What is graft versus host disease (GVHD) in patients with hematological malignancies such as leukemia or lymphoma who have undergone allogeneic bone marrow or stem cell transplants?

What is Graft-Versus-Host Disease (GVHD)?

Graft-versus-host disease (GVHD) is a condition in which transplanted donor cells recognize the recipient's tissues as foreign and mount an immune attack against them, occurring exclusively after allogeneic hematopoietic stem cell transplantation. 1

Fundamental Mechanism

GVHD is mediated by donor T lymphocytes that react against host tissues after allogeneic transplantation. 1, 2 The donor immune cells, particularly T-lymphocytes, are the principal effectors that recognize recipient cells as "nonself" and initiate an immunologic assault. 1 This represents a fundamental reversal of the typical transplant rejection scenario—instead of the host rejecting the graft, the graft attacks the host. 3

Critical Clinical Distinction: Acute vs. Chronic GVHD

Acute GVHD

• Acute GVHD typically occurs within the first 2-6 weeks to 100 days after transplantation and primarily targets the skin, gastrointestinal tract, and liver. 1, 2

• The disease manifests with T cell infiltration of skin epithelia, mucous membranes, bile ducts, and intestinal tract. 2

• Acute GVHD is graded on a scale of I-IV based on severity of organ involvement. 1

• Incidence reaches 35-50% in HLA-matched allogeneic transplants and up to 70% in HLA-mismatched transplants, despite prophylactic immunosuppression. 1, 2, 3

• Approximately half of patients with moderately severe to severe acute GVHD die, usually from associated infections rather than the GVHD itself. 3

Chronic GVHD

• Chronic GVHD was traditionally defined as occurring after 100 days post-transplant, but can develop as early as 40 days. 1

• The clinical presentation resembles autoimmune connective tissue disorders such as scleroderma or systemic lupus erythematosus. 1, 4

• Chronic GVHD is classified as either limited or extensive and affects approximately 45-50% of long-term allogeneic transplant survivors. 1, 3, 4

• Target organs include skin, liver, eyes, mouth, lacrimal and salivary glands, and serous membranes. 3, 4

• The 10-year survival for mild chronic GVHD is approximately 80%, but drops to less than 5% for severe chronic GVHD. 4

Risk Factors for GVHD Development

The degree of HLA mismatch between donor and recipient is the single most important risk factor for GVHD. 1

• Patients receiving grafts from HLA-matched siblings have the lowest risk. 1

• Matched unrelated donors, umbilical cord blood, or mismatched family members confer substantially higher GVHD risk. 1

• Increasing recipient age significantly elevates chronic GVHD risk. 1, 3

• Prior acute GVHD is a major risk factor for subsequent chronic GVHD. 1, 3

• Use of peripheral blood stem cells (versus bone marrow) increases GVHD incidence. 1, 4

Immunologic Consequences and Complications

GVHD creates profound and prolonged immunodeficiency that dramatically increases infection risk. 1

• Patients develop abnormal CD4/CD8 T-cell ratios with decreased CD4 and increased CD8 counts. 1

• Immunoglobulin deficiencies (IgG2, IgG4, IgA) persist for months to years after transplant. 1

• Chronic GVHD causes macrophage deficiency, impaired neutrophil chemotaxis, and poor vaccination responses. 1

• Patients with chronic GVHD face particularly high risk for life-threatening bacterial infections from encapsulated organisms including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. 1

• The immunosuppressive medications used to treat GVHD further compound vulnerability to opportunistic viral and fungal pathogens. 1

Critical Transplant Type Distinction

Autologous and syngeneic (identical twin) transplants do NOT cause chronic GVHD because the transplanted cells are genetically identical or derived from the patient themselves. 1 This is a crucial clinical distinction—GVHD is exclusively a complication of allogeneic transplantation where genetic disparity exists between donor and recipient. 1

Prevention Strategies

T-lymphocyte depletion from donor grafts reduces GVHD rates but creates a problematic trade-off. 1 While T-cell depletion lowers GVHD incidence, it simultaneously increases rates of graft rejection, cytomegalovirus infection, invasive fungal infections, and Epstein-Barr virus-associated lymphoproliferative disease. 1

Standard GVHD prophylaxis involves combination immunosuppression with cyclosporine or tacrolimus plus methotrexate or corticosteroids. 1, 5 These medications themselves cause significant complications including fluid retention and edema. 5

High-dose post-transplantation cyclophosphamide represents a newer approach that promotes tolerance in alloreactive T cells, particularly useful for partially HLA-mismatched transplants. 6

Clinical Impact on Mortality and Morbidity

Infection remains the leading cause of death among allogeneic transplant recipients, with GVHD serving as the primary predisposing factor. 1 In one large registry study, infection accounted for 37% of deaths among 462 unrelated allogeneic transplant recipients. 1

Death from severe chronic GVHD is usually a consequence of infectious complications rather than direct organ damage from the GVHD itself. 4 The combination of GVHD-induced immune dysfunction and immunosuppressive treatment creates a perfect storm for opportunistic infections. 1