What are the clinical features and management of Graft versus Host Disease (GVHD)?

Graft-Versus-Host Disease: Clinical Features and Management

Overview

GVHD is a major complication following allogeneic hematopoietic cell transplantation that requires early recognition and prompt treatment, with systemic corticosteroids remaining the cornerstone of first-line therapy for both acute and chronic forms, though newer targeted agents like ruxolitinib and ibrutinib now provide FDA-approved options for steroid-refractory disease. 1, 2

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Clinical Features of Acute GVHD

Primary Target Organs

Acute GVHD primarily affects three organ systems and typically develops within the first 100 days post-transplant 3, 4:

Skin manifestations:

• Maculopapular rash that may progress to involve varying percentages of body surface area 1, 3
• Often the earliest and most common presentation 5

Gastrointestinal involvement:

• Diarrhea, nausea, vomiting, and abdominal pain 1, 3
• Requires exclusion of infectious causes, particularly C. difficile and CMV, before attributing symptoms solely to GVHD 3

Hepatic disease:

• Hyperbilirubinemia and elevated liver function tests 1, 3
• Often asymptomatic, requiring routine monitoring 3

Diagnostic Approach

• Acute GVHD is primarily a clinical diagnosis based on characteristic organ involvement 1
• Biopsy confirmation is recommended when feasible but treatment should not be delayed while awaiting biopsy results 3
• Organ-directed biopsies include: lower GI biopsy for diarrhea, upper GI biopsy for nausea/vomiting, skin biopsy for rash, and liver biopsy for unexplained liver function abnormalities 3
• Always exclude alternative causes through stool testing for infectious agents, imaging studies, and viral reactivation testing 3

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Clinical Features of Chronic GVHD

Multi-System Involvement

Chronic GVHD is the leading cause of non-relapse mortality after allogeneic HCT and profoundly impacts quality of life 6:

• Usually develops within the first year after transplant but can occur many years later 6
• Affects multiple organ systems with fibrosis and clinical features resembling autoimmune disorders 6
• Approximately 45% of long-term survivors develop chronic GVHD 4

Diagnostic Clinical Signs

Chronic GVHD requires at least one diagnostic clinical sign OR at least one distinctive manifestation confirmed by biopsy or relevant testing 1, 3:

Affected organs include:

• Skin and appendages (lichenoid or sclerodermatous changes) 3, 7
• Mouth (oral mucosal lesions) 3, 5
• Eyes (lacrimal gland involvement) 3, 4
• Female genitalia 3
• Esophagus 3
• Lungs (bronchiolitis obliterans syndrome) 1, 3
• Connective tissues 3
• Nails, hair, and mucous membranes 4, 7

Bronchiolitis Obliterans Syndrome (BOS)

• BOS is a devastating inflammatory lung condition 6
• Unless pathologically diagnosed via lung biopsy, clinical characteristics of BOS assessed by pulmonary function tests are only diagnostic of lung chronic GVHD if distinctive features of chronic GVHD are present in another organ 6, 1, 3

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Management of Acute GVHD

Grade I Disease

For Grade I acute GVHD, continue or restart the original immunosuppressive agent and apply topical therapies 1, 2:

• Medium- to high-potency topical steroids 2
• Antihistamines for symptomatic pruritus relief 2

Grades II-IV Disease

Systemic corticosteroids are the cornerstone of first-line therapy 1, 2:

• Grade II: Methylprednisolone 0.5-1 mg/kg/day 1, 2
• Grades III-IV: Methylprednisolone 1-2 mg/kg/day (maximum 2 mg/kg/day) 1, 2

Response criteria:

• Complete resolution or improvement in ≥1 organ without progression in others 2
• Taper steroids as clinically feasible once response is achieved to mitigate long-term side effects and infection risk 2

Steroid-Refractory Disease

Ruxolitinib is the only FDA-approved therapy for steroid-refractory acute GVHD 6, 1:

• 6-month survival is comparable to other agents 6, 1
• The NCCN panel does not prefer any specific second-line agent and encourages clinical trial enrollment 6
• Approximately 40-50% of patients develop steroid-refractory disease, which carries high mortality risk 1

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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 6, 2:

• Initial corticosteroid dose varies depending on organs involved, severity, and patient comorbidities 6
• Clinical trial enrollment is encouraged for all patients presenting with chronic GVHD 6, 1

Organ-Specific Topical Therapies

Topical treatments should be used as clinically indicated 6, 2:

• Skin: Triamcinolone, clobetasol, or topical tacrolimus 6, 1, 2
• Oral cavity: Dexamethasone oral rinse 6, 1, 2
• Vulvovaginal: Topical estrogen 6
• Lung involvement: Inhaled steroids (budesonide or fluticasone) plus azithromycin (FAM regimen: fluticasone, azithromycin, and montelukast) 6

Critical caveat: Azithromycin should be used only for treatment of BOS and not for prophylaxis due to increased risk of cancer relapse 6

Steroid-Refractory Chronic GVHD

Ibrutinib is the only FDA-approved second-line therapy for steroid-refractory chronic GVHD 6, 1, 2:

• Indicated after failure of one or more lines of systemic therapy 1
• Belumosudil is an additional treatment option for steroid-refractory chronic GVHD 8
• The NCCN panel encourages clinical trial enrollment for steroid-refractory disease 6

Advanced Lung Disease

Patients with progressive or worsening lung chronic GVHD following 2-3 lines of therapy may be evaluated for lung transplant 6, 1

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Critical Management Principles

Multidisciplinary Approach

Multidisciplinary care in specialized transplant centers is strongly recommended to prevent irreversible organ damage and preserve function 6, 1, 2:

• Early recognition of signs and symptoms is essential 6, 1
• Organ-specific supportive interventions should be integrated throughout treatment 1, 2

Steroid Tapering Strategy

Taper steroids according to NIH Response Criteria once improvement is documented 2:

• Slow taper is essential to prevent GVHD flares while minimizing long-term steroid complications 2
• Mitigate long-term side effects and risk of infection 6

Severity-Based Treatment Intensity

Treatment intensity must be matched to global severity 1:

• Mild disease: Managed with topical therapies and observation 1
• Moderate-to-severe disease: Requires systemic corticosteroids as first-line therapy 1

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Common Pitfalls and How to Avoid Them

Do not delay treatment while awaiting biopsy confirmation 3:

• Clinical diagnosis is acceptable when typical features are present 3
• Biopsy has imperfect sensitivity and is not absolutely required 3

Always rule out infectious causes before attributing symptoms solely to GVHD 3:

• Particularly C. difficile and CMV 3
• Perform stool testing and viral reactivation testing 3

Do not perform colonoscopy routinely 3:

• Upper endoscopy with flexible sigmoidoscopy is safer and equally effective 3

Do not use azithromycin for BOS prophylaxis 6:

• Data suggest increased risk for cancer relapse in HCT patients receiving azithromycin prophylactically 6