What is the management approach for Graft-versus-Host Disease (GvHD)?

Management of Graft-versus-Host Disease

Systemic corticosteroids are the cornerstone of first-line therapy for both acute and chronic GVHD, with treatment intensity stratified by disease grade and organ involvement. 1

Acute GVHD Management

Grade I (Skin-Only Disease)

• Continue or restart the original immunosuppressive agent (tacrolimus or cyclosporine) as the foundation of therapy 1, 2
• Apply medium- to high-potency topical steroids (triamcinolone, clobetasol) to affected body areas, but use low-potency hydrocortisone on the face to prevent skin atrophy 1, 2
• Add antihistamines for symptomatic pruritus relief 1, 2
• Observation without treatment is acceptable if the rash is asymptomatic and stable 1
• If topical therapy fails and pruritus persists, escalate to Grade II-IV treatment protocols 1

Grades II-IV (Multi-Organ or Severe Disease)

First-Line Therapy:

• Methylprednisolone 0.5-1 mg/kg/day for Grade II disease (or prednisone equivalent) 1, 2
• Methylprednisolone 1-2 mg/kg/day for Grade III-IV disease—never exceed 2 mg/kg/day as higher doses provide no additional benefit 1, 2
• Restart, continue, or escalate the original calcineurin inhibitor (tacrolimus or cyclosporine) with therapeutic drug monitoring 1, 2
• For Grade II aGVHD with upper GI symptoms (nausea, vomiting) and diarrhea <1,000 mL/day, add GI topical steroids (beclomethasone dipropionate or budesonide) to low-dose systemic prednisone 1, 2

Response Assessment and Steroid Tapering:

• Define response as complete resolution or improvement in ≥1 organ without progression in others 1
• Taper steroids as clinically feasible once response is achieved to minimize infection risk and metabolic complications 1, 2

Steroid-Refractory Acute GVHD

Critical consideration: Approximately 40-50% of patients develop steroid-refractory disease, which carries high mortality primarily from infectious complications 1

Second-Line Options (when first-line therapy fails):

• Ruxolitinib is the only FDA-approved therapy for steroid-refractory acute GVHD and should be strongly considered 1
• Alternative agents include anti-thymocyte globulin (ATG): rabbit ATG (Thymoglobulin) 2.5 mg/kg/day for 4-6 days or horse ATG (ATGAM) 15 mg/kg twice daily for 5 days 2
• Basiliximab (IL-2 receptor antagonist) 20 mg on days 1 and 4 2
• Etanercept 25 mg twice weekly for 4 weeks, then weekly for 4 weeks 2
• Enrollment in clinical trials is strongly encouraged given the lack of clearly superior second-line agents 1

Important caveat: Skin aGVHD responds better to treatment than GI or liver involvement 2

Chronic GVHD Management

First-Line Therapy

• Systemic corticosteroids 0.5-1 mg/kg/day (methylprednisolone or prednisone equivalent) combined with continuation or escalation of the original calcineurin inhibitor 1
• Initial steroid dose varies based on organs involved, severity, and comorbidities 1

Organ-Specific Topical Therapies:

• Skin: triamcinolone, clobetasol, or topical tacrolimus 1
• Oral cavity: dexamethasone oral rinse 1
• Vulvovaginal: topical estrogen 1
• Lung involvement (bronchiolitis obliterans syndrome): inhaled steroids (budesonide or fluticasone) ± azithromycin (FAM regimen: fluticasone, azithromycin, montelukast) 1

Critical warning: Use azithromycin only for treatment of established BOS, not prophylaxis, as prophylactic use increases cancer relapse risk 1

Steroid-Refractory Chronic GVHD

• Ibrutinib is the only FDA-approved second-line therapy for steroid-refractory chronic GVHD 1
• No specific agent is preferred beyond ibrutinib; selection should be based on organ involvement, toxicity profile, prior treatments, and patient tolerability 1
• Clinical trial enrollment is strongly encouraged given the lack of established standard therapy and poor overall survival 1
• For progressive lung cGVHD failing 2-3 lines of therapy, evaluate for lung transplantation 1

Critical Management Principles

Infection Prophylaxis:

• Intensive antimicrobial prophylaxis is mandatory for all patients receiving GVHD treatment, as infections are the leading cause of death in steroid-refractory disease 3
• Monitor closely for invasive fungal, bacterial, and viral infections 3

Steroid Tapering Strategy:

• Taper according to NIH Response Criteria once improvement is documented 1
• Slow taper is essential to prevent GVHD flares while minimizing long-term steroid complications (hyperglycemia, infections, osteoporosis) 1
• In steroid-dependent disease, continue corticosteroids until alternative steroid-sparing agents demonstrate response 1

Common Pitfall: Never escalate methylprednisolone above 2 mg/kg/day for acute GVHD, as higher doses provide no benefit and increase toxicity 1, 2

Supportive Care:

• Multidisciplinary care is essential to prevent irreversible organ damage and preserve function 1
• Organ-specific supportive interventions should be integrated throughout treatment 1