Diagnosis and Management of Graft-Versus-Host Disease
Diagnosis of Acute GVHD
Acute GVHD is primarily a clinical diagnosis based on characteristic involvement of skin, gastrointestinal tract, and liver, with biopsy confirmation recommended when feasible but not required to initiate treatment. 1, 2
Clinical Recognition and Target Organs
- Skin manifestations present as maculopapular rash that may progress to involve varying percentages of body surface area 2
- Gastrointestinal involvement includes diarrhea, nausea, vomiting, and abdominal pain 1, 2
- Hepatic disease manifests as hyperbilirubinemia and elevated liver function tests, often asymptomatic and requiring routine monitoring 1, 2
Excluding Alternative Diagnoses
Before confirming GVHD, perform testing to rule out mimicking conditions:
- Stool testing for infectious causes including C. difficile and CMV 2
- Viral reactivation testing as clinically indicated 1, 2
- Imaging studies when appropriate 1, 2
Role of Biopsy
- Organ-directed biopsies should be performed as clinically indicated: rectosigmoid biopsy for diarrhea (highest sensitivity), upper GI biopsy for nausea/vomiting, skin biopsy for rash, and liver biopsy for unexplained liver function abnormalities 1, 2
- Pathologic confirmation is not absolutely sensitive and treatment should not be delayed while awaiting biopsy results in patients with typical symptoms 1, 2
- Rectosigmoid biopsies demonstrate higher sensitivity and negative predictive value than other GI sites 1
Grading
- Use modified Glucksberg (Keystone) criteria to determine organ staging and overall grade (I-IV) to guide therapy choice and monitor disease 1, 2
- Grade III/IV acute GVHD carries poor prognosis 3
Diagnosis of Chronic GVHD
Chronic GVHD requires at least one diagnostic clinical sign OR at least one distinctive manifestation confirmed by biopsy or relevant testing in the same or another organ. 1, 2
Diagnostic Criteria
- Diagnostic signs involve skin and appendages, mouth, eyes, female genitalia, esophagus, lungs (bronchiolitis obliterans syndrome), and connective tissues 2, 4
- Bronchiolitis obliterans syndrome (BOS) diagnosed by pulmonary function tests is only diagnostic of lung chronic GVHD if distinctive features of chronic GVHD are present in another organ, unless pathologically confirmed via lung biopsy 1, 2
- Biopsy is not mandatory if the patient has at least one diagnostic finding defined by the NIH Consensus Development Project 1, 2
Grading
- Apply NIH Consensus Development Project criteria for chronic GVHD grading to guide therapy and monitoring 1, 2
Management of Acute GVHD
Grade I Disease
For Grade I acute GVHD (skin stage 1-2, ≤50% body surface area, no GI or liver involvement), continue or restart the original immunosuppressive agent and apply topical therapies. 1, 5
- Medium- to high-potency topical steroids (triamcinolone, clobetasol) except on the face where low-potency hydrocortisone is used 1, 5
- Topical tacrolimus as an alternative 1, 5
- Antihistamines for symptomatic pruritus relief 1, 5
- Observation without treatment is acceptable if rash is asymptomatic and stable 1
Grades II-IV Disease
Systemic corticosteroids are the cornerstone of first-line therapy for Grades II-IV acute GVHD. 5
- Grade II: methylprednisolone 0.5-1 mg/kg/day 5
- Grades III-IV: methylprednisolone 1-2 mg/kg/day (maximum 2 mg/kg/day) 5
- Response definition: complete resolution or improvement in ≥1 organ without progression in others 5
- Taper steroids as clinically feasible once response is achieved to mitigate long-term side effects and infection risk 1, 5
Steroid-Refractory Disease
- Ruxolitinib is the only FDA-approved therapy for steroid-refractory acute GVHD with 6-month survival comparable to other agents 1, 6
- Clinical trial enrollment is strongly encouraged as the NCCN Panel does not prefer any specific second-line agent due to lack of high-quality evidence 1
- Sirolimus may be considered as an alternative to systemic corticosteroids for standard-risk acute GVHD, though phase III confirmation is needed 1
Management of Chronic GVHD
First-Line Therapy
Systemic corticosteroids (0.5-1 mg/kg/day methylprednisolone or prednisone) combined with continuation or escalation of the original calcineurin inhibitor constitute first-line therapy for chronic GVHD. 1, 5
Organ-Specific Topical Therapies
- Skin: triamcinolone, clobetasol, or topical tacrolimus 1, 5
- Oral cavity: dexamethasone oral rinse 1, 5
- Vulvovaginal: topical estrogen 1, 5
- Lung involvement: inhaled steroids (budesonide or fluticasone) plus azithromycin (FAM regimen: fluticasone, azithromycin, montelukast) 1
- Critical caveat: azithromycin should only be used for BOS treatment, not prophylaxis, due to increased cancer relapse risk 1
Steroid-Refractory Chronic GVHD
Ibrutinib is the only FDA-approved second-line therapy for steroid-refractory chronic GVHD after failure of one or more lines of systemic therapy. 5, 6
- Belumosudil (ROCK2 inhibitor) is FDA-approved for patients who received at least 2 prior lines of treatment 6
- Ruxolitinib is FDA-approved for chronic GVHD after failure of one to two lines of systemic therapy 6
Steroid Tapering
- Taper according to NIH Response Criteria once improvement is documented 5
- Slow taper is essential to prevent GVHD flares while minimizing long-term steroid complications 5
Critical Management Principles
Multidisciplinary Care
Multidisciplinary care in specialized transplant centers is strongly recommended to prevent irreversible organ damage and preserve function. 1, 5
- Early recognition of signs and symptoms is essential 1
- Organ-specific supportive interventions should be integrated throughout treatment 5
Special Considerations
- Progressive or worsening lung chronic GVHD after 2-3 lines of therapy may warrant lung transplant evaluation 1
- Clinical trial enrollment is encouraged for all patients presenting with chronic GVHD 1, 5
- Approximately 50% of patients with acute GVHD will eventually develop chronic GVHD manifestations 3
Common Pitfalls to Avoid
- Do not delay treatment while awaiting biopsy confirmation in patients with typical symptoms 1, 2
- Do not rely solely on biopsy as sensitivity is imperfect; clinical diagnosis is acceptable with typical features 1, 2
- Always exclude infectious causes (particularly C. difficile and CMV) before attributing symptoms solely to GVHD 2
- Avoid azithromycin for BOS prophylaxis due to increased cancer relapse risk 1