Browsing by Author "Hakim, Frances T."

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease
    (Elsevier, 2017-02) Cooke, Kenneth R.; Luznik, Leo; Sarantopoulos, Stefanie; Hakim, Frances T.; Jagasia, Madan; Fowler, Daniel H.; van den Brink, Marcel R. M.; Hansen, John A.; Parkman, Robertson; Miklos, David B.; Martin, Paul J.; Paczesny, Sophie; Vogelsang, Georgia; Pavletic, Steven; Ritz, Jerome; Schultz, Kirk R.; Blazar, Bruce R.; Department of Pediatrics, School of Medicine
    Chronic graft-versus-host disease (GVHD) is the leading cause of late, nonrelapse mortality and disability in allogeneic hematopoietic cell transplantation recipients and a major obstacle to improving outcomes. The biology of chronic GVHD remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: • Summarize the current state of the science regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps. • Develop working hypotheses/overriding concepts for chronic GVHD development. • Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies. • Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.
  • Thumbnail Image
    Item
    Characterization of Hepatic Dysfunction in subjects diagnosed with Chronic GVHD by NIH Consensus Criteria
    (Elsevier, 2022) Yang, Alexander H.; Han, Ma Ai Thanda; Samala, Niharika; Rizvi, Bisharah S.; Marchalik, Rachel; Etzion, Ohad; Wright, Elizabeth C.; Cao, Liang; Hakim, Frances T.; Jones, Elizabeth; Kapuria, Devika; Hickstein, Dennis D.; Fowler, Daniel; Kanakry, Jennifer A.; Kanakry, Christopher G.; Kleiner, David E.; Koh, Christopher; Pavletic, Steven Z.; Heller, Theo; Medicine, School of Medicine
    Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality.
  • Thumbnail Image
    Item
    National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease: III. The 2014 Biomarker Working Group Report
    (Elsevier B.V., 2015-05) Paczesny, Sophie; Hakim, Frances T.; Pidala, Joseph; Cooke, Kenneth; Lathrop, Julia; Griffith, Linda M.; Hansen, John; Jagasia, Madan; Miklos, David; Pavletic, Steven; Parkman, Robertson; Russek-Cohen, Estelle; Flowers, Mary E.D.; Lee, Stephanie; Martin, Paul; Vogelsang, Georgia; Walton, Marc; Schultz, Kirk R.; Department of Pediatrics, IU School of Medicine
    Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic GVHD after allogeneic hematopoietic cell transplantation (HCT) or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include: a) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity, b) prognostic risk to develop chronic GVHD, and c) prediction of response to therapy. Sample collection for chronic GVHD biomarkers studies should be well-documented following established quality control guidelines for sample acquisition, processing, preservation and testing, at intervals that are both calendar- and event-driven. The consistent therapeutic treatment of subjects and standardized documentation needed to support biomarker studies are most likely to be provided in prospective clinical trials. To date, no chronic GVHD biomarkers have been qualified for utilization in clinical applications. Since our previous chronic GVHD Biomarkers Working Group report in 2005, an increasing number of chronic GVHD candidate biomarkers are available for further investigation. This paper provides a four-part framework for biomarker investigations: identification, verification, qualification, and application with terminology based on Food and Drug Administration and European Medicines Agency guidelines.