal permeability will be assessed by measuring beta-lactoglobulin in a blood sample using the ELISA technique, while changes in the intestinal microbiota will be analyzed by genomic sequencing at baseline and at the end of follow-up. Statistical analysis: Descriptive analysis will use measures of central tendency and dispersion. For quantitative variables, the mean and standard deviation or median with minimum and maximum values will be calculated depending on the distribution type. Frequencies and proportions will be calculated for qualitative variables, presented in tabular and graphical form. To compare the quantitative variables between the four interventions, a multi-way ANOVA test will be used. The risk of gastrointestinal toxicity and adverse events will be analyzed by calculating the relative risk and 95% confidence interval. Differences between the interventions will be analyzed using survival analysis with the Kaplan-Meier and Log-Rank tests. Sequencing data will be analyzed using the Qiime2 program, filtered to generate a phylogenetic tree using the Silva database. Corresponding plots will be generated for each taxonomic level. Alpha (intra-group) and Beta (inter-group) diversity will be presented by ordination plots using principal component analysis with the ANCOM program

Timeline

Start

2025-02-01

Primary completion

2025-12-31

Completion

2026-08-31

Publications

• Results Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998 Aug 27;339(9):605-15. doi: 10.1056/NEJM199808273390907. No abstract available.
• Results Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009 Jun 25;360(26):2730-41. doi: 10.1056/NEJMoa0900386.
• Results Rivera-Luna R, Velasco-Hidalgo L, Zapata-Tarres M, Cardenas-Cardos R, Aguilar-Ortiz MR. Current outlook of childhood cancer epidemiology in a middle-income country under a public health insurance program. Pediatr Hematol Oncol. 2017 Feb;34(1):43-50. doi: 10.1080/08880018.2016.1276236. Epub 2017 Mar 13.
• Results Moricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Arico M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rossig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. doi: 10.1182/blood-2015-09-670729. Epub 2016 Feb 17.
• Results Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother. 2007 Jun;8(8):1039-58. doi: 10.1517/14656566.8.8.1039.
• Results Schmiegelow K, Muller K, Mogensen SS, Mogensen PR, Wolthers BO, Stoltze UK, Tuckuviene R, Frandsen T. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Res. 2017 Apr 7;6:444. doi: 10.12688/f1000research.10768.1. eCollection 2017.
• Results Gorschluter M, Marklein G, Hofling K, Clarenbach R, Baumgartner S, Hahn C, Ziske C, Mey U, Heller R, Eis-Hubinger AM, Sauerbruch T, Schmidt-Wolf IG, Glasmacher A. Abdominal infections in patients with acute leukaemia: a prospective study applying ultrasonography and microbiology. Br J Haematol. 2002 May;117(2):351-8. doi: 10.1046/j.1365-2141.2002.03434.x.
• Results Inaba H, Pei D, Wolf J, Howard SC, Hayden RT, Go M, Varechtchouk O, Hahn T, Buaboonnam J, Metzger ML, Rubnitz JE, Ribeiro RC, Sandlund JT, Jeha S, Cheng C, Evans WE, Relling MV, Pui CH. Infection-related complications during treatment for childhood acute lymphoblastic leukemia. Ann Oncol. 2017 Feb 1;28(2):386-392. doi: 10.1093/annonc/mdw557.
• Results Ribeiro ILA, Limeira RRT, Dias de Castro R, Ferreti Bonan PR, Valenca AMG. Oral Mucositis in Pediatric Patients in Treatment for Acute Lymphoblastic Leukemia. Int J Environ Res Public Health. 2017 Nov 28;14(12):1468. doi: 10.3390/ijerph14121468.
• Results Raja RA, Schmiegelow K, Albertsen BK, Prunsild K, Zeller B, Vaitkeviciene G, Abrahamsson J, Heyman M, Taskinen M, Harila-Saari A, Kanerva J, Frandsen TL; Nordic Society of Paediatric Haematology and Oncology (NOPHO) group. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol. Br J Haematol. 2014 Apr;165(1):126-33. doi: 10.1111/bjh.12733. Epub 2014 Jan 15.
• Results Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W, Krull KR, Green DM, Armstrong GT, Nottage KA, Jones KE, Sklar CA, Srivastava DK, Robison LL. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA. 2013 Jun 12;309(22):2371-2381. doi: 10.1001/jama.2013.6296.
• Results Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB. Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol. 2001 Jun 15;19(12):3066-72. doi: 10.1200/JCO.2001.19.12.3066.
• Results Zawitkowska J, Lejman M, Zaucha-Prazmo A, Drabko K, Plonowski M, Bulsa J, Romiszewski M, Mizia-Malarz A, Koltan A, Derwich K, Karolczyk G, Ociepa T, Cwiklinska M, Trelinska J, Owoc-Lempach J, Niedzwiecki M, Kiermasz A, Kowalczyk J. Grade 3 and 4 Toxicity Profiles During Therapy of Childhood Acute Lymphoblastic Leukemia. In Vivo. 2019 Jul-Aug;33(4):1333-1339. doi: 10.21873/invivo.11608.
• Results Boussios S, Pentheroudakis G, Katsanos K, Pavlidis N. Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann Gastroenterol. 2012;25(2):106-118.
• Results Ruiz-Esquide G, Nervi B, Vargas A, Maiz A. [Treatment and prevention of cancer treatment related oral mucositis]. Rev Med Chil. 2011 Mar;139(3):373-81. Epub 2011 Aug 25. Spanish.
• Results Moscardo Guilleme C, Fernandez Delgado R, Sevilla Navarro J, Astigarraga Aguirre I, Rives Sola S, Sanchez de Toledo Codina J, Fuster Soler JL, Parra Ramirez L, Molina Garicano J, Gonzalez Martinez B, Madero Lopez L. [Update on L-asparaginase treatment in paediatrics]. An Pediatr (Barc). 2013 Nov;79(5):329.e1-329.e11. doi: 10.1016/j.anpedi.2013.03.015. Epub 2013 May 31. Spanish.
• Results El-Mahallawy HA, El-Din NH, Salah F, El-Arousy M, El-Naga SA. Epidemiologic profile of symptomatic gastroenteritis in pediatric oncology patients receiving chemotherapy. Pediatr Blood Cancer. 2004 Apr;42(4):338-42. doi: 10.1002/pbc.10394.
• Results Maroun JA, Anthony LB, Blais N, Burkes R, Dowden SD, Dranitsaris G, Samson B, Shah A, Thirlwell MP, Vincent MD, Wong R. Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea. Curr Oncol. 2007 Feb;14(1):13-20. doi: 10.3747/co.2007.96.
• Results Ahern PP, Maloy KJ. Understanding immune-microbiota interactions in the intestine. Immunology. 2020 Jan;159(1):4-14. doi: 10.1111/imm.13150. Epub 2019 Nov 27.
• Results Icaza-Chavez ME. [Gut microbiota in health and disease]. Rev Gastroenterol Mex. 2013 Oct-Dec;78(4):240-8. doi: 10.1016/j.rgmx.2013.04.004. Epub 2013 Nov 28. Spanish.
• Results Hawrelak JA, Myers SP. The causes of intestinal dysbiosis: a review. Altern Med Rev. 2004 Jun;9(2):180-97.
• Results Forsgard RA, Marrachelli VG, Korpela K, Frias R, Collado MC, Korpela R, Monleon D, Spillmann T, Osterlund P. Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats. Cancer Chemother Pharmacol. 2017 Aug;80(2):317-332. doi: 10.1007/s00280-017-3364-z. Epub 2017 Jun 23.
• Results Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, Johnson C, Karlsson EA, Chang TC, Jeha S, Pui CH, Sun Y, Pounds S, Hayden RT, Tuomanen E, Rosch JW. Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia. Clin Infect Dis. 2018 Aug 1;67(4):541-548. doi: 10.1093/cid/ciy153.
• Results Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, Bruley des Varannes S, Le Vacon F, de La Cochetiere MF. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications. Aliment Pharmacol Ther. 2014 Sep;40(5):409-21. doi: 10.1111/apt.12878. Epub 2014 Jul 11.
• Results Reyna-Figueroa J, Barron-Calvillo E, Garcia-Parra C, Galindo-Delgado P, Contreras-Ochoa C, Lagunas-Martinez A, Campos-Romero FH, Silva-Estrada JA, Limon-Rojas AE. Probiotic Supplementation Decreases Chemotherapy-induced Gastrointestinal Side Effects in Patients With Acute Leukemia. J Pediatr Hematol Oncol. 2019 Aug;41(6):468-472. doi: 10.1097/MPH.0000000000001497.
• Results Wei D, Heus P, van de Wetering FT, van Tienhoven G, Verleye L, Scholten RJ. Probiotics for the prevention or treatment of chemotherapy- or radiotherapy-related diarrhoea in people with cancer. Cochrane Database Syst Rev. 2018 Aug 31;8(8):CD008831. doi: 10.1002/14651858.CD008831.pub3.
• Results Alexander JL, Wilson ID, Teare J, Marchesi JR, Nicholson JK, Kinross JM. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol. 2017 Jun;14(6):356-365. doi: 10.1038/nrgastro.2017.20. Epub 2017 Mar 8.
• Results Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: a systematic review. Ann Oncol. 2014 Oct;25(10):1919-1929. doi: 10.1093/annonc/mdu106. Epub 2014 Mar 11.
• Results Lu D, Yan J, Liu F, Ding P, Chen B, Lu Y, Sun Z. Probiotics in preventing and treating chemotherapy-induced diarrhea: a meta-analysis. Asia Pac J Clin Nutr. 2019;28(4):701-710. doi: 10.6133/apjcn.201912_28(4).0005.
• Results Rodriguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N, Avershina E, Rudi K, Narbad A, Jenmalm MC, Marchesi JR, Collado MC. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015 Feb 2;26:26050. doi: 10.3402/mehd.v26.26050. eCollection 2015.
• Results Van den Nieuwboer M, Brummer RJ, Guarner F, Morelli L, Cabana M, Claasen E. The administration of probiotics and synbiotics in immune compromised adults: is it safe? Benef Microbes. 2015 Mar;6(1):3-17. doi: 10.3920/BM2014.0079.

Drugs

Indications