The Future of Chronic Graft-Versus-Host Disease

Steven Pavletic, MD
Senior Clinician, Immune Deficiency Cellular Therapy Program, National Cancer Institute
Kirk Schultz, MD
Investigator and Director, Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital; Co-Lead, Childhood Cancer and Blood Research Group, BC Children's Hospital

An Update From the 3rd NIH Chronic GVHD Consensus Conference

In this edition, Steven Pavletic, MD, and Kirk Schultz, MD, report on the progress and challenges in the management of chronic graft-versus-host disease – the subject of a recent National Institutes of Health Consensus Conference.

Chronic graft-versus-host disease (cGVHD) remains the most significant long-term complication after a successful allogeneic hematopoietic cell transplantation (alloHCT) and is associated with late mortality and disability. The steadily growing number of transplants and improvements in safety means there are more transplant survivors. Improved telemedicine capability also means more community-based management of patients who have undergone HCT, bringing the complex issue of cGVHD to the mainstage of a busy hematology clinical practice.

While cGVHD is relatively rare and can be considered an orphan disease, it affects about 15,000 patients in the U.S. The complexity and multiplicity of medical issues, chronicity of the disease, and the number of organ-specific problems represent a challenge for both patients and clinicians. Feedback from all key stakeholders has revealed major barriers to accessing expert subspecialty care.

Much has been accomplished in the field of cGVHD since it was first clinically described in the late 1970s.1 The rapid expansion of alloHCT as a best proven form of cancer immunotherapy led to the 1st National Institutes of Health (NIH) Consensus Conference in 2005, which, based on expert recommendations, established new standards for the diagnosis, staging, and assessment of clinical response to therapy for cGVHD. The articles composing the working group’s resultant report became some of the most highly referenced in the transplant field.2 In 2014, the 2nd NIH Consensus Conference further refined the consensus based on a decade of new evidence and progress that led to the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for cGVHD, ibrutinib, in 2017.3

The field of cGVHD today is markedly different from where it was at the time of the first consensus conference. The scope of the disease and its clinical course are now much more thoroughly characterized, and its complex pathophysiology better understood. Moreover, there are now an increasing number of investigational agents available for treatment, thanks in part to greater industrial collaboration and government funding.

In addition, newly established regulatory approval pathways bring the prospect of new drug approvals in the near future. This momentum also led to the first National Comprehensive Cancer Network guidelines for GVHD management in 2020.4

Despite commendable progress, the algorithm for the selection of the appropriate systemic therapy for cGVHD has remained unchanged since the 1980s.

Despite this commendable progress and improved access to active agents, the algorithm for the selection of the appropriate systemic therapy for cGVHD has remained unchanged since the 1980s. Initial treatment is still prednisone with calcineurin inhibitor. Best choice of subsequent treatment is still undefined, there are no standard approaches to prevention or preemption, and highly morbid forms of cGVHD still exist.

To address these challenges, a 3rd NIH Consensus Conference project was initiated in November 2019. Four working groups were formed, addressing prevention, early diagnosis and preemption, systemic therapy, and highly morbid entities. The main goal of this project, in contrast to prior consensus conferences, is not to standardize clinical research tools, but to create a process that will allow for implementation of fundamental changes in cGVHD management over the next three to seven years. Groups were charged with “thinking outside the box” to determine the accomplishments and gaps in the field of cGVHD and alloHCT and what next steps should to be taken to advance the field in a fundamentally new way.

Due to the COVID-19 pandemic, the 3rd NIH Chronic GVHD Consensus Conference was held as a virtual meeting over three days, with six two-hour sessions on November 18, 19, and 20, 2020. This virtual format allowed much broader live participation of all interested stakeholders nationally and internationally, with more than 850 registered participants.
Based on comments from independent external peer reviewers and conference participants, as well as responses received during a 30-day post-conference public com-ment period, the five papers have been further revised and are planned for submission to the journal Transplantation and Cellular Therapy (formerly Biology of Blood and Marrow Transplantation) starting in February 2021.5

In their reports, Working Groups 1 and 2 were tasked with identifying knowledge gaps in how best to assess risk and prevent or preempt cGVHD. “Prevention” strategy is defined as an intervention which is planned at the time of transplant. For such strategies to become standard, the key is to develop risk-stratified approaches, decipher early biologic events, and study second insults that may be amenable to therapeutic targeting.

“Preemption” strategy is defined as intervention planned after transplant in a patient who is found to be at increased risk, most likely by biomarkers, for the development of moderate or severe cGVHD. For such strategies to become a reality in clinical practice, it is necessary to develop methods for timely and reliable prediction of who will develop moderate or severe cGVHD.

Systemic treatments for cGVHD, the topic of Working Group 3’s report, still suffer from some major limitations. Most responses to salvage therapies are partial responses, underscoring the pronounced need for more effective therapies, likely combinations of agents. There also is an imperative to develop individualized therapeutic approaches to determine which agent would be effective in a given patient and avoid cumulative toxic treatments as occurs in the current “trial and error” paradigm.

Systemic treatments for cGVHD still suffer from some major limitations. There is an urgent need to develop frontline treatment regimens that involve minimal or no use of corticosteroids.

Finally, there is an urgent need to develop frontline treatment regimens that involve minimal or no use of corticosteroids. Master trial protocols and adaptive platform designs are needed to accelerate new drug development in cGVHD.6 New organizational structures will be needed to optimally organize such trials, likely using the “trusted third party” intermediary.

Definitions from the FDA’s Biomarkers, EndpointS, and other Tools (BEST) Resource: Harmonizing Biomarker Terminology and the agency’s biomarker qualification pathways should be used to integrate biomarkers into drug development.7

Working Group 4 reviewed highly morbid forms of cGVHD, such as lung, skin sclerosis, and ocular disease, that pose a special challenge due to their rare and recalcitrant nature. A better understanding of fibrosis in cGVHD biology has identified several promising new targets and combination approaches to be tested. Age-related issues were raised, including cGVHD in young children who are not able to be assessed adequately with current diagnostic modalities, such as a pulmonary function tests, and the impact of cGVHD on physical mobility in older patients.

In addition, the 2020 Chronic GVHD NIH Consensus Conference’s industry summit addressed the need for tighter collaboration among manufacturers on trials of combination therapies, as well as creation of new structures, such as digital biobanks, to access patient samples from multicenter trials. The patient advocacy summit identified three constituencies of primary interest: patients and families, health care providers, and “others” (including government, industry, payors, academia, hospitals, and foundations). Establishing a national network of centers of excellence will be a top priority for the new Advocacy Network Consortium. Advocates identified the heavy toll that cGVHD takes on the long-term well-being of patients, including chronic fatigue, depression, and insufficient support in the community.8

Attendees also highlighted the crucial role professional societies play in advancing these efforts. The American Society for Transplantation and Cellular Therapy has initiated a coordinated action with the American Society of Hematology, the American Society of Clinical Oncology, the European Society for Blood and Marrow Transplantation, and other national and international organizations. Special thanks to the National Cancer Institute’s Center for Cancer Research and the NIH for spearheading sustained communal efforts to study cGVHD.


  1. Graze PR, Gale RP. Chronic graft versus host disease: a syndrome of disordered immunity. Am J Med. 1979;66(4):611-20.
  2. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-56.
  3. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant. 2015;21(3):289-401.
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hematopoietic Cell Transplantation. Accessed January 12, 2021, from
  5. National Institutes of Health. 2020 Chronic GVHD Consensus Conference: Draft Paper Overview. Accessed January 12, 2021, from
  6. The Adaptive Platform Trials Coalition. Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov. 2019;18:797-807.
  7. FDA. The BEST Resource: Harmonizing Biomarker Technology. Accessed January 12, 2021, from
  8. BMT InfoNet. 2020 National Cancer Institute (NCI) GVHD Patient Advocacy Summit. Accessed January 12, 2021, from

Steering Committee of the 3rd NIH Chronic GVHD Consensus Conference

Members of the steering committee meeting in November 2019.

Members meeting virtually in 2020.


  • Stephanie Lee, MD, MPH (Seattle)
  • Steven Pavletic, MD (Bethesda)
  • Kirk Schultz, MD (Vancouver)
  • Daniel Wolff, MD (Regensburg)


  • Bruce Blazar, MD (Minneapolis)
  • Meredith Cowden, LPCC-S (Akron)
  • Corey Cutler, MD, MPH (Boston)
  • Hildegard Greinix, MD (Graz)
  • Paul Martin, MD (Seattle)
  • Sophie Paczesny, MD, PhD (Charleston)
  • Joseph Pidala, MD, PhD (Tampa)
  • Stefanie Sarantopoulos, MD, PhD (Durham)
  • Gérard Socié, MD, PhD (Paris)