Acute Graft-Versus-Host Disease (aGVHD)

Introduction

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a leading cause of non-relapse mortality. This article outlines the background, pathophysiology, clinical manifestations, diagnostic approach, and current treatment paradigms for aGVHD, with emphasis on recent updates to the NCCN guidelines. Advances in therapeutic strategies, including corticosteroids, ruxolitinib, and emerging agents, are discussed alongside their mechanisms of action and clinical outcomes. Finally, challenges and future directions in aGVHD management are highlighted.

Background

Acute graft-versus-host disease (aGVHD) arises in 30–50% of patients following allogeneic HSCT despite prophylaxis and is a primary cause of early post-transplant morbidity and mortality. It occurs when immunocompetent donor T cells recognize host antigens as foreign, initiating an immune-mediated attack primarily on the skin, liver, and gastrointestinal tract [1].

Historically, aGVHD was classified based on time of onset (<100 days post-transplant), but current clinical practice focuses more on clinical presentation and pathophysiology, recognizing that late-onset aGVHD may occur beyond day 100, particularly with reduced-intensity conditioning regimens.

Pathophysiology

The pathogenesis of aGVHD involves three interrelated phases [2]:

1. Tissue Damage and Cytokine Storm: Conditioning regimens (e.g., chemotherapy or radiation) damage host tissues, leading to release of inflammatory cytokines (TNF-α, IL-1, IL-6).
2. Donor T-cell Activation: Host antigen-presenting cells (APCs) present alloantigens to donor T cells, activating cytotoxic T lymphocytes (CTLs) and helper T cells.
3. Effector Phase: Activated donor T cells, natural killer (NK) cells, and macrophages mediate tissue destruction through perforin-granzyme pathways and further cytokine release, exacerbating inflammation and tissue injury.

Symptoms and Clinical Presentation

Acute GVHD most commonly affects the skin, gastrointestinal tract, and liver. The severity is graded from I to IV based on organ involvement and functional impairment.

Diagnosis

Diagnosis is primarily clinical but may require biopsy for confirmation, especially in atypical cases. Important diagnostic steps include:

• Physical Examination: Rash, jaundice, GI symptoms
• Laboratory Testing: Liver function tests, stool studies to rule out infection
• Histopathology:
  • Skin: Vacuolar interface dermatitis, apoptotic keratinocytes
  • GI tract: Crypt cell apoptosis, crypt dropout
  • Liver: Bile duct damage, lymphocytic infiltration

Other potential causes (e.g., infection, drug toxicity) must be excluded.

NCCN Guidelines – Treatment

According to the 2025 NCCN Guidelines [3], treatment is guided by disease severity:

• Grade I (Skin only): Topical corticosteroids ± observation
• Grade II-IV: Systemic therapy with corticosteroids (prednisone 2 mg/kg/day or methylprednisolone 1–2 mg/kg/day)

Second-Line Therapies (Steroid-Refractory aGVHD):

• Ruxolitinib (Jakafi): JAK1/2 inhibitor approved for steroid-refractory aGVHD
• Other options (off-label or investigational):
  • Extracorporeal photopheresis (ECP)
  • Anti-IL-2 receptor antibodies (e.g., basiliximab)
  • Mesenchymal stem cells
  • Infliximab (anti-TNF-α)

Goals of Treatment & Mechanisms of Action

Ruxolitinib demonstrated superior overall response rates in the REACH2 trial, with a 62% response rate at day 28 compared to 39% with best available therapy [4].

Conclusion and Future Directions

Acute GVHD remains a significant barrier to the success of allogeneic HSCT. While corticosteroids are the cornerstone of treatment, up to 50% of patients are steroid-refractory and require alternative therapies. Ruxolitinib has shifted the treatment paradigm, but challenges remain in optimizing sequencing, combinations, and managing chronic sequelae.

Future directions include:

• Biomarker-based risk stratification (e.g., ST2, REG3α)
• Personalized therapy based on immune profiling
• Clinical trials investigating novel agents (e.g., ROCK2 inhibitors, anti-GM-CSF)

Continued research and multi-center collaboration will be essential in improving long-term outcomes and quality of life for patients undergoing allo-HSCT.

References

1. Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373(9674):1550–61.
2. Hill GR, Ferrara JLM. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95(9):2754–9.
3. NCCN Clinical Practice Guidelines in Oncology. Hematopoietic Cell Transplantation. Version 2.2025.
4. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020;382:1800–10.

*Information presented on RxTeach does not represent the opinion of any specific company, organization, or team other than the authors themselves. No patient-provider relationship is created.