Graft-Versus-Host Disease

Graft-Versus-Host Disease (GVHD)

Definition

• A complication of allogeneic HSCT where donor T-lymphocytes recognize recipient tissues as foreign and mount an immune attack.
• Does not occur in autologous HSCT.

Pathophysiology

1. Conditioning regimen → host tissue damage → cytokine release (TNF-α, IL-1, IL-6).
2. Donor T-cells activated → recognize recipient HLA as foreign.
3. Cytotoxic T-cells & inflammatory cytokines attack host tissues.
4. Major targets: skin, GI tract, liver.

Types of GVHD

1. Acute GVHD (aGVHD)
   • Classically within first 100 days post-HSCT (but may occur later with RIC or DLI).
   • Organs involved:
     • Skin → maculopapular rash (palms, soles, ears, trunk)
     • Liver → ↑ bilirubin, LFTs
     • GI tract → diarrhea, abdominal pain, nausea, ileus
   • Grading (I–IV): based on % body surface rash, bilirubin, stool volume.
2. Chronic GVHD (cGVHD)
   • Usually >100 days post-HSCT.
   • Resembles autoimmune disorders:
     • Skin → scleroderma-like changes, lichen planus
     • Eyes → sicca syndrome (dry eyes)
     • Mouth → xerostomia, ulcers
     • Lungs → bronchiolitis obliterans
     • Joints/fascia → contractures
   • Can be limited or extensive, mild/moderate/severe.

Risk Factors

• Donor factors: HLA mismatch, unrelated donor, older donor
• Recipient factors: older age, female recipient of male donor
• Transplant factors: peripheral blood stem cells > bone marrow, TBI conditioning, absence of T-cell depletion
• Prevention failure: inadequate immunosuppression

Prevention (Pharmacist Focus)

• Standard prophylaxis:
  • Calcineurin inhibitor (CNI): tacrolimus or cyclosporine
  • PLUS methotrexate (low-dose) or mycophenolate mofetil (MMF)
• Haploidentical HSCT: add post-transplant cyclophosphamide (PTCy, day +3/+4)
• Alternative regimens: sirolimus-based, ATG (antithymocyte globulin), alemtuzumab (anti-CD52)

Treatment

1. First-line:
   • Systemic corticosteroids: methylprednisolone 2 mg/kg/day (acute GVHD)
   • Prednisone ± topical therapies (for chronic GVHD)
2. Steroid-refractory GVHD (SR-GVHD):
   • Ruxolitinib (Jakafi®) – JAK1/2 inhibitor (FDA-approved for both aGVHD & cGVHD)
   • Belumosudil (Rezurock®) – ROCK2 inhibitor (cGVHD after ≥2 prior therapies)
   • Ibrutinib (Imbruvica®) – BTK inhibitor (cGVHD after ≥1 prior therapy)
   • Other options: ATG, extracorporeal photopheresis, mesenchymal stromal cells

Pharmacist Considerations

• CNI monitoring:
  • Tacrolimus: target trough 5–15 ng/mL (center-specific)
  • Cyclosporine: target trough 150–250 ng/mL
  • Watch for nephrotoxicity, hypertension, neurotoxicity, drug–drug interactions (azoles, macrolides, antivirals).
• Steroid monitoring: infection risk, hyperglycemia, osteoporosis, GI protection.
• Infection prophylaxis essential:
  • HSV/VZV → acyclovir
  • CMV → letermovir (high-risk allo)
  • PCP → TMP-SMX (or atovaquone/pentamidine)
  • Antifungal → fluconazole/posaconazole depending on GVHD risk
• Vaccinations: restart at 6–12 months post-HSCT, delayed if on high-dose immunosuppression.

Key Points for Pharmacists

• Acute GVHD = rash, liver, gut (before day 100).
• Chronic GVHD = autoimmune-like multi-organ (after day 100).
• Prevention is CNI + MTX/MMF ± PTCy.
• Treatment is steroids first, then targeted agents like ruxolitinib, belumosudil, ibrutinib if refractory.
• Role: drug monitoring, prophylaxis, toxicity prevention, patient education.