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Graft-Versus-Host Disease

Basics

Description

- Following associated with greater risk of aGVHD - Human leukocyte antigen (HLA) discrepancy between host and donor - Type and remission status of disease - Conditioning regimen - Age of recipient - Sex disparity; highest risk = female donor to male recipient; risk increases for each pregnancy - ABO blood group incompatibility - Prophylactic immunosuppressive medications - Cytomegalovirus (CMV) serostatus disparity

- Risk factors for cGVHD - Antecedent aGVHD episodes - HLA disparity - Use of peripheral blood stem cells - Sex disparity; highest risk = female donor to male recipient; risk increases for each pregnancy - Splenectomy

- aGVHD - Prophylactic immunosuppression with, calcineurin inhibitor plus short-course methotrexate or mycophenolate or sirolimus - Depletion of host alloantigens - Depletion of donor T cells - Emerging role for statins in donor and/or recipient

- Infectious complications - Invasive fungal infections - Pneumocystis jiroveci pneumonia - Herpesvirus infection - CMV infection

  • Tissue destruction in allogeneic hematopoietic stem cell transplant (HSCT) recipients is due to donor T cells responding to host antigens.
  • 2 types: Acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD); traditionally delineated by time from transplant (aGVHD occurs <100 days, whereas cGVHD occurs ≥100 days). Current designation separates by clinical manifestations.Overlap syndrome may occur; that is, "acute-on-chronic"пїЅ graft-versus-host disease (GVHD).
  • aGVHD: Skin, liver, and gastrointestinal tract (GIT) are most commonly involved.
  • cGVHD: may involve any organ; pleomorphic presentation mimicking rheumatologic phenomena

Epidemiology

Incidence

  • 25-50% develop aGHVD, depending on disease, conditioning regimen, immunosuppressives, and patient- and donor-specific factors.
  • 30-70% develop cGVHD.

Etiology and Pathophysiology

  • aGVHD: Antigen-presenting cells are activated by conditioning chemotherapy and/or subsequent infections. This leads to activation of donor T-helper type 1 effector cells causing direct cytotoxicity via released cytokines.
  • cGVHD is poorly understood; chronic T-cell activation plays role.

Genetics

Major histocompatibility complex determines degree of host-donor match; greater match leads to decreased aGVHD and cGVHD. пїЅ

Risk Factors

  • Following associated with greater risk of aGVHDHuman leukocyte antigen (HLA) discrepancy between host and donorType and remission status of diseaseConditioning regimenAge of recipientSex disparity; highest risk = female donor to male recipient; risk increases for each pregnancyABO blood group incompatibilityProphylactic immunosuppressive medicationsCytomegalovirus (CMV) serostatus disparity
  • Risk factors for cGVHDAntecedent aGVHD episodesHLA disparityUse of peripheral blood stem cellsSex disparity; highest risk = female donor to male recipient; risk increases for each pregnancySplenectomy

General Prevention

  • aGVHDProphylactic immunosuppression with, calcineurin inhibitor plus short-course methotrexate or mycophenolate or sirolimusDepletion of host alloantigensDepletion of donor T cellsEmerging role for statins in donor and/or recipient
  • cGVHDNo commonly accepted prophylaxis; limiting flares of aGVHD may minimize cGVHD

Commonly Associated Conditions

  • Direct organ injury
  • Secondary risks of infection

Diagnosis

History

  • GVHD can affect any organ, and comprehensive history should be performed.
  • Most common sites of involvement in aGVHD include skin, GI, and hepatic organs.
  • Additional sites of involvement in cGVHD include oral, eyes, lungs, and neuromuscular.
  • Symptoms are dependent on the organ involved.Symptoms of aGVHD may include new skin lesions, anorexia, nausea, vomiting, diarrhea, abdominal pain, GI bleeding, or abdominal cramping.

Physical Exam

  • Skin: maculopapular exanthema, lichenoid skin lesions, jaundice
  • GI: abdominal tenderness, abnormal bowel sounds, mucosal atrophy/mucositis
  • Ocular: photophobia, conjunctivitis, keratoconjunctivitis, episcleritis
  • Pulmonary: wheezing from bronchiolitis obliterans
  • Musculoskeletal: polymyositis, myasthenia gravis

Differential Diagnosis

  • Erythema multiforme
  • Gastroenteritis
  • Hepatitis
  • Mixed connective tissue disease
  • Scleroderma
  • Sj пїЅgren syndrome

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)

  • CBC
  • Liver function studies
  • Serum electrolytes
  • Hepatic and Doppler sonographies

Follow-up tests & special considerations

  • Skin biopsy
  • Esophagogastroduodenoscopy (EGD)/colonoscopy
  • Liver biopsy

Diagnostic Procedures/Other

  • Skin punch biopsyIn patients with suspicious skin lesions
  • EGD and biopsyPerformed in patients with persistent anorexia and vomiting
  • Flexible sigmoidoscopy or colonoscopy with biopsy
  • Liver biopsy is risky.For patients with isolated transaminitis to suggest hepatic involvement

Test Interpretation

  • Cytopenias may result from poor engraftment in cGVHD.
  • Elevated alkaline phosphatase (ALP), transaminitis, and bilirubinemia may be a consequence of hepatic involvement.
  • Electrolyte derangements and hypoalbuminemia may be evident in patients with GI involvement.

Treatment

General Measures

  • aGVHD is graded from I to IV, with IV being most severe.
  • cGVHD is graded from 0 to 3, with 3 being most severe.

Medication

First Line

  • aGVHD of skinGrades I-II: topical triamcinolone 0.1% b.i.d.-t.i.d. to all affected areas but face; hydrocortisone 0.5% on face (adults) and all affected areas (children) (1)[A]Grades III-IV: methylprednisolone or prednisone 2 mg/kg/day, tapered slowly over weeks to months (no standard taper exists) plus calcineurin inhibitor titrated to optimal dose by therapeutic drug monitoring (1)[A]Topical corticosteroids may be administered concomitantly with systemic corticosteroids.
  • aGVHD of GITGrade I: enteric-coated budesonide 6-9 mg daily in divided doses and/or beclomethasone corn oil emulsion 2 mg q.i.d. (1)[A]Grades II-IV: methylprednisolone or prednisone 2 mg/kg/day, tapered slowly over weeks to months (no standard taper exists) plus calcineurin inhibitor titrated to optimal dose by therapeutic drug monitoring (1)[A]Enteric-coated budesonide and/or beclomethasone corn oil emulsion 2 mg q.i.d. may be used concomitantly (1)[A].
  • aGVHD of liver and atypical presentationsGrades I-IV: methylprednisolone or prednisone 2 mg/kg/day, tapered slowly over weeks to months (no standard taper exists) plus calcineurin inhibitor titrated to optimal dose by therapeutic drug monitoring (1)[A].
  • cGVHDPrednisone 1 mg/kg/day; no standard taper schedule (2)[A]Additional treatment should be tailored to specific organ(s) involved (2)[C].

Second Line

  • Second-line therapy of aGVHD is often termed "steroid-refractory GVHD"пїЅ; despite nomenclature, high-dose corticosteroids continue concomitantly with second-line therapy of aGVHD.
  • Failure of first-line corticosteroids determined at days 5-7 of treatment for aGVHD.
  • Second-line therapy for aGVHD is mycophenolate mofetil 15 mg/kg PO/IV b.i.d. in those who have not received mycophenolate mofetil (1)[A].
  • Preferred second-line therapy for cGVHD is not known (2)[B].Corticosteroids used concomitantly with those listed in the following text.
  • aGVHD of skinEquine antithymocyte globulin 40 mg/kg/day IV пїЅ 4 days (1),(3)[C]Denileukin diftitox 9 Ојg/kg IV on days 1, 3, 5, 15, 17, and 19 (3)[C]Extracorporeal photopheresis (3)[C]Pentostatin 1.4 mg/m2/day IV пїЅ 3 days q14 days (1)[C]Sirolimus 3-4 mg/day orally titrated to serum level 3-12 ng/mL(1),(3)[C]Topical tacrolimus 0.03-0.1% ung or pimecrolimus 1% cream b.i.d. (1),(3)[C]
  • aGVHD of GITAlemtuzumab 10-30 mg IV daily for 3-5 days(1),(3)[C]Equine antithymocyte globulin 40 mg/kg/day IV пїЅ 4 days (1),(3)[C]Denileukin diftitox 9 Ојg/kg IV on days 1, 3, 5, 15, 17, and 19 (3)[C]Etanercept 0.4 mg/kg SQ twice weekly пїЅ 8 weeks (max: 25 mg total) (1),(3)[C]Infliximab 10 mg/kg IV weekly пїЅ 4 weeks (GVHD grades I-II) (1),(3)[C]Pentostatin 1.4 mg/m2/day IV пїЅ 3 days q14 days (1)[C]Sirolimus 3-4 mg/day orally titrated to serum level 3-12 ng/mL(1),(3)[C]
  • aGVHD of liverAlemtuzumab 10-30 mg IV daily for 3-5 days(1),(3)[C]Equine antithymocyte globulin 40 mg/kg/day IV пїЅ 4 days (1),(3)[C]Denileukin diftitox 9 Ојg/kg IV on days 1, 3, 5, 15, 17, and 19 (3)[C]Extracorporeal photopheresis (1),(3)[C]Pentostatin 1.4 mg/m2/day IV пїЅ 3 days q14 days or 1.5 mg/m2/day IV on days 1-3 and 15-17 (1),(3)[C]Sirolimus 3-4 mg/day orally titrated to serum level 3-12 ng/mL(1),(3)[C]
  • cGVHDEtanercept 0.4 mg/kg SQ twice weekly пїЅ 8 weeks (max: 25 mg total dose) (1),(3)[C]Extracorporeal photopheresis (1),(3)[C]Mycophenolate mofetil 15 mg/kg PO/IV b.i.d. (1),(3)[C]Topical tacrolimus 0.03-0.1% ointment or pimecrolimus 1% cream b.i.d. (1),(3)[C]Triamcinolone 0.1% (all but face) and hydrocortisone 0.5% b.i.d.-t.i.d. (1),(3)[C]

Issues for Referral

Specialists to help manage organ-specific management of cGVHD пїЅ

Additional Therapies

  • Limiting sun exposure (1)[B]
  • Bowel rest (1)[A]
  • Total parenteral nutrition (1)[A]
  • Anti-infectives, including antibacterial, antiviral, antifungal, and antipneumocystis agents (1)[A]
  • Physical therapy
  • Pain management
  • Vaccinations (once GVHD resolves and immunosuppression ends)

Surgery/Other Procedures

Not indicated пїЅ

Complementary & Alternative Therapies

None recommended пїЅ

Inpatient Considerations

Admission Criteria/Initial Stabilization

  • GI antispasmodics after excluding infection
  • IV fluids to prevent dehydration
  • May consider total parenteral nutrition if severe malabsorption.
  • Treat infections with anti-infective agents
  • Wound care for high-grade skin lesions

IV Fluids

IV fluids with electrolyte replacement for patients presenting with electrolyte dyscrasias пїЅ

Nursing

No specific nursing instructions, except for close symptom monitoring and routine nursing care. пїЅ

Discharge Criteria

Safe discharge requires resolution of presenting symptoms and provisions for adequate follow-up. пїЅ

Ongoing Care

Follow-up Recommendations

Patients should continue to follow-up with their transplant physician, consulting physicians, and supportive care staff. пїЅ

Patient Monitoring

  • Nutritional status, including oral fluid intake
  • Use of long-term corticosteroids requires blood pressure, glucose, and osteoporosis screening.

Pediatric Considerations

Developmental assessment every 6-12 months пїЅ

Diet

  • Increase oral intake once diarrhea <500mL/day
  • Lactose-free diet
  • High-protein diet ≥1.5 g/kg/day) to offset catabolic effect of medications and disease
  • No role for neutropenic or low-bacteria diet

Patient Education

  • Avoidance of excessive exposure to the sun
  • Patients should avoid sedentary lifestyle and exercise regularly while on corticosteroids.
  • Patients should minimize infectious risks while on immunosuppressive medications.

Prognosis

  • The response and overall grade of aGVHD correlates with outcome.Patients with complete response have 22% mortality rate compared to 75% mortality rate in nonresponders (4).
  • Extensive disease, progressive onset, thrombocytopenia, HLA-nonidentical marrow donors, and failure to taper steroids for aGVHD before the onset of progressive cGVHD correlate with high mortality.

Complications

  • Infectious complicationsInvasive fungal infectionsPneumocystis jiroveci pneumoniaHerpesvirus infectionCMV infection
  • Proximal muscle wasting
  • Organ failure and graft rejection

References

1.Martin пїЅPJ, Rizzo пїЅJD, Wingard пїЅJR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012;18(8):1150-1163. пїЅ

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2.Dignan пїЅFL, Scarisbrick пїЅJJ, Cornish пїЅJ, et al. Organ-specific management and supportive care in chronic graft-versus-host disease. Br J Haematol. 2012;158(1):62-78. пїЅ

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3.Pidala пїЅJ, Anasetti пїЅC. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(11):1504-1518. пїЅ

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4.Deeg пїЅHJ, Henslee-Downey пїЅPJ. Management of acute graft-versus-host disease. Bone Marrow Transplant. 1990;6(1):1-8. пїЅ

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Codes

ICD09

  • 279.50 Graft-versus-host disease, unspecified
  • 279.51 Acute graft-versus-host disease
  • 279.52 Chronic graft-versus-host disease
  • 279.53 Acute on chronic graft-versus-host disease
  • 996.80 Complications of transplanted organ, unspecified

ICD10

  • D89.813 Graft-versus-host disease, unspecified
  • D89.810 Acute graft-versus-host disease
  • D89.811 Chronic graft-versus-host disease
  • D89.812 Acute on chronic graft-versus-host disease

SNOMED

  • 234646005 Graft-versus-host disease (disorder)
  • 402355000 Acute graft-versus-host disease
  • 402356004 Chronic graft-versus-host disease
  • 47650006 Graft versus host reaction (finding)

Clinical Pearls

  • Acute GVHD develops within 100 days after allogeneic hematopoietic-cell transplantation.
  • Most common sites involved in aGVHD include skin, GI, and liver.
  • Rate of response and depth of involvement correlate with outcome in patients with GVHD.