What is the recommended management of acute graft‑versus‑host disease after allogeneic hematopoietic stem cell transplantation?

Management of Acute Graft-Versus-Host Disease Post Allogeneic Stem Cell Transplantation

Initiate systemic corticosteroids with methylprednisolone at 2 mg/kg/day (or prednisone equivalent) as first-line therapy for acute GVHD grades II-IV, while Grade I disease can be managed with topical steroids and continuation of baseline immunosuppression. 1, 2

First-Line Treatment Strategy

Grade I Acute GVHD (≤50% BSA skin involvement, no other organ involvement)

• Continue or restart the original immunosuppressive agent used for transplant prophylaxis 2, 3
• Apply medium to high-potency topical corticosteroids to affected body areas, using low-potency hydrocortisone on facial skin to prevent atrophy 2, 3
• Add topical tacrolimus as adjunctive therapy for affected skin areas 3
• Prescribe antihistamines for symptomatic relief of pruritus 2, 3

Grade II-IV Acute GVHD (>50% BSA or visceral organ involvement)

• Administer methylprednisolone at 1-2 mg/kg/day intravenously, with the higher dose (2 mg/kg/day) reserved for Grade III-IV disease 1, 2
• The NCCN guidelines specify methylprednisolone at 1.6 mg/kg/day (or prednisone dose equivalent) based on the BMT CTN 0802 trial, though 2 mg/kg/day is commonly used for severe disease 1
• Restart, continue, or escalate the original immunosuppressive agent if GVHD developed during immunosuppression tapering 2, 3
• For upper gastrointestinal symptoms, add topical GI steroids 2

Important caveat: The addition of mycophenolate mofetil (MMF) to methylprednisolone provides no benefit over methylprednisolone alone for first-line therapy, as demonstrated by the BMT CTN 0802 trial which met futility criteria with equivalent outcomes in overall survival, chronic GVHD incidence, and infection risk. 1

Alternative First-Line Option for Standard-Risk Disease

• Sirolimus may be used as an alternative to systemic corticosteroids for patients with standard-risk acute GVHD (defined by Minnesota clinical risk score or Ann Arbor biomarker status), with similar day 28 overall response rates (65% vs 73% for prednisone) 1
• Sirolimus carries reduced risk of hyperglycemia and infections but increased risk of thrombotic microangiopathy (10% vs 1.6%) compared to prednisone 1
• This approach requires confirmation in phase III trials before becoming standard practice 1

Assessment of Treatment Response

Evaluate response at specific timepoints:

• Day 3: If disease progresses, proceed immediately to second-line therapy 4
• Day 7: If no improvement observed, initiate second-line therapy 4
• Day 28: Assess overall response rate and organ-specific responses 1

Critical prognostic insight: Skin GVHD demonstrates superior response rates to treatment (79% improvement with salvage therapy) compared to gut (40% progression) and liver GVHD (66% progression), which carry significantly worse prognoses. 5

Second-Line Therapy for Steroid-Refractory Disease

Ruxolitinib is the only FDA-approved agent for steroid-refractory acute GVHD, though the NCCN panel does not prefer any specific second-line agent and strongly encourages enrollment in clinical trials. 1

Second-Line Treatment Options

When steroids fail, consider the following agents (no clear superiority established):

Anti-thymocyte globulin (ATG):

• Thymoglobulin (rabbit ATG): 2.5 mg/kg/day for 4-6 consecutive days 2
• ATGAM (horse ATG): 15 mg/kg twice daily for 5 days 2
• Particularly effective for skin GVHD (61-96% response rates) 3
• Major limitation: Only 30% of patients show initial improvement, with 90% mortality despite treatment, primarily from progressive GVHD and/or infection (74%), ARDS (15%), or relapse (11%) 5
• Long-term survival occurs in only 10% of patients, predominantly those with skin-limited disease at ATG initiation 5

Calcineurin inhibitors (tacrolimus or cyclosporine):

• Can be used as second-line therapy if not already part of the prophylaxis regimen 2, 6

Basiliximab (IL-2 receptor antagonist):

• Dose: 20 mg on days 1 and 4 2
• Shows 77% response rate with at least one-grade reduction in skin GVHD 3

Etanercept:

• 25 mg twice weekly for 4 weeks, then 25 mg weekly for 4 weeks 2

Extracorporeal photopheresis (ECP):

• Immunomodulating modality used in combination with calcineurin inhibitors 1, 6

Other agents with limited evidence:

• Mycophenolate mofetil (MMF) 6
• Pentostatin 6
• Rituximab (for selected patients with chronic GVHD features) 6

Recommended Approach for Steroid-Refractory Disease

For rapid progression or lack of response to steroids, initiate ATG as second-line therapy, or alternatively use calcineurin inhibitor plus extracorporeal photopheresis. 1

This recommendation is based on expert consensus from Blood guidelines for managing transplant-related GVHD, though it acknowledges the poor overall outcomes with current second-line therapies. 1

Special Considerations for PD-1 Blockade-Associated GVHD

For patients who develop transplant-exacerbated GVHD (teGVHD) after PD-1 blockade:

• Immediately stop anti-PD-1 therapy 1
• Initiate IV methylprednisolone at 2 mg/kg/day rapidly 1
• Implement early intervention with second-line immunosuppression if no rapid response to steroids, preferring ATG or calcineurin inhibitor plus ECP 1

Critical warning: teGVHD is often refractory to standard GVHD-directed treatment, with common refractoriness requiring multiple immunosuppressive agents. 1

Post-Transplant Maintenance and GVHD Prevention

For FLT3-ITD mutated AML patients, initiate sorafenib maintenance therapy (400 mg twice daily) as soon as possible post-transplant once adequate hematologic reconstitution is achieved, except in patients with active acute GVHD. 1, 7

Key maintenance considerations:

• Sorafenib should be transiently discontinued if GVHD requires systemic corticosteroid treatment, but may be cautiously resumed once GVHD remission is documented 1, 7
• Cutaneous GVHD develops in a substantial proportion of patients within days of sorafenib initiation, suggesting immunomodulatory effects, and is typically corticosteroid-sensitive 7
• Continue maintenance for minimum 2 years depending on tolerance 1, 7

Prognosis and Outcomes

Patients with Grade III-IV acute GVHD have poor outcomes, with steroid-refractory disease carrying particularly high mortality. 4

Approximately 50% of patients respond to first-line methylprednisolone therapy. 4 For those who become steroid-refractory, mortality remains high (90% in some series) despite second-line interventions, with death primarily from progressive GVHD, infection, or ARDS. 5

About 50% of patients with acute GVHD will eventually develop manifestations of chronic GVHD, requiring long-term management. 4

Critical Clinical Pitfalls

• Do not add MMF to first-line corticosteroids - this provides no benefit and was shown futile in the BMT CTN 0802 trial 1
• Do not delay second-line therapy - waiting beyond day 7 without improvement or day 3 with progression significantly worsens outcomes 4
• Monitor closely for infections - infection is a major cause of mortality in GVHD patients, particularly those receiving multiple immunosuppressive agents 3, 5
• Recognize organ-specific response patterns - skin GVHD responds better than visceral organ involvement, which should inform prognostic discussions 5