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Published in final edited form as: Biol Blood Marrow Transplant. 2008 Apr;14(4):379–384. doi: 10.1016/j.bbmt.2008.01.005

Chronic Graft-versus-Host Disease - Implementation of the National Institutes of Health Consensus Criteria for Clinical Trials

Linda M Griffith 1, Steven Z Pavletic 2, Stephanie J Lee 3, Paul J Martin 4, Kirk R Schultz 5, Georgia B Vogelsang 6
PMCID: PMC2293302  NIHMSID: NIHMS43828  PMID: 18342779

Based on collaborative discussions of the community of hematopoietic cell transplant (HCT) physicians, the National Institutes of Health (NIH) Consensus Criteria for Clinical Trials in Chronic Graft-versus-Host Disease (GVHD) established for the first time comprehensive diagnostic, staging, and response criteria for chronic GVHD. The recommendations from this group were published in a series of articles in this journal1-6. Implementation of the criteria and follow-up research are needed to ensure continued progress. Therefore, representatives of the national and international chronic GVHD community met in Bethesda, MD, on March 8 and 9, 2007 to report on continuing studies, identify unmet needs and consider future options. Here, we summarize findings of the two day meeting and the present spectrum of activities in the field of chronic GVHD.

I. Diagnosis, staging and response criteria

There is considerable need to evaluate the diagnosis, staging and response criteria prospectively in clinical trials and retrospectively using existing databases. It is highly likely that refinements will be needed, since such criteria should always be considered a “work in progress” as clinical practice and treatments evolve over time. Challenges to completion of validation studies include the large number of patients from multiple centers required for an adequate statistical evaluation, the protracted time frame needed for adequate observation, and funding needed to support the effort. Jagasia et al7 and Arora et al8 have recently completed the first single-site retrospective validation studies of the diagnosis and staging criteria. These studies showed a correlation of GVHD subtype (late acute versus classic chronic) and severity with overall survival. At the workshop, Jacobsohn and Vogelsang presented a comparison of the Johns Hopkins Hospital skin response criteria as used in the recently published pentostatin trial9 with the NIH consensus response criteria. Their data showed that the two scales had similar and complementary, although not identical, properties. Mitchell et al10 have performed a small assessment of feasibility and reproducibility of the NIH response criteria in a prospective study conducted at multiple sites in the United States (US). A large prospective cohort investigation has recently received NIH funding and is led by S. Lee of Fred Hutchinson Cancer Research Center (FHCRC). A validation project is currently underway led by D. Wolff and the German / European Union (EU) collaborative group11.

II. Organ-specific research and ancillary and supportive care

Because the multiple-organ clinical manifestations of chronic GVHD can persist for prolonged periods of time, supportive care is critical in long-term management. Since there is a profound lack of data in these areas, most of the NIH consensus recommendations are based on extrapolation of clinical results from other fields of medicine. To conduct trials in this area it will be essential to develop organ-specific severity scales, which will require long term data. Research addressing organ dysfunction includes skin, pulmonary and oral mucosal complications and conjunctival therapeutic intervention studies. The bronchiolitis obliterans syndrome (BOS) is a rare, but devastating, complication in need of improved diagnostic criteria and therapy12. Studies of oral mucosa suggest that immunologic features of chronic GVHD might be quantified by immunohistochemistry. This type of research represents an opportunity to study the immunologic processes of chronic GVHD directly at the anatomic site of the disease13.

III. Biology, biomarkers and new targets

Chronic GVHD is remarkable for lack of insight into the basic biology of the disease. Because of this, there are no validated biomarkers. Targeted drug therapy has been impaired by this absence of specific immunologic targets. Preclinical mouse models that approximate the full spectrum of human chronic GVHD are lacking, although there are several useful models that demonstrate selected aspects of the disease process (reviewed by Shlomchik et al14; Chu and Gress15). The long duration of follow-up required to assess murine chronic GVHD has inhibited both the development and utilization of these models. Prior studies using patient samples have focused mainly on peripheral blood, which likely misses mechanisms that function within tissues affected by chronic GVHD. Studies to characterize new biomarkers and confirm or refute those suggested by smaller studies in chronic GVHD will require large numbers of samples linked to detailed information on the clinical course. Small studies have suggested a role for diverse immunologic cells / soluble factors including T cells and T cell subsets, thymic dependent and independent pathways of T cell recovery, B cells and B cell subsets, and B cell activating factor (BAFF)16-19. For example, four inflammatory plasma markers and an activated B cell population identified as potential biomarkers in chronic GVHD in a study performed by the Children's Oncology Group (COG) will require validation in a larger population that includes adults16,17. Larger cooperative studies, in particular those conducted by the EU, have included examination of gene polymorphisms in chronic GVHD20, 21, and proteomics studies22.

IV. Graft-versus-leukemia (GVL) effects

Growing clinical evidence suggests a major contribution of chronic GVHD in mediating allogeneic GVL effects. Research in this important area is lacking and efforts to investigate the pathophysiologic basis of the GVL effect as compared to the GVHD effect should be pursued. Representative presentations at the workshop addressed preclinical models and their limitations, T cell and B cell aspects of the GVL effect, and the role of hematopoietic chimerism. The possibility of a humoral component in the GVL effect, in addition to the documented T cell contribution, was discussed23-27. The relation of chronic GVHD biomarkers to the GVL effect will be investigated in the COG study of GVHD prophylaxis for children receiving allogeneic HCT for acute lymphoblastic leukemia (see also #NCT00382109 at www.ClinicalTrials.gov).

V. Therapeutic clinical trials

Regarding design of clinical trials in chronic GVHD in general, the selection of short term endpoints was emphasized as key, including consideration of composite endpoints. Challenges to endpoint design include lack of validated short-term predictors (less than 6 months) of the more long-term outcomes (years) of the natural history of chronic GVHD, as well as the obvious need for validation studies of response criteria in chronic GVHD. The trajectory of disease progression should be given more attention when patients are enrolled in a clinical trial. For example, stabilization of disease manifestations could be considered a benefit in a patient with rapidly progressive chronic GVHD manifestations but not in those with improving or stable manifestations before an intervention. Biological markers that could be used as short term predictors of therapeutic benefit would be especially helpful for early drug development trials in chronic GVHD. Results from recent relatively small phase II studies suggestive of benefit from extracorporeal photopheresis (ECP) and Rituximab (humanized anti-CD20) for the treatment chronic GVHD were presented28,29. Multi-center studies of mycophenolate mofetil (MMF) and its enteric coated formulation as an adjunct to standard front line chronic GVHD therapy are currently underway in the US led by P. Martin at FHCRC (see also #NCT00089141 at www.ClinicalTrials.gov) and in Europe led by G. Socie (#NCT00298324 at www.ClinicalTrials.gov) respectively.

VI. Resources - transplant networks and clinical trials consortia

The total number of patients with chronic GVHD is small, so that chronic GVHD qualifies as a “rare disease”, even though as many as half of all patients undergoing allogeneic HSCT experience this complication. Cooperative clinical studies in chronic GVHD will be needed to accomplish progress in the field. There is a corresponding need to identify the type of infrastructure that will best facilitate such multi-center projects. Both national and international clinical collaborations should be strongly encouraged. In the US, one or more existing networks, for example the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), may be well positioned to provide the type of infrastructure needed. In the recent “BMT CTN State of the Science Symposium”30, chronic GVHD was identified as an area of immediate need for both intensive studies of disease mechanisms as well as therapeutic clinical trials. A proposal for a prospective multi-center clinical trial in chronic GVHD that would be coupled with immunologic ancillary studies is currently in development by the consortium. The Pediatric Blood and Marrow Transplant Consortium (PBMTC), which is a member of the BMT CTN, is an important resource for study of aspects of chronic GVHD. The database of the Center for International Blood and Marrow Transplant Research (CIBMTR), which contains information on over 240,000 HCT procedures performed worldwide, serves as a unique and perhaps insufficiently utilized resource available for retrospective analyses in HCT including chronic GVHD. Practical aspects of International collaborations were discussed at the workshop by representatives of the European Group for Blood and Marrow Transplantation (EBMT), the BMT CTN, and the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP).

VII. Resources – investigator initiated research

Availability of funding support for studies in chronic GVHD has been extremely limited. The standard NIH Research Project (R01) format may not be a good fit for applications in chronic GVHD which need a multi-center or inter-disciplinary clinical trials design. For chronic GVHD in particular, the relatively small number of cases, with lack of clear assignment of responsibility to a single NIH Institute / Center (IC) presents an additional challenge in applying for and successfully obtaining NIH funding. However, even in this era of relative fiscal constraint for the NIH, using the National Institute of Allergy and Infectious Diseases (NIAID) as an example, over half of the annual budget of the Division of Allergy, Immunology and Transplantation (DAIT) remains available for investigator-initiated research, representing a significant opportunity31. It may be reasonable to consider cooperation of NIH ICs having a direct or partial interest in chronic GVHD studies, or support through existing networks or other consortia, when developing a funding plan for large cooperative clinical trials. A Program Project (P01) approach may be appropriate. Interactive discussions with US Government funding agencies should be pursued, to promote intramural and extramural NIH and government-wide collaborations where feasible. Investigators should approach NIH ICs with their proposals for joint ventures. It's likely that the NIH would view collaborative efforts which result in elimination of redundant funding or cost saving as advantageous. Opportunities for funding other than NIH should be considered, including other US Government agencies, such as, for example, the Food and Drug Administration (FDA) Office of Orphan Products Development, as well as private foundations such as the Biomarkers Consortium of the Foundation for the NIH, and others.

Acknowledgments

The opinions expressed are those of the authors and do not represent the position of the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Institutes of Health, or the US Government.

This workshop was sponsored by the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the Office of Rare Diseases, National Institutes of Health, Bethesda, MD, USA.

Appendix: Workshop Participants

Co-Chairs

Linda M. Griffith, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD; Steven Z. Pavletic, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD

Session Chairs and Speakers

Barry D. Anderson, National Cancer Institute, Bethesda, MD; Joseph H. Antin, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Mukta Arora, Center for International Blood and Marrow Transplant Research (CIBMTR), University of Minnesota, Minneapolis, MN; Kristin Baird, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Paul A. Carpenter, Fred Hutchinson Cancer Research Center, Seattle, WA; Jason W. Chien, Fred Hutchinson Cancer Research Center, Seattle, WA Daniel R. Couriel, MD Anderson Cancer Center, University of Texas, Houston, TX; Corey S. Cutler, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Anne M. Dickinson, University of Newcastle-Upon-Tyne, Newcastle-Upon-Tyne, UK; James L. M. Ferrara, University of Michigan, Ann Arbor, MI; Mary E. D. Flowers, Fred Hutchinson Cancer Research Center, Seattle, WA; Thea M. Friedman, Hackensack University Medical Center, Hackensack, NJ; Hildegard T. Greinix, Vienna Medical School, Vienna, Austria; Ronald E. Gress, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Fran Hakim, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Lee J. Helman, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD; *Ernst Holler, University Hospital Regensburg, Regensburg, Germany; Matin M. Imanguli, Center for Cancer Research, National Cancer Institute, Bethesda, MD; David A. Jacobsohn, Children's Memorial Hospital, Chicago, IL; Madan Jagasia, Vanderbilt University, Nashville, TN; David Kleiner, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Stephanie J. Lee, Fred Hutchinson Cancer Research Center, Seattle, WA; Paul J. Martin, Fred Hutchinson Cancer Research Center, Seattle, WA; George B. McDonald, Fred Hutchinson Cancer Research Center, Seattle, WA; Joseph P. McGuirk, University of Missouri, Kansas City, MO; Sandra Mitchell, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Dietger W. Niederwieser, University of Leipzig, Leipzig, Germany; Tan T. Nguyen, Office of Orphan Products Development, Food and Drug Administration, Rockville, MD; Donna Przepiorka, University of Tennessee, Memphis, TN; Christoph Rader, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Pavan Reddy, University of Michigan, Ann Arbor, MI; Kirk R. Schultz, University of British Columbia, Vancouver, BC, Canada; Sam S. Shekar, Office of Extramural Research, Office of Director, NIH, Bethesda, MD; Warren D. Shlomchik, Yale University School of Medicine, New Haven, CT; Howard Shulman, Fred Hutchinson Cancer Research Center, Seattle, WA; Janine A. Smith, National Eye Institute, Bethesda, MD; *Georgia B. Vogelsang, Johns Hopkins University School of Medicine, Baltimore, MD; Daniel Weisdorf, University of Minnesota, Minneapolis, MN; Eva M. Weissinger, Hannover Medical School, Hannover, Germany; Daniel Wolff, University of Rostock, Rostock, Germany

Discussants

Gorgun Akpek, University of Maryland, Baltimore, MD; Robert Baitty, Health Resources and Services Administration (HRSA), Rockville, MD; F. Javier Bolanos-Meade, Johns Hopkins University School of Medicine, Baltimore, MD; Sivasubramanian Baskar, Center for Cancer Research, National Cancer Institute, Bethesda, MD; L. Michelle Bennett, Office of the Director, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Rachel J. Bishop, National Eye Institute, NIH, Bethesda, MD; Henry Chang, National Heart, Lung and Blood Institute, NIH, Bethesda, MD; Nelson J. Chao, Duke University Medical Center, Durham, NC; Edward W. Cowen, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Manuel B. Datiles, National Eye Institute, NIH, Bethesda, MD; Nancy L. DiFronzo, National Heart, Lung and Blood Institute, NIH, Bethesda, MD; Patricia A. Dinndorf, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD; Raymond A. Dionne, National Institute for Nursing Research, NIH, Bethesda, MD; John F. DiPersio, Washington University, St. Louis, MO; Jane M. Fall-Dickson, National Institute for Nursing Research, NIH, Bethesda, MD; Daniel H. Fowler, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Nancy L. Geller, National Heart, Lung and Blood Institute, NIH, Bethesda, MD; Andrew Gilman, University of North Carolina, Chapel Hill, NC; Jean-Pierre Guadagnini, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD; Robert J. Hartzman, Naval Medical Research Center, Rockville, MD; Lee Ann Jensen, National Cancer Institute, Bethesda, MD; Laura Johnston, Stanford University School of Medicine, Stanford, CA; Carrie Lynn Kitko, University of Michigan, Ann Arbor, MI; Robert Korngold, Hackensack University Medical Center, Hackensack, NJ; Li Li, Clinical Center, NIH, Bethesda, MD; Haresh Mani, Center for Cancer Research, National Cancer Institute, Bethesda, MD; James G. McNamara, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD; William D. Merritt, National Cancer Institute, NIH, Bethesda, MD; Phyllis I. Mitchell, National Heart, Lung and Blood Institute, NIH, Bethesda, MD; Tan T. Nguyen, Office of Orphan Products Development, Food and Drug Administration, Rockville, MD; Iskra Pusic, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Scott D. Rowley, Hackensack University Medical Center, Hackensack, NJ; Benjamin I. Rubin, National Eye Institute, NIH, Bethesda, MD; Denise Russo, Office of Extramural Research, Office of the Director, NIH, Bethesda, MD; Robert A. Sokolic, National Human Genome Research Institute, NIH, Bethesda, MD; Maria L. Turner, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Marcel R. M. van den Brink, Memorial Sloan Kettering Cancer Center, New York, NY; Dan Wang, Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, MN; Alan S. Wayne, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Kirsten M. Williams, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Josiah F. Wedgwood, National Institute of Allergy and Infectious Diseases, Bethesda, MD; Roy S. Wu, National Cancer Institute, Bethesda, MD

Footnotes

*

Dr. Holler and Dr. Vogelsang contributed substantially to presentations at this meeting, although they were unable to attend personally.

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Contributor Information

Linda M. Griffith, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Steven Z. Pavletic, Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Stephanie J. Lee, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.

Paul J. Martin, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA.

Kirk R. Schultz, University of British Columbia, Vancouver, BC, Canada.

Georgia B. Vogelsang, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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