Original Article

Azithromycin for Prevention of Graft-Versus-Host Disease: A Randomized Placebo-Controlled Trial


Background: Allogeneic hematopoietic stem cell transplantation has been used widely to treat various types of malignant and non-malignant disorders. Graft-versus-host disease is one of the main complications of this procedure which is associated with considerable mortality and affects quality of life. Despite careful selection of HLA-matched donors and implementing immunosuppressive therapy, the incidence rate of graft-versus-host disease remains high. Macrolide antibiotics are well-known immunomodulatory agents and have been effective as prophylaxis for graft-versus-host disease in preclinical studies.
Materials and Methods: Ninety-six adult patients with acute leukemia were recruited into a double-blind, randomized, placebo-controlled trial. All patients were first-time transplant candidates for a full-matched related or unrelated donor. Patients were allocated to receive azithromycin 500 mg daily (n=48) or placebo (n=48) from day -6 to +12. All patients received high-dose chemotherapy, standard immunosuppressive regimen and supportive care according to institutional protocols.
Results: The incidence of acute graft-versus-host disease grade III-IV and chronic graft-versus-host disease garde I-III was not significantly different between the two study arms. Oral mucositis grade 1-3 occurred in significantly lower number of patients in the azithromycin group compared with placebo.
Conclusion: Based on the results of this study, protective effect of azithromycin on graft-versus-host disease could not be demonstrated.



Marks DI, Alonso L, Radia R. Allogeneic hematopoietic cell transplantation in adult patients with acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2014; 28(6):995-1009.

Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease. N Engl J Med. 2009;361(24):2309-17.

Sengsayadeth S, Savani BN, Blaise D, et al. Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission - a review from the Acute Leukemia Working Party of the EBMT. Haematologica. 2015;100(7):859-69.

Cooke KR, Olkiewicz K, Erickson N, et al. The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. J Endotoxin Res. 2002;8(6):441-8.

Ball LM, Egeler RM, et a.l Acute GvHD: pathogenesis and classification. Bone Marrow Transplant. 2008;41 Suppl 2:S58-64.

Armand P, Kim HT, Sainvil MM, et al. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol. 2016;173(1):96-104.

Windreich RM, Goyal RK, Joshi R, et al. A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients. Biol Blood Marrow Transplant. 2016;22(4):682-689.

Kanoh S, Rubin BK. Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications. Clin Microbiol Rev. 2010 Jul;23(3):590-615.

Murphy DM, Forrest IA, Corris PA, et al. Azithromycin attenuates effects of lipopolysaccharide on lung allograft bronchial epithelial cells. J Heart Lung Transplant. 2008;27(11):1210-6.

Iwamoto S, Azuma E, Kumamoto T, et al. Efficacy of azithromycin in preventing lethal graft-versus-host disease. Clin Exp Immunol. 2013;171(3):338-45.

Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-56.

WHO handbook for reporting results of cancer treatment - See more at: http://apps.who.int/iris/handle/10665/37200#sthash.kZJyux8Z.dpuf : Geneva : World Health Organization; 1979. Available from: http://www.who.int/iris/handle/10665/37200.

Carnevale-Schianca F, Leisenring W, Martin PJ, et al. Longitudinal assessment of morbidity and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation: retrospective analysis of a multicenter phase III study. Biol Blood Marrow Transplant. 2009;15(6):749-56.

Socié G, Schmoor C, Bethge WA, et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011;117(23):6375-82.

Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100(9 Suppl):1995-2025.

Aghai ZH, Kode A, Saslow JG, et al. Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants. Pediatr Res. 2007;62(4):483-8.

Cheung PS, Si EC, Hosseini K. Anti-inflammatory activity of azithromycin as measured by its NF-kappaB, inhibitory activity. Ocul Immunol Inflamm. 2010;18(1):32-7.

Blandizzi C, Malizia T, Lupetti A, et al. Periodontal tissue disposition of azithromycin in patients affected by chronic inflammatory periodontal diseases. J Periodontol. 1999;70(9):960-6.

IssueVol 12, No 2 (2018) QRcode
SectionOriginal Article(s)
Azithromycin Graft-versus-host disease Mucositis

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Barkhordar M, Mohammadi M, Shamshiri AR, Hadjibabaie M, Ghavamzadeh A. Azithromycin for Prevention of Graft-Versus-Host Disease: A Randomized Placebo-Controlled Trial. Int J Hematol Oncol Stem Cell Res. 2018;12(2):77-83.