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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 817-835 |
| Number of pages | 19 |
| Journal | Transplantation and Cellular Therapy |
| Volume | 27 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2021 |
Bibliographical note
Funding Information:Financial disclosure: Supported by the Intramural Program of the National Cancer Institute – Center for Cancer Research, the NIH Intramural and Extramural Research Programs Institutes and Centers. D.W. is a consultant for Novartis, Incyte, Syndax, Pfizer, and Behring; receives honoraria from Mallinckrodt, MACO, Takeda, and Neovii. V.R. is a consultant for Regeneron. R.L. is a consultant for Pfizer, Bristol Myers Squibb, Boehringer-Ingelheim, Formation, Sanofi, Boehringer-Mannheim, Merck and Genentech/Roche; receives research support from Corbus, Formation, Moderna, Regeneron, Pfizer, and Kinksa. R.C. is co-inventor on U.S. patents covering hybrid CB 1 R/ inducible nitric oxide synthase antagonists. S.L. receives research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda; is a member of a steering committee for Incyte. O.P. receives honoraria or travel support from Astellas, Gilead, Jazz, MSD, Neovii Biotech, Novartis, Pfizer, and Therakos; research support from Gilead, Incyte, Jazz, Neovii Biotech, and Takeda; is an advisory board member of Jazz, Gilead, MSD, Omeros, Shionogi, and SOBI. T.T. receives grants from Kyowa Kirin, Chugai, Sanofi, Astellas, Teijin Pharma, Fuji Pharma, and Nippon Shinyaku; honoraria from Novartis, Merck, Kyowa Kirin, Takeda, Pfizer, Bristol-Myers Squibb, and Janssen. B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; research funding from BlueRock Therapeutics and Rheos Medicines; is a steering committee member for Kadmon Corporation; is a co-founder of Tmunity Therapeutics. A.B. receives research grants from SOS Oxygen; honoraria from Zambon, Shire, Pfizer, and Gilead. A.S. receives consulting fees from Psioxus Therapeutics. S.J. is a consultant for Ocugen Inc., and Neutrolis Inc.; has personal financial interest in Advaite, Inc., and Selagine Inc.; holds patents US9867871B2 and PCT/US19/60566. P.S. is a consultant for GSK, Bausch+Lomb, Ursapharm Arzneimittel GmbH; receives research funding from Roche. Y.O. has a patent in Japan (patent no. 4966019; Name; Topical application and oral intake of tranilast for the treatment of chronic GVHD-related dye eye disease) and patent application number JP 2017-018643 published as JPA2017-178922, application number JP2018-510646 published as WO2017/175808 and application number JP 2019-004730 published as JPA2020-111548. Z.K.L. has U.S. patent filed by Glia LLC on oGVHD treatment; receives research funding from Glia LLC. T.D-N. receives honoraria from Alcon/Novartis, Santen, Alimera Sciences, and Bayer. D.R.S. is a consultant for Dompé and Roche; receives financial support from Dompé and Novartis. S.R.McC. receives grant/research/clinical trial support from Gilead Sciences, Aprea Therapeutics, and McCabe Fund. P.J.M. is on the advisory boards for Mesoblast and Rigel Pharmaceuticals Inc.; receives honoraria from Janssen. J.L.T. receives research support from Boehringer Ingelheim, CareDx, and AstraZeneca. J.P. has consulting and advisory board membership for Syndax, CTI Biopharma, Amgen, Regeneron, Incyte; receives clinical trial support from Novartis, Amgen, Takeda, Janssen, Johnson & Johnson, Pharmacyclics, Abbvie, CTI Biopharma, BMS. D.R.C. is a consultant for Fresenius Kabi and Incyte; a non-promotional speaker for Mallinckrodt. E.H. is on the advisory board for Novartis, Medac, and Maat-Pharma; receives honoraria from Novartis, Neovii. C.C. receives consulting honoraria from Incyte, Jazz, CareDx, Mesoblast, Syndax, Omeros, Pfizer. H.T.G. receives honoraria for presentations in scientific meetings and consultations from Novartis, Celgene/BMS, Sanofi, Janssen, and Therakos. S.S. serves on the advisory board for Rigel Pharmaceuticals, Inc. R.R.J. receives consultant role fees from Merck, Karius, and Microbiome DX; advisory member role fees from Seres, Kaleido, MaaT Pharma, Prolacta, and LISCure; patent licensing fees from Seres. A.M.H. holds intellectual property related to Interleukin-22. B.D.S. receives consulting honoraria from Janssen/Legend, Celgene, Kite/Gilead, and BMS; is an advisory board member for In8bio. G-S.C. is a consultant for Janssen Pharmaceutica. S.P. holds intellectual property on Biomarkers and assay to detect chronic graft versus host disease
Funding Information:
Special acknowledgement goes to the Meredith Cowden GVHD foundation, France Lymphome Espoir, NBMTLink; Anthony Nolan, National Marrow Donor Program, BMT InfoNet and other patient advocacy groups for partnering and collaboration. Thanks go to all working groups and consensus conference participants, professional societies, US government agencies and stakeholders in the field of hematopoietic stem cell transplantation for the generous donation of their work, time, talents and expertise. We especially acknowledge the ASTCT and EBMT for their roles in the dissemination, education and implementation of the concepts and best practices evolving from this project. The authors thank Eneida Nemecek for contribution of the cutaneous section and Sarah Anand for support of the pulmonary section. Special thanks go to the independent external peer reviewers who provided they comments and critiques to the 2020 NIH Chronic GVHD Consensus Project: Nicolaus Kr?ger, M.D. Professor & Clinical Director of the Department of Stem Cell Transplantation, University of Hamburg, Hamburg, Germany, President EBMT; Ryotaro Nakamura, M.D. Professor & Director of the Center for Stem Cell Transplantation City of Hope Cancer Center, Duarte, California; John DiPersio, MD, PhD, Chief, Division of Oncology; Director, Center for Gene and Cellular Immunotherapy; Deputy Director, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri; Mark Juckett, MD, Professor & Director of the Blood and Marrow Transplant Program, University of Wisconsin, Madison, Wisconsin; George Chen, MD, Associate Professor of Medicine, University at Buffalo, Buffalo, New York; Rafael Duarte, MD, PhD, FRCP, Head of Department of Hematology and Director of the Hematopoietic Transplant Program, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; Franco Locatelli, M.D. Professor of Pediatrics Universit? Sapienza, Roma, Head of the Department of Pediatric Hematology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Ges?, Roma, Italy; Areej El-Jawahri, MD, Associate Professor, Director of the Bone Marrow Transplant Survivorship Program, and Associate Director of the Cancer Outcomes Research and Education Program at Massachusetts General Hospital, Boston, Massachusetts; Robert Soiffer, MD, Professor, Chief of the Division of Hematologic Malignancies, Chair of the Executive Committee for Clinical Programs, Vice Chair for the Department of Medical Oncology, Chief of the Division of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, Massachusetts; Daniel Weisdorf, MD, Professor of Medicine & Deputy Director of Clinical Science and Translational Science Institute; Director, Clinical and Translational Research Services, University of Minnesota, Minneapolis, Minnesota; Keith Sullivan. MD, Professor of Medicine, Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina; Catherine Lee, MD, Assistant Professor, Hematology and Hematologic Malignancies, Huntsman Cancer Institute - University of Utah, Salt Lake City, Utah; Jose Antonio Perez-Simon, MD, Professor of Hematology, University of Seville, Head of Department of Hematology, University Hospital Virgen del Rocio and Vice director of the Biomedical Research Institute of Seville (IBIS), Seville, Spain; Doris Ponce, MD, Associate Professor of Medicine, Hematologic Oncologist, Memorial Sloan-Kettering Cancer Center, New York City, New York; Andrew Harris, MD, Pediatric Hematologist-Oncologist & Assistant Professor of Pediatrics, Pediatric BMT and Cellular Therapy Program, University of Utah/Primary Children's Hospital, Salt Lake City, Utah. The opinions expressed are those of the authors and do not represent the position of the National Cancer Institute, the National Institutes of Health, or the United States Government. Financial disclosure: Supported by the Intramural Program of the National Cancer Institute ? Center for Cancer Research, the NIH Intramural and Extramural Research Programs Institutes and Centers. D.W. is a consultant for Novartis, Incyte, Syndax, Pfizer, and Behring; receives honoraria from Mallinckrodt, MACO, Takeda, and Neovii. V.R. is a consultant for Regeneron. R.L. is a consultant for Pfizer, Bristol Myers Squibb, Boehringer-Ingelheim, Formation, Sanofi, Boehringer-Mannheim, Merck and Genentech/Roche; receives research support from Corbus, Formation, Moderna, Regeneron, Pfizer, and Kinksa. R.C. is co-inventor on U.S. patents covering hybrid CB1R/ inducible nitric oxide synthase antagonists. S.L. receives research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda; is a member of a steering committee for Incyte. O.P. receives honoraria or travel support from Astellas, Gilead, Jazz, MSD, Neovii Biotech, Novartis, Pfizer, and Therakos; research support from Gilead, Incyte, Jazz, Neovii Biotech, and Takeda; is an advisory board member of Jazz, Gilead, MSD, Omeros, Shionogi, and SOBI. T.T. receives grants from Kyowa Kirin, Chugai, Sanofi, Astellas, Teijin Pharma, Fuji Pharma, and Nippon Shinyaku; honoraria from Novartis, Merck, Kyowa Kirin, Takeda, Pfizer, Bristol-Myers Squibb, and Janssen. B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; research funding from BlueRock Therapeutics and Rheos Medicines; is a steering committee member for Kadmon Corporation; is a co-founder of Tmunity Therapeutics. A.B. receives research grants from SOS Oxygen; honoraria from Zambon, Shire, Pfizer, and Gilead. A.S. receives consulting fees from Psioxus Therapeutics. S.J. is a consultant for Ocugen Inc. and Neutrolis Inc.; has personal financial interest in Advaite, Inc. and Selagine Inc.; holds patents US9867871B2 and PCT/US19/60566. P.S. is a consultant for GSK, Bausch+Lomb, Ursapharm Arzneimittel GmbH; receives research funding from Roche. Y.O. has a patent in Japan (patent no. 4966019; Name; Topical application and oral intake of tranilast for the treatment of chronic GVHD-related dye eye disease) and patent application number JP 2017-018643 published as JPA2017-178922, application number JP2018-510646 published as WO2017/175808 and application number JP 2019-004730 published as JPA2020-111548. Z.K.L. has U.S. patent filed by Glia LLC on oGVHD treatment; receives research funding from Glia LLC. T.D-N. receives honoraria from Alcon/Novartis, Santen, Alimera Sciences, and Bayer. D.R.S. is a consultant for Domp? and Roche; receives financial support from Domp? and Novartis. S.R.McC. receives grant/research/clinical trial support from Gilead Sciences, Aprea Therapeutics, and McCabe Fund. P.J.M. is on the advisory boards for Mesoblast and Rigel Pharmaceuticals Inc.; receives honoraria from Janssen. J.L.T. receives research support from Boehringer Ingelheim, CareDx, and AstraZeneca. J.P. has consulting and advisory board membership for Syndax, CTI Biopharma, Amgen, Regeneron, Incyte; receives clinical trial support from Novartis, Amgen, Takeda, Janssen, Johnson & Johnson, Pharmacyclics, Abbvie, CTI Biopharma, BMS. D.R.C. is a consultant for Fresenius Kabi and Incyte; a non-promotional speaker for Mallinckrodt. E.H. is on the advisory board for Novartis, Medac, and Maat-Pharma; receives honoraria from Novartis, Neovii. C.C. receives consulting honoraria from Incyte, Jazz, CareDx, Mesoblast, Syndax, Omeros, Pfizer. H.T.G. receives honoraria for presentations in scientific meetings and consultations from Novartis, Celgene/BMS, Sanofi, Janssen, and Therakos. S.S. serves on the advisory board for Rigel Pharmaceuticals, Inc. R.R.J. receives consultant role fees from Merck, Karius, and Microbiome DX; advisory member role fees from Seres, Kaleido, MaaT Pharma, Prolacta, and LISCure; patent licensing fees from Seres. A.M.H. holds intellectual property related to Interleukin-22. B.D.S. receives consulting honoraria from Janssen/Legend, Celgene, Kite/Gilead, and BMS; is an advisory board member for In8bio. G-S.C. is a consultant for Janssen Pharmaceutica. S.P. holds intellectual property on Biomarkers and assay to detect chronic graft versus host disease, Kelli MacDonald, PhD, Berghofer Research Institute; Robert Zeiser, MD, University Hospital Freiburg; Vijaya Bhatt, MD, University of Nebraska Medical Center; W. Taylor Kimberly, MD, PhD, Massachusetts General Hospital; Klemens Angstwurm, University of Regensburg; Sarah Anand, MD, University of Michigan; Eneida R. Nemecek, MD, MS, MBA, Oregon Health & Science University; Iago Pinal Fernandez, MD, PhD, NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Publisher Copyright:
© 2021 The American Society for Transplantation and Cellular Therapy
Keywords
- Allogeneic hematopoietic cell transplantation
- Chronic graft-versus-host disease
- Consensus
- Gastrointestinal tract
- Lung
- Ocular
- Sclerosis
- Skin