@article {1619413, title = {National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report}, journal = {Transplant Cell Ther}, volume = {27}, number = {10}, year = {2021}, month = {2021 10}, pages = {817-835}, abstract = {Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.}, keywords = {Chronic Disease, Consensus, Graft vs Host Disease, Humans, Incidence, National Institutes of Health (U.S.), Quality of Life, United States}, issn = {2666-6367}, doi = {10.1016/j.jtct.2021.06.001}, author = {Wolff, Daniel and Radojcic, Vedran and Lafyatis, Robert and Cinar, Resat and Rosenstein, Rachel K and Cowen, Edward W and Cheng, Guang-Shing and Sheshadri, Ajay and Bergeron, Anne and Williams, Kirsten M and Todd, Jamie L and Teshima, Takanori and Cuvelier, Geoffrey D E and Holler, Ernst and McCurdy, Shannon R and Jenq, Robert R and Hanash, Alan M and Jacobsohn, David and Santomasso, Bianca D and Jain, Sandeep and Ogawa, Yoko and Steven, Philipp and Luo, Zhonghui Katie and Dietrich-Ntoukas, Tina and Saban, Daniel and Bilic, Ervina and Penack, Olaf and Griffith, Linda M and Cowden, Meredith and Martin, Paul J and Greinix, Hildegard T and Sarantopoulos, Stefanie and Socie, Gerard and Blazar, Bruce R and Pidala, Joseph and Kitko, Carrie L and Couriel, Daniel R and Cutler, Corey and Schultz, Kirk R and Pavletic, Steven Z and Lee, Stephanie J and Paczesny, Sophie} }