Acute GvhdEdit
Acute graft-versus-host disease (acute GvHD) is a immune-mediated complication that most commonly follows allogeneic hematopoietic stem cell transplantation. It arises when donor-derived immune cells recognize recipient tissues as foreign and mount an attack, most often targeting the skin, liver, and gastrointestinal tract. Acute GvHD typically manifests within the first 100 days after transplant, though onset can be earlier or later in some cases. Its occurrence reflects a balance between the beneficial graft-versus-leukemia effect and the risks of immune-mediated injury, infection, and organ failure. Effective prevention and prompt, tiered treatment are central to improving outcomes in patients undergoing allogeneic transplantation graft-versus-host disease allogeneic hematopoietic stem cell transplantation.
The condition is influenced by several factors, including the degree of human leukocyte antigen (HLA) matching between donor and recipient, donor type (matched sibling, unrelated donor, or haploidentical donor), conditioning intensity, and the use of GVHD prophylaxis. In settings with greater HLA disparity or mismatched donors, the risk of acute GvHD increases. Conversely, strategies that blunt immune reactivity to prevent GvHD can also dampen the beneficial graft-versus-leukemia effect, potentially raising relapse risk for the underlying malignancy. This tension has driven ongoing refinement of prophylactic regimens and approaches to post-transplant immunoregulation graft-versus-leukemia and transplant medicine more broadly.
Pathophysiology
Acute GvHD is traditionally described as a two-stage process. The first stage involves tissue injury from conditioning regimens (chemotherapy and/or radiation) that damages the recipient’s barriers and releases inflammatory signals. The second stage centers on donor T cells that become activated in response to host antigens presented by recipient antigen-presenting cells. Activated donor lymphocytes proliferate and orchestrate an inflammatory attack on host tissues, with cytokines amplifying the response. The end result is inflammation and tissue injury in the involved organs, most notably the skin, liver, and gastrointestinal tract. Minor histocompatibility antigen disparities, dendritic-cell activation, and regulatory T-cell dynamics all contribute to the overall risk and severity of the syndrome. The integrity of the gut barrier and the composition of the host microbiome are increasingly recognized as modifiers of risk and clinical course graft-versus-host disease.
Clinical features and grading
Acute GvHD is classically described by a triad of organ involvement:
- Skin: a maculopapular rash that can progress to erythroderma and, in severe cases, blistering or desquamation. Sunburn-like patterns may be observed, and involvement can be widespread.
- Liver: cholestasis with elevated bilirubin, alkaline phosphatase, and transaminases. Jaundice may be present.
- Gastrointestinal tract: diarrhea (which may be profuse), abdominal pain, and sometimes vomiting or nausea. GI involvement is frequently a marker of more extensive disease.
Grading systems integrate involvement across organs to categorize severity. The severity of skin involvement, liver function abnormalities, and GI symptoms collectively determine the overall grade, which guides initial management decisions. While specific criteria have evolved over time, the general principle is that higher grades correlate with greater risk of complications and poorer prognosis. Diagnostic confirmation often involves ruling out infections and drug reactions, with tissue biopsies of skin, liver, or GI tract providing additional diagnostic support in uncertain cases. Biopsy findings can show characteristic patterns of inflammation and tissue injury, but the diagnosis is primarily clinical and is made in the context of compatible organ involvement and timing after transplantation biopsy.
Diagnosis
Diagnosis of acute GvHD rests on clinical presentation, timing after allo-HSCT, and the exclusion of competing etiologies such as infection, medication reactions, or other inflammatory conditions. Laboratory testing and imaging may aid assessment of organ involvement and complication monitoring. Biopsy can support the diagnosis when the presentation is uncertain or when confirmation is needed to guide therapy, especially in atypical cases. Because infections are common in this patient population and can mimic or complicate GVHD, thorough evaluation for infectious etiologies is a standard part of the diagnostic workup. Clinicians also consider the patient’s immunosuppressive regimen and previous GVHD history when interpreting findings biopsy.
Prevention
Prevention focuses on reducing donor T-cell–mediated attack while preserving the graft’s anti-leukemic effects. Common prophylaxis regimens combine a calcineurin inhibitor (such as tacrolimus or cyclosporine) with a short-interval antimetabolite (like methotrexate or mycophenolate mofetil). Prophylaxis strategies vary with donor type and institutional practice, with unrelated donor and haploidentical transplants often employing additional measures such as anti-thymocyte globulin or post-transplant cyclophosphamide to further reduce GvHD risk. Advances in donor selection, conditioning intensity, and cell processing (including approaches to T-cell depletion) have contributed to shifts in how acute GvHD is prevented across different transplant settings tacrolimus cyclosporine post-transplant cyclophosphamide graft-versus-host disease.
Management
Management depends on the severity of disease. The cornerstone of treatment for acute GvHD is systemic immunosuppression, typically initiated with corticosteroids (for example, prednisone or methylprednisolone) at standard dosing once GvHD is diagnosed or suspected. The goal is rapid control of immune-mediated tissue injury while monitoring for infectious complications and relapse of the underlying disease. If patients do not respond to initial corticosteroid therapy (steroid-refractory disease), clinicians turn to second-line options that aim to modulate the immune response with acceptable toxicity profiles. These second-line therapies may include agents such as JAK inhibitors (notably ruxolitinib), extracorporeal photopheresis, and other targeted therapies, as well as supportive measures to manage infections and organ dysfunction. The choice of second-line therapy can depend on disease pattern, organ involvement, patient comorbidities, and access to treatment modalities. The evolving landscape of therapy reflects an ongoing effort to reduce steroid exposure and improve outcomes while managing infection risk and relapse potential. See the discussions on specific treatments and their evidence base in contemporary guidelines and trial reports ruxolitinib extracorporeal photopheresis.
Supportive care is integral to management and includes rigorous surveillance for infections, nutritional support, wound care for skin involvement, and management of liver and GI complications. The interplay between GVHD control, relapse risk of the underlying malignancy, and infection risk requires careful, individualized decision-making by transplant teams infection.
Prognosis and outcomes
Acute GvHD remains a major determinant of non-relapse mortality after allogeneic transplantation. Prognosis depends on the extent and sites of organ involvement, the grade of disease, and the patient’s response to initial therapy. Skin-predominant disease with limited organ involvement generally carries a better prognosis than multi-organ involvement or steroid-refractory disease. Ongoing research continues to refine prognostic models, incorporating clinical features, laboratory data, and, increasingly, biomarkers to guide risk stratification and treatment decisions. The graft-versus-leukemia effect remains a variable that clinicians must balance against GVHD risk in the overall management of patients undergoing allo-HSCT graft-versus-leukemia.
Controversies and debates
As with many areas of transplant medicine, there are active debates about optimal strategies to prevent and treat acute GvHD. Key topics include:
Prophylaxis regimens and donor-type differences: determining the best combination of calcineurin inhibitors, antimetabolites, and adjunctive agents for different donor types (matched related, unrelated, haploidentical) remains a subject of ongoing study. The trade-off between stronger GVHD prevention and potential suppression of graft-versus-leukemia and infection risk guides center-specific choices post-transplant cyclophosphamide.
Post-transplant cyclophosphamide in haploidentical transplants: widely adopted in many centers, but its long-term impact on relapse risk and immune reconstitution continues to be evaluated in comparative studies against other donor settings and prophylaxis strategies post-transplant cyclophosphamide.
Steroid-sparing approaches: the field is exploring strategies to reduce corticosteroid exposure to lessen infection, metabolic complications, and quality-of-life impacts while maintaining disease control. Critics and proponents weigh short- and long-term outcomes, relapse risk, and immune reconstitution in different patient groups.
Steroid-refractory disease and access to novel therapies: newer agents such as ruxolitinib offer evidence of improved control in many cases, but cost, access, and long-term safety remain considerations, particularly in resource-constrained settings. Debates also focus on which patients are most likely to benefit from specific second-line options and how to sequence therapies for durable responses ruxolitinib.
Diagnostic standardization and biomarkers: there is interest in establishing uniform criteria and reliable biomarkers to diagnose and stage acute GvHD earlier and more accurately, which would help harmonize care across centers and enable more precise trials. Differences in organ-specific scoring and timing can affect comparisons of outcomes across studies biomarkers.
Balancing relapse risk and GVHD control: pursuit of aggressive GVHD prevention can increase relapse risk for the underlying hematologic disease. Clinicians aim for a nuanced balance, guided by disease status, donor type, and patient factors, with some arguing for personalized approaches over one-size-fits-all regimens graft-versus-leukemia.