Pre-clinical animal models and clinical trials have demonstrated the inter-relationships between bacterial infections and onset of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT). Pre-existing acute GVHD is one of the strongest predictors for development of chronic GVHD, the most common cause of mortality in survivors beyond two years after HCT. Inhibition, of T cell activation and GVHD prophylaxis approaches, have not significantly improved acute GVHD incidence and severity rates. We hypothesize that reducing or minimizing the impact of bacterial microbes in the post-engraftment phase with potent, well-tolerated antibacterials will reduce infections in immuno-compromised allogeneic HCT recipients and lower the likelihood that the infused graft will be more activated against the host and thereby reduce the severity of GVHD. Decreasing post-engraftment infections will reduce the release of pro-inflammatory cytokines/other mediators, lower acute GVHD and subsequently chronic GVHD, and contribute to better long- term treatment outcomes.
Specific Aims are: 1. Determine if use of prophylactic antibacterial agents prevent infection in the post-engraftment phase of allogeneic HCT. We will utilize a randomized, double-blinded, placebo-controlled trial design to show if susceptible bacterial infections can be prevented or reduced using antibacterial prophylaxis (moxifloxacin) in the post-engraftment phase (up to 100 days) after allogeneic HCT. Secondary objectives include determination of cumulative incidence of non-relapse mortality, acute and chronic GVHD rates and determination of overall survival of each cohort. 2. Determine the incidence and the onset of antibiotic resistance in all breakthrough bacterial isolates obtained from patients receiving placebo versus moxifloxacin study drug. This effort will be critical to understanding whether selection and emergence of multi-drug-resistant bacteria could be a detrimental consequence of extended antibiotic prophylaxis. 3. Determine differences in genetic, transcriptional, and proteomic biomarkers in patients receiving placebo versus study drug. This objective prospectively will identify biomarkers, including candidate molecules such as IL-113, IL-6, IL-1 Ra, IL-10 and TNF-a and other markers of immune engraftment and GVHD that may predict for risk of infection after HCT. Biostatisticians will perform multivariate analyses to identify the link between laboratory marker and clinical events (immune-dysregulation with acute and chronic GVHD, regimen-related toxicity and overall outcome). This approach will lead to creation of a risk profile for infection and GVHD. We will employ companion protocols developed within the BMT CTN.

Public Health Relevance

Hematologic malignancies will account for 137,260 new cases and 54,020 deaths in the United States in 2010. HCT has made a significant impact upon improving outcome in this patient population. Distinct and critical barriers to further advances in HCT are infection and GVHD. Our proposed investigations using prophylactic antibacterials have the potential to reduce bacterial infections and GVHD in the post-engraftment phase of allogeneic HCT.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Cooperative Clinical Research--Cooperative Agreements (U10)
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Special Emphasis Panel (ZHL1-CSR-K (M3))
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Di Fronzo, Nancy L
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Steering Committee Of The Blood And Marrow Transplant Clinical Trials Network (2016) The Blood and Marrow Transplant Clinical Trials Network: An Effective Infrastructure for Addressing Important Issues in Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:1747-1757
Yanik, Gregory A; Horowitz, Mary M; Weisdorf, Daniel J et al. (2014) Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials ne Biol Blood Marrow Transplant 20:858-64
Ferrara, James L M (2014) Blood and Marrow Transplant Clinical Trials Network: progress since the State of the Science Symposium 2007. Biol Blood Marrow Transplant 20:149-53
Giralt, Sergio; McCarthy, Philip L; Anderson, Kenneth C et al. (2013) Anatomy of a successful practice-changing study: a Blood and Marrow Transplantation Clinical Trials Network-National Cancer Institute Cooperative Group collaboration. Biol Blood Marrow Transplant 19:858-9
Vose, Julie M; Carter, Shelly; Burns, Linda J et al. (2013) Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT C J Clin Oncol 31:1662-8
BolaƱos-Meade, Javier; Wu, Juan; Logan, Brent R et al. (2013) Lymphocyte phenotype during therapy for acute graft-versus-host disease: a brief report from BMT-CTN 0302. Biol Blood Marrow Transplant 19:481-5
Mauskopf, Josephine; Chirila, Costel; Graham, Jon et al. (2013) Comparative cost-effectiveness analysis of voriconazole and fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants. Am J Health Syst Pharm 70:1518-27
Pasquini, Marcelo C; Devine, Steven; Mendizabal, Adam et al. (2012) Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transpl J Clin Oncol 30:3194-201
Levine, John E; Logan, Brent R; Wu, Juan et al. (2012) Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood 119:3854-60
McCarthy, Philip L; Owzar, Kouros; Hofmeister, Craig C et al. (2012) Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-81

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