32 Allogeneic Transplantation & GVHD
- Allogeneic HCT: curative for hematologic malignancies & aplastic anemia; dual GVT effect + immune reconstitution
- aGVHD: <100d post-tx, donor T cell-mediated; target organs: skin, GI, liver
- Graded I–IV (Glucksberg scale)
- Tx: steroids 1–2 mg/kg ± CNI; ruxolitinib for steroid-refractory
- cGVHD: >100d, multi-organ fibrotic; T cell & B cell autoimmunity
- Risk: older age, PB stem cells, prior aGVHD, HLA mismatch
- Tx: steroids, ruxolitinib, ibrutinib, belumosudil
- aGVHD ppx: CNI + MTX; PTCy-based (↓ incidence & relapse)
- Complications: infection (most common death), hyperglycemia, bone loss, myopathy
- GVL effect: balance disease eradication w/ GVHD toxicity; ↑ T-cell depletion → ↑ relapse
32.1 Overview & Pathophysiology
Allogeneic HCT—why & how: - Curative potential for hematologic malignancy, aplastic anemia - Donor T cells: ↑ GVT effect targeting disease; ↑ immune reconstitution vs pathogens - Challenge: maximize GVT while minimizing GVHD damage to host tissues - Over-aggressive T-cell depletion paradoxically ↑ relapse (↓ GVL)
GVHD pathobiology: - Donor T cells alloactivated by host antigens → inflammation & tissue damage - aGVHD: T cell-driven; acute, immune-mediated - cGVHD: T cell + B cell autoimmunity; fibrotic/sclerotic tissue changes - Monitor: biomarkers (ST2, REG3α), hyperglycemia, bone loss, mood disturbance
32.2 Acute GVHD
Definition & organ involvement: - aGVHD: life-threatening, <100d post-transplant, immune-mediated - Target organs: skin, GI tract, liver - Skin: maculopapular (morbilliform) rash → erythroderma ± bullous/desquamation - GI: anorexia, nausea, vomiting, diarrhea (500–>2,000 mL/day), ± hemorrhage - Liver: ↑ bilirubin >1.0 mg/dL (±↑ transaminases); cholestasis
Risk factors & biomarkers: - Age mismatch (older → ↑ risk), PB stem cells >BM, prior aGVHD, HLA mismatch - Early biomarkers: ST2 >90.5 ng/mL, REG3α ↑ at day 28 → very high mortality risk - Assess response at day 7–14 post-initiation; early pivot needed if inadequate
Prophylaxis strategies: - CNI + MTX: tacrolimus/cyclosporine + methotrexate - PTCy-based: posttransplant cyclophosphamide (↓ aGVHD & relapse) - Other: ± abatacept (CTLA-4-Ig), mycophenolate mofetil (MMF) - Goal: balance immune activation reduction w/ GVL preservation
Table 32-1. aGVHD Staging & Grading (Glucksberg)
| Organ | Grade I | Grade II | Grade III | Grade IV |
|---|---|---|---|---|
| Skin | Rash <25% BSA | Rash 25–50% BSA | Rash >50% BSA | Erythroderma ± bullae/desquamation |
| Liver | Bili 1.0–1.5 | Bili 1.6–3.0 | Bili 3.1–6.0 | Bili >6.0 |
| GI | 500–1,000 mL/d stool or nausea | 1,000–1,500 mL/d | 1,500–2,000 mL/d ± cramping | >2,000 mL/d or gross bleeding |
Treatment—first-line: - Steroids: methylprednisolone 1–2 mg/kg/day IV ÷ 2–4 doses; taper over 8–10 wks - Add CNI (tacrolimus or cyclosporine) to mitigate immune damage - Topical: emollients & topical steroids for skin; oral rinses/care for mucosal
Steroid-refractory aGVHD (progressing on ≥2 mg/kg methylprednisolone): - Ruxolitinib (JAK1/2 inhibitor): 5–10 mg BID; FDA-approved 2019 → 2–3x ↑ CR vs standard salvage - Alternative: tacrolimus escalation, ± pentamidine, other investigational agents - Assess response day 7–14; pivot early if inadequate - SE: infection (most common with high-dose steroids), myopathy, hyperglycemia, bone loss, mood disturbance
- Steroid-refractory (progressing on ≥2 mg/kg methylprednisolone) → ruxolitinib ↑ CR 2–3x vs standard
- Day 28 biomarkers: ST2 >90.5 ng/mL or REG3α ↑ → very high mortality risk; early intervention critical
- Assess response day 7–14 post-initiation; delay pivoting >2 wks increases mortality
32.3 Chronic GVHD
Definition & pathophysiology: - cGVHD: >100d post-tx, multifactorial; T cell alloreactivity + B cell autoimmunity - Fibrotic/sclerotic tissue changes; mild to life-threatening organ dysfunction - Risk: older age, PB stem cells, prior aGVHD, HLA mismatch
Multi-organ involvement (NIH criteria): - Skin (sclerodermoid changes, lichenoid), mouth (sicca, ulcers), liver (cholestasis) - Lungs (bronchiolitis obliterans syndrome [BOS]), GI (strictures), eyes (keratoconjunctivitis sicca), genitalia - Grade: mild/moderate/severe based on functional impact
Treatment—first-line: - Steroids (prednisone 0.5–1 mg/kg/day) + CNI (tacrolimus/cyclosporine) - Second-line (refractory or steroid-sparing): - Ruxolitinib (JAK1/2 inhibitor) - Ibrutinib (Bruton tyrosine kinase inhibitor) - Belumosudil (ROCKi) - PTCy-based regimens (if used prospectively)
Organ-specific supportive care: - Skin: emollients, topical steroids, phototherapy (severe) - Mouth: topical steroids, saline rinses, oral hygiene - GI: dietary adjustment, antiemetics, antidiarrheals, ± TPN - Liver: ursodeoxycholic acid, avoid hepatotoxic drugs - Lungs: pulmonary rehab, vaccination, azathioprine ± inhaled steroids - Eyes: lubricants, punctal plugs, ophthalmology referral - Bone: Ca/Vit D, weight-bearing exercise, DEXA monitoring - Psychological: support groups, activity to combat fatigue
Table 32-2. cGVHD Management
| Organ | Treatment | Monitoring |
|---|---|---|
| Skin | Topical/systemic steroids, phototherapy (severe) | Extent/activity |
| Mouth | Topical steroids, saline rinses | Oral function, nutrition |
| Eye | Lubricants, punctal plugs, ± rituximab | Ophthalmology assessment |
| GI | Dietary mgmt, antiemetics, antidiarrheals, ± TPN | Nutrition status, weight |
| Liver | Ursodeoxycholic acid, avoid hepatotoxins | LFTs, bilirubin |
| Lungs | Steroids, azathioprine, ± pentamidine | PFTs, imaging if BOS |
| Cardiac | ACE-I, beta-blockers (if needed) | EKG, echo if indicated |
| Genitalia | Topical steroids ± systemic; PT for dysfunction | Sexual/urinary function |
| Muscle/Fascia | PT, steroids, stretching | Strength, ROM, mobility |
| Bone | Ca/Vit D, weight-bearing, ± bisphosphonates | DEXA q1–2y, fracture risk |
Complications & prognosis: - Most common death: infection (immunosuppression + impaired immunity) - Prophylaxis: TMP-SMX for PCP, itraconazole for fungi, consider IgG replacement if hypogammaglobulinemia - Monitor: hyperglycemia, hypertension, dyslipidemia, bone loss, mood disturbance - PTCy-based regimens significantly ↓ cGVHD & relapse vs traditional myeloablative
- PTCy-based regimens (posttransplant cyclophosphamide) ↓↓ cGVHD & relapse vs traditional conditioning
- Multi-organ disease risk ↑ w/ disease progression; balance corticosteroids (infection risk) w/ GVHD control
- Comorbidity monitoring: hyperglycemia, bone loss, dyslipidemia, psychosocial distress → improve QoL & survival
32.4 Key Takeaways
- GVT effect balance: maximize disease control while minimizing GVHD toxicity
- aGVHD: steroids 1–2 mg/kg ± CNI; ruxolitinib for steroid-refractory → assess day 7–14
- cGVHD: steroids + CNI; ruxolitinib/ibrutinib/belumosudil ± PTCy for optimization
- Prevention: CNI + MTX ± PTCy more effective than aggressive T-cell depletion
- Infection: most common cGVHD death; prophylaxis & monitoring essential
- Biomarkers: ST2, REG3α at day 28 predict poor prognosis; inform escalation strategy