Acute graft-versus-host disease (GVHD)

Pathophysiology and Risk

• About 50% of patients develop GVHD after allogeneic transplant. In HLA-matched sibling transplants, GVHD causes roughly 9% of deaths in the first 100 days and 7% of deaths after day 100.
• Three-phase model: (1) conditioning-induced tissue damage releases cytokines; (2) donor and recipient antigen-presenting cells activate donor T cells, driving a cytokine storm; (3) effector phase, with apoptosis (the hallmark of acute GVHD) and inflammation in host tissue. Fibrosis occurs later and is the hallmark of chronic GVHD.
• Risk factors: HLA disparity (acute GVHD risk about 28% when fully HLA-matched; each single mismatch raises the rate by about 10% and drops 1-year survival by about 10%); older donor and/or recipient; conditioning intensity (MAC > RIC); sex mismatch (female donor into male recipient, related to parity/alloimmunization); GVHD prophylaxis type; peripheral blood > bone marrow graft source; T-cell-replete grafts; low-dose immunosuppression.

Terminology and Timing

• Acute and chronic are classically separated at 100 days, but the distinction is now clinical rather than purely temporal.
• Overlap syndrome: diagnostic chronic GVHD features plus concurrent acute GVHD features, at any time post-transplant (not defined by onset before day 100).
• Late acute GVHD: acute features (rash, diarrhea, transaminitis, hyperbilirubinemia) presenting > 100 days, as persistent, recurrent, or de novo disease without chronic features.

Organ Staging (Skin, Liver, GI)

• The four assessed areas are skin (active erythema only), liver (bilirubin), upper GI (persistent anorexia/nausea/vomiting; staged 0 or 1 only, no stage 2; isolated upper-GI involvement gives overall grade II), and lower GI (stool output per day).
• Skin: acute GVHD most commonly appears first on palms and soles, often around engraftment. Histology shows keratinocyte apoptosis with basal vacuolization.
• Lower GI: large watery diarrhea from (1) immune-mediated mucosal destruction with failed fluid resorption (especially ileum); (2) brush-border and disaccharidase loss causing osmotic diarrhea from undigested carbohydrate; (3) dysbiosis with loss of polysaccharide-metabolizing flora; (4) loss of tight junctions with protein-driven oncotic fluid shifts. Endoscopic biopsy sensitivity is wide (about 35% to 85%), so a normal biopsy does not exclude GI GVHD. Pathologic grading is separate from clinical grading.
• Liver: cholestatic pattern with rising total bilirubin and hepatocyte apoptosis. DDx: SOS/VOD, cyclosporine, azoles, liposomal amphotericin, TMP-SMX, infection (CMV, viral hepatitis), and MMF (which itself can cause diarrhea with GI eosinophilia).

Overall Grading (Glucksberg / MAGIC)

• Grade I: skin stage 1 to 2 only (no liver or GI). Manage with topical steroids (eg, triamcinolone or clobetasol).
• Grade II: skin stage 3, OR liver stage 1, OR GI stage 1. Give systemic steroids.
• Grade III: liver stage 2 to 3, OR lower GI stage 2 to 3 (with skin stage 0 to 3).
• Grade IV: skin stage 4, liver stage 4, OR lower GI stage 4 (MAGIC; the older 1994 consensus/modified Glucksberg placed GI stage 4 in grade III).
• Systemic steroids are indicated for grade II to IV disease. Grade at day 28 is prognostically critical: non-responders have higher nonrelapse (transplant-related) mortality and worse overall survival. Biomarkers of tissue damage and inflammation (elevated ST2 and REG3a) and the revised Minnesota risk model help predict steroid response.

Diagnosis

• Timing: classically < 100 days post-transplant; late acute > 100 days is possible without chronic features.
• Diagnosis: clinical, with corroborating biopsy if atypical (skin biopsy: vacuolar interface dermatitis, lymphocyte exocytosis, satellite necrosis). Workup of LFTs/diarrhea must exclude infection (CMV, C. difficile) and drug toxicity.

Prophylaxis

• Calcineurin inhibitor + methotrexate: tacrolimus + MTX is the historical standard (tacrolimus gives less grade II to IV acute GVHD than cyclosporine, without a survival advantage). Continue the CNI about 3 to 6 months then taper; for aplastic anemia (no graft-versus-leukemia needed) it can be continued longer.
• Post-transplant cyclophosphamide (PTCy): days +3, +4; reduces alloreactive T-cell proliferation. Both marrow and peripheral blood are accepted for haploidentical PTCy transplants; marrow gives less acute and chronic GVHD, while peripheral blood may lower relapse in some malignancies, with no significant graft-failure difference. When tapering hydration around PTCy, watch for hemorrhagic cystitis.
• Other regimens: MMF + sirolimus; antithymocyte globulin (ATG).
• Abatacept (Orencia): CTLA4-Ig; FDA Dec 15, 2021 for aGVHD prophylaxis with a CNI + MTX in patients ≥ 2 years receiving HSCT from a matched or 1-allele-mismatched unrelated donor (7/8 cohort: day-180 OS 98% vs 75%).
• CNI toxicity note: tacrolimus is a macrolide that inhibits calcineurin (reducing IL-2 transcription and T-cell signaling). Adverse effects include nephrotoxicity, immunosuppression, TTP/TMA, and PRES (posterior reversible encephalopathy, presenting with hypertension, headache, seizures, vision changes, altered mental status and characteristic MRI findings). For PRES, withdraw the CNI and switch to sirolimus (or MMF/steroids); patients typically recover.

Treatment

• First line, corticosteroids: methylprednisolone (or prednisone equivalent) 2 mg/kg/day for grade ≥ 3, and 1 mg/kg/day for grade 2 (0.5 mg/kg/day may be considered for grade IIa, weak evidence). About 50% of patients respond. Do not switch agents when starting a second-line drug: keep steroids until a response is achieved.
• GI-directed steroids: beclomethasone and budesonide (poorly absorbed, local effect) treat GI GVHD and reduce systemic steroid exposure; a randomized survival benefit is shown for oral beclomethasone (orBec), not budesonide.

Steroid-Refractory Acute GVHD

• Definition (SR-aGVHD): progression after 3 to 5 days, no improvement after 5 to 7 days at 2 mg/kg/day, or steroid dependence (cannot taper).
• Ruxolitinib (JAK1/2 inhibitor): standard second line. FDA May 24, 2019 for SR-aGVHD (≥ 12 years). REACH-1 (phase 2) and REACH-2 (phase 3, ORR 62% vs 39% for best available therapy). Median time to response about 7 days, so begin the steroid taper around then.
• Remestemcel-L (Ryoncil): FDA Dec 18, 2024 for pediatric SR-aGVHD (≥ 2 months); allogeneic bone-marrow-derived mesenchymal stromal cell therapy, the first MSC therapy FDA-approved.
• Extracorporeal photopheresis (ECP): UVA plus psoralen increases regulatory T cells; allows steroid tapering. Phase 2 data: about 82% complete response in skin, about 61% in liver and gut GVHD.
• Other options: MMF, ATG, alemtuzumab (anti-CD52), rituximab: primarily a chronic GVHD agent (about 70% ORR, about 10% CR in chronic GVHD); not established for acute GVHD, low-dose IL-2 (expands Tregs; about 50 to 60% response in chronic GVHD, generally well tolerated at low dose); chronic-GVHD data, not established for acute GVHD, pentostatin.
• Vedolizumab (anti-α4β7 integrin): off-label for steroid-refractory lower GI aGVHD (Floisand et al, BBMT 2017); limits gut-homing of donor T cells.
• Itacitinib (JAK1 inhibitor): GRAVITAS-301 phase 3 (itacitinib + steroids as initial aGVHD therapy) did not meet its primary endpoint (day-28 ORR 74% vs 66%, P=.078); not FDA-approved.
• Old comparative trials: BMT-CTN 0302 (phase 2: etanercept vs MMF vs denileukin vs pentostatin) favored MMF, but BMT-CTN 0802 (phase 3) showed MMF was not better than placebo added to steroids.
• Topical / supportive: skin, topical steroids plus tacrolimus; lower GI, budesonide PO. Aggressive electrolyte/fluid replacement, infection prophylaxis, GI motility management, and parenteral nutrition for severe GI disease.