Natural History and Pathophysiology of Gastrointestinal Graft-versus-Host Disease

This study has been withdrawn prior to enrollment.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00723593
First received: July 25, 2008
Last updated: February 19, 2014
Last verified: February 2013
  Purpose

This study will determine the best location to biopsy the gastrointestinal (GI) tract for early and accurate diagnosis of GI graft-versus-host-disease (GVHD). (A biopsy is the surgical removal of a small piece of tissue for examination under the microscope.) GVHD is a life-threatening complication of stem cell transplantation in which the donor s immune cells destroy the patient s healthy tissues. It most commonly affects the skin, liver and GI tract. This study will establish where to best biopsy tissue from the GI tract and study the tissue to try to explore how GI GVD occurs and how it may be possible to better diagnose and treat it.

Patients 18 years of age and older who have undergone or are who will undergo stem cell transplantation and who are at high risk for developing GI GVHD may be eligible for this study. Participants may enter the study before the transplant procedure or later if they develop GVHD symptoms.

Participants undergo the following tests and procedures:

I. Before starting conditioning chemotherapy or radiation therapy for the transplantation

  • Medical history and physical examination
  • Sigmoidoscopy (endoscopy of the lower part of the large intestine) and biopsies
  • Blood draw
  • Stool sample collection

II. Two to 3 weeks after conditioning regimen

  • Sigmoidoscopy with biopsies
  • Blood draw
  • Stool sample collection

III. 30, 45, 60 and 90 days after transplantation

-Blood draw

IV. After completing the tests in part II and at the appearance of GI symptoms suspected to be due to GVHD

  • Updated medical history and physical examination
  • Esophagogastroduodenoscopy (endoscopy of the esophagus, stomach and upper small intestine)
  • Colonoscopy (endoscopy of the entire part of the large intestine) with biopsies
  • Blood draw
  • Stool collection

V. Two weeks after starting therapy in patients diagnosed with GVHD

  • Sigmoidoscopy with biopsies
  • Blood draw
  • Stool sample collection
  • PET/CT scan in selected patients (nuclear medicine and x-ray imaging of the GI tract

Condition
Graft-Versus-Host-Disease

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: Natural History and Pathophysiology of Gastrointestinal Graft Versus Host Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Enrollment: 0
Study Start Date: July 2008
Estimated Study Completion Date: February 2013
Detailed Description:

Graft-versus-host disease (GVHD) affects up to 70% of patients who undergo stem cell transplantation. GVHD is associated with significant morbidity and mortality, and commonly affects the skin, liver, and gastrointestinal (GI) system. Gastrointestinal (GI) manifestations of GVHD include anorexia, nausea, vomiting, abdominal pain, and diarrhea. In patients with GI GVHD, the extent of gut involvement and its relationship to underlying symptoms is unclear. Furthermore, diagnosis requires histologic evaluation that entails cumbersome invasive endoscopic procedures for tissue procurement. Histologic findings that support this diagnosis are nonspecific and have poor sensitivity and specificity. Treatment of GI GVHD is also nonspecific, and has many systemic side effects that account for a large portion of associated morbidity and mortality.

Such uncertainties regarding the diagnosis and treatment of GI GVHD stem from a lack of understanding of the pathophysiology of the disease. Cytokines produced by T lymphocytes, mononuclear phagocytes, and natural killer cells have been shown to play an integral role in the regulation of tissue damage. Human studies performed to date have examined peripheral blood cytokines, but results have been conflicting and with little clinical correlation. Current analysis of gut tissue has been limited mostly to animal subjects with little correlation to humans.

The primary objective of this study is to identify areas of the GI tract to be biopsied that would achieve the highest yield for the diagnosis of GI GVHD. This will be accomplished by performing esophagogastroduodenoscopy, colonoscopy, and ileoscopy in all post transplant patients with GI symptoms, suspected to be due to GVHD. Endoscopic biopsies will be evaluated by a single designated GI pathologist to make the diagnosis of GVHD. A novel application of a quantitative histological apoptotic assay will be evaluated in a blinded fashion for its diagnostic utility. A GVHD diagnostic yield rate for each area of the GI tract will be the primary outcome measure.

Other biopsies obtained at baseline, following the conditioning regimen as well as before and after therapy for GI GVHD will be used to achieve the secondary objective of understanding the immune response underlying GI GVHD. A comprehensive evaluation of the inflammatory milieu of gut tissues will be achieved using immunohistochemistry and flow cytometric immunophenotyping of mucosal mononuclear cells and microarray, qRT-PCR and ELISA of mucosal cytokines. Other secondary objectives include the evaluation of serum proteomic pattern analysis, serum citrulline, fecal calprotectin and 18F-FDG PET/CT for the noninvasive diagnosis of GI GVHD.

Better understanding of the pathophysiology of GI GVHD will allow us to develop more focused and effective diagnostic and therapeutic options that are less invasive and have fewer systemic side effects leading to reduced morbidity and mortality.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

All patients 18 years or older who have undergone or plan to undergo any type of allogeneic bone marrow or peripheral stem cell transplant. (This will be coordinated with all different institutes at NIH to involve patients who participate in NIH affiliated protocols.)

EXCLUSION CRITERIA:

  1. Patients who are under the age of 18 years.
  2. Patients with a platelet count less than 30,000/mm(3).
  3. Patients with an elevated prothrombin or partial thromboplastin time more than 1.5 times greater than the upper limit of normal or an absolute neutrophil count less than 500/mm(3) of blood or a history of a bleeding diathesis.
  4. Women who are pregnant, as determined by laboratory evaluation performed according to the referring transplant protocol, or breast feeding.
  5. Patients who are unable to provide informed consent.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00723593

Sponsors and Collaborators
Investigators
Principal Investigator: Stephen A Wank, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00723593     History of Changes
Other Study ID Numbers: 080187, 08-DK-0187
Study First Received: July 25, 2008
Last Updated: February 19, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Graft-Versus-Host Disease
Gastrointestinal
Apoptotic Assay
Serum Proteomic Pattern Analysis
Mucosal Biopsy
Graft Versus Host Disease
GVHD

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases

ClinicalTrials.gov processed this record on August 28, 2014