DESCRIPTION

Graft-versus-host disease (GVHD) can arise following allogeneic hematopoietic cell transplant (HCT) when donor immune cells recognize major and/or minor histocompatibility antigens in the recipient. This immunologic reaction results in inflammation and injury in affected organs. GVHD can develop at any time after allogeneic HCT. Historically, GVHD is divided into acute (occurring within 100 days of HCT) versus chronic (occurring beyond 100 days after HCT) subtypes. However, it is now recognized that acute GVHD can present beyond 100 days and chronic GVHD can occur as early as 60 days post-HCT. Thus, GVHD is more accurately delineated by clinicopathologic findings of acute versus chronic or a combination (referred to as overlap syndrome) rather than timing relative to HCT.

• Acute GVHD (aGVHD)
  • Lacks features of chronic GVHD
  • Affects skin, gastrointestinal (GI) tract, and/or liver
• Chronic (cGVHD)
  • Lacks features of acute GVHD
  • Can affect all systems with diverse features resembling autoimmune syndromes; inflammation results in fibrosis in affected organs. Most often occurs following a history of aGVHD, but may arise de novo
• Overlap GVHD has features of both acute and chronic GVHD.

EPIDEMIOLOGY

• Acute GVHD (grades II to IV): 10–80% of patients receiving T-cell–replete HCT
  • 35–45% for human leukocyte antigen (HLA)—identical related donor bone marrow; 60–80% if one-antigen HLA-mismatched unrelated donor bone marrow or peripheral stem cells; 35–65% if two-antigen HLA-mismatched unrelated umbilical cord blood
• Chronic GVHD: most common cause of late morbidity and mortality of allogeneic HCT
  • 15–25% if HLA-identical related marrow; 40–60% if HLA-matched unrelated marrow; 54–70% if HLA-matched unrelated peripheral stem cells; 20% if unrelated umbilical cord blood

RISK FACTORS

• HLA disparity (both major and minor antigens)
• Older donor or recipient age
• Stem cell source:
  • Highest risk: peripheral blood stem cells
  • Lower risk: bone marrow
  • Lowest risk: cord blood
• Donor lymphocyte infusions (DLIs)
• Reactivation of viruses (e.g., human herpesvirus [HHV]-6, cytomegalovirus [CMV])
• Acute GVHD-specific: higher intensity conditioning regimen; prior pregnancies in female donors; use of total body irradiation
• Chronic GVHD-specific:
  • Severity of acute GVHD
  • Malignancy as indication for transplantation
  • Gender mismatch (female donor for male recipient)
  • Type of immunosuppressive prophylaxis

GENERAL PREVENTION

• Donor selection: HLA-identical donors preferred; well-matched family members prioritized over unrelated donors as unrecognized minor histocompatibility antigens likely matched
• Graft manipulation: T-cell depletion, stem cell selection
• Graft source: use of bone marrow over peripheral blood stem cells
• Conditioning: utilization of lower-toxicity therapies that reduce potential for donor immune response and activation post-HCT
• Recipient immunosuppression: cyclosporine, tacrolimus, methotrexate, sirolimus, mycophenolate mofetil, post-HCT cyclophosphamide, corticosteroids, abatacept, antithymocyte globulin (ATG), alemtuzumab

PATHOPHYSIOLOGY

• Acute GVHD: interaction of donor and host innate and adaptive immune responses
  • Severity related to degree of HLA mismatch
  • Three phases ending in “cytokine storm” (i) tissue damage by conditioning regimen; (ii) priming and activation of donor T cells; (iii) infiltration of activated T cells into skin, GI tract, and liver resulting in apoptosis
• Chronic GVHD: findings similar to autoimmune disorders: donor T cells directed against host antigens, donor T-cell alloreactivity, B-cell dysregulation, regulatory T-cell deficiency; marked collagen deposition in target organs and lack of T-cell infiltration