Chronic graft-versus-host disease (GVHD)

Overview and Timing

• Chronic GVHD occurs in more than 50% of long-term survivors of HLA-identical sibling transplants. Median onset is about 6 months; roughly 10% occur > 1 year. It can follow prior or ongoing acute GVHD, or arise de novo.
• Fibrosis is the pathologic hallmark of chronic GVHD (in contrast to apoptosis in acute GVHD).
• Overlap syndrome: coexisting acute and chronic features; chronic features can present < 100 days. Conversely, acute features > 100 days are termed late acute (persistent, recurrent, or de novo) GVHD.

Diagnosis and Classification

• Timing: classic chronic GVHD usually > 100 days but can occur earlier; overlap = both acute and chronic features; late acute (acute features > 100 days) is acute, not chronic, GVHD.
• NIH 2014 consensus criteria: at least one diagnostic clinical sign is sufficient, OR at least one distinctive manifestation confirmed by pertinent biopsy or relevant test (eg, Schirmer test) in the same or another organ.
• Diagnostic features (establish the diagnosis alone): poikiloderma, lichen planus-like or sclerotic skin, lichen-type oral changes, esophageal web/stricture, bronchiolitis obliterans (biopsy-proven), lichen planus-like vaginal scarring or stenosis, fasciitis, and joint contractures from sclerosis.
• Distinctive features (suggestive but need corroboration): depigmentation, nail dystrophy, alopecia, xerostomia, keratoconjunctivitis sicca, and BOS diagnosed by PFTs plus radiology.

Target Organs and Manifestations

• Skin: lichen planus-like changes or scleroderma-like cutaneous disease (tight, dry, itchy skin; abnormal appearance; sweat and nail changes).
• Liver: rising LFTs and bilirubin (cholestatic pattern).
• GI / mouth: dry oral mucosa with ulcerations, dysphagia with weight loss, chronic diarrhea; GI chronic GVHD can present as a wasting syndrome (assess temporal relationship to steroid tapering).
• Eyes: sicca (keratoconjunctivitis sicca), dryness, irritation, vision change.
• Pulmonary: bronchiolitis obliterans syndrome (BOS), with FEV1 always < 75%; managed with FAM (fluticasone, azithromycin, montelukast) and close PFT monitoring. Cryptogenic organizing pneumonia (COP) presents with fever, dry cough, dyspnea and infiltrates, and may show normal or restrictive spirometry (unlike BOS, which is obstructive with FEV1 < 75%).
• Other: eye and female genital changes, thrombocytopenia, sicca syndrome, polymyositis, myasthenia gravis, nephrotic syndrome/minimal change disease, vaginal inflammation and stenosis.
• Infection risk: chronic GVHD causes functional hyposplenia and hypogammaglobulinemia with impaired response to polysaccharide antigens, predisposing to encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis, Klebsiella, Salmonella typhi, E. coli). Consider lifelong penicillin prophylaxis.

Risk Factors and Severity

• Risk factors: higher-degree HLA mismatch; older donor and/or recipient; donor-recipient gender disparity (female donor into male recipient); donor alloimmunization (prior pregnancy, transfusions); stem cell source (PBSC > bone marrow or cord blood); prior acute GVHD; unirradiated donor buffy coat / donor lymphocyte infusions; previous splenectomy; CMV seropositivity (donor and/or recipient); donor EBV seropositivity.
• NIH severity: mild, moderate, or severe, graded by the number of organs involved and each organ score.

Treatment

• Mild disease: systemic immunosuppression is not required, unless higher-risk features are present (platelets < 100, or the patient was on systemic steroids at chronic GVHD onset).
• First line: prednisone about 1 mg/kg, with continuation of a calcineurin inhibitor.
• Steroid-refractory cGVHD, FDA-approved options:
  • Ruxolitinib (Jakafi): JAK1/2 inhibitor; FDA Sep 22, 2021 for SR-cGVHD (≥ 12 years). REACH-3 (phase 3, moderate to severe steroid-refractory/dependent cGVHD, ≥ 12 yr) showed superiority to best available therapy, with about 50% response. Often second line.
  • Belumosudil (Rezurock): ROCK2 inhibitor (formerly KD025), aims to reduce fibrosis; FDA Jul 16, 2021 for cGVHD after ≥ 2 prior lines. ROCKstar trial (KD025-213), ORR about 75%; watch hepatotoxicity.
  • Ibrutinib (Imbruvica): FDA Aug 2017 for cGVHD after ≥ 1 prior line; about 60% response but limited by adverse effects (often used only a few months). Less used now given other options.
  • Axatilimab (Niktimvo): anti-CSF1R; FDA Aug 14, 2024 for cGVHD (≥ 40 kg) after ≥ 2 prior lines. AGAVE-201 trial, about 75% ORR.
• Extracorporeal photopheresis (ECP): UVA plus psoralen upregulates regulatory T cells; allows steroid tapering with frequent skin and visceral responses in chronic GVHD.
• Other systemic agents (per NCCN): abatacept, alemtuzumab, calcineurin inhibitors (tacrolimus, cyclosporine), etanercept, hydroxychloroquine, imatinib, low-dose IL-2, low-dose methotrexate, mTOR inhibitors (sirolimus), MMF, pentostatin, rituximab.
• Supportive: eye drops for sicca; oral hygiene and dental care; skin moisturization and sun protection; physical therapy for fasciitis/sclerosis; FEV1 monitoring with bronchodilators and FAM (fluticasone/azithromycin/montelukast) for BOS.
• Vaccines: start non-live vaccines on a fixed post-HCT schedule regardless of immunosuppression (pneumococcal conjugate and COVID ~3 to 6 mo; influenza, hepatitis B, HPV ~6 to 12 mo); live vaccines (MMR, varicella) need >=24 mo, no active GVHD, and off systemic immunosuppression.

GVHD Prophylaxis (Modern Era)

• Standard CNI/MTX: tacrolimus + methotrexate (historical standard).
• PTCy-based (new standard per BMT CTN 1703 in reduced-intensity matched related, matched unrelated, and 7/8 mismatched unrelated donor HCT): post-transplant cyclophosphamide days +3, +4 plus tacrolimus and MMF; significantly reduces chronic GVHD; now extended from haploidentical to MUD.
• Sirolimus-based regimens: alternative; increased TA-TMA risk.
• ATG addition: reduces chronic GVHD; used in selected settings.