How chronic graft-versus-host disease unfolds ten years after transplant

Hematopoietic cell transplantation (HCT) is a lifesaving treatment for people diagnosed with fatal blood cancers or other blood disorders. The procedure involves replacing the recipient’s blood forming stem cells, which give rise to the immune system, with healthy cells from a donor.

But the newly transplanted cells can create serious complications. In graft-versus-host disease (GVHD), donor immune cells attack the recipient’s tissues, transforming a lifesaving procedure into a medical battle that can unfold over months or years. Chronic GVHD can affect multiple organ systems and is a major cause of morbidity and mortality after HCT.

Although outcomes are improving, up to 30% of HCT recipients are still diagnosed with chronic GVHD. Understanding what drives persistent and severe GVHD complications has become a major focus of modern transplant medicine.

The Chronic GVHD Consortium, a national collaborative effort led by Dr. Stephanie Lee from the Clinical Research Division at Fred Hutch, brings together transplant recipients and researchers from across 13 sites to study the causes, prevention, and treatment of GVHD. Nearly 1000 transplant recipients were enrolled and followed over time to track the development of GVHD and to build a repository of biological samples for future research.

Initial findings from this prospective study were published in 2016. Now, a decade later, long-term follow up of this work is offering a broader view of how GVHD arises and evolves over time.

GVHD exhibits a variety of clinical manifestations and is subcategorized into distinct syndromes based on presenting symptoms, the organ systems involved, and severity. This study focused on four syndromes of GVHD: late acute GVHD (where the symptoms of acute GVHD occur more than 100 days after HCT), chronic GVHD, and two particularly difficult to treat forms of chronic GVHD known as bronchiolitis obliterans syndrome, which affects the lungs, and cutaneous sclerosis, which causes thickening and hardening of the skin.

Researchers examined how GVHD progressed after diagnosis, including which organ systems were involved, the administration of immunosuppressive therapies, long-term treatment success, and survival.

The results from this work broadly indicate that GVHD remains a threat well beyond the first few years after transplantation. The cumulative incidence of late acute GVHD was 11%, while chronic GVHD occurred in 54% of patients, with a median time to onset of 5.5 months and 7.4 months, respectively. Although bronchiolitis obliterans syndrome (4%) and cutaneous sclerosis (10%) were less common, they tended to have a later onset and often developed after an initial diagnosis of chronic GVHD. Among patients who were initially diagnosed with late acute GVHD, 46% later developed the chronic form of the disease.

These patterns highlight the evolving nature of GVHD and the need for long-term monitoring of transplant survivors.

Immunosuppressive drugs remain the primary defense against GVHD, but long-term use carries significant risks. These medications can cause serious side effects and leave patients vulnerable to infections. Once moderate to severe GVHD develops, patients often require multiple lines of systemic immunosuppressive therapy and may remain on treatment for years. In this study, fewer than half of patients were able to stop systemic immunosuppression within five to ten years after transplantation. For those with bronchiolitis obliterans syndrome, treatment discontinuation was possible in only about 20% of cases.

The study also examined long-term survival after transplantation. GVHD-free, relapse-free survival was 22% at two years and declined to 15% at ten years after HCT. Non-relapse mortality also increased over time, doubling by the ten-year mark to 35% among patients with late acute GVHD, 31% for chronic GVHD, 62% for bronchiolitis obliterans syndrome, and 36% for cutaneous sclerosis.

For many patients HCT represents a difficult trade, escaping a fatal blood disease while facing the possibility of long-term complications from GVHD. Large longitudinal studies like this one are critical for understanding how GVHD develops and progresses years after transplant. By revealing patterns of disease evolution, these data can help clinicians identify high-risk patients earlier, intervene sooner, and design strategies to prevent the most severe forms of chronic GVHD, ultimately improving long-term outcomes for transplant survivors.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Paul Carpenter and Stephanie J. Lee contributed to this research.

The spotlighted research was funded by the National Institutes of Health.

Pidala J, Onstad L, Carpenter P, Hamilton BK, Kitko CL, Juckett M, Cutler C, and Lee SJ. 2026. Longitudinal Study of Late Acute and Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation: A Long-Term Follow-up Study from the Chronic Graft-Versus-Host Disease Consortium. Transplantation and Cellular Therapy. DOI: 10.1016/j.jtct.2025.10.026