Graft Versus Host Disease 

Updated: Dec 11, 2017
Author: Romeo A Mandanas, MD, FACP; Chief Editor: Mary C Mancini, MD, PhD, MMM 

Overview

Practice Essentials

Graft versus host disease (GVHD) is an immune-mediated disease resulting from a complex interaction between donor and recipient adaptive immunity.[1] Acute GVHD describes a distinctive syndrome of dermatitis (see the image below), hepatitis, and enteritis developing within 100 days after allogeneic hematopoietic-cell transplantation (HCT). Chronic GVHD describes a more diverse syndrome developing after day 100. In addition to allogeneic HCT, procedures associated with high risk of GVHD include transplantation of solid organs containing lymphoid tissue and transfusion of unirradiated blood products.

Autologous graft versus host disease (GVHD) involv Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.

Signs and symptoms

Presentation in acute GVHD is as follows:

  • A pruritic or painful rash (median onset, day 19 posttransplantation; range, 5-47 days)[2]

  • Pruritus from initially asymptomatic liver involvement, anorexia, weight loss, followed rarely by hepatic coma

  • Diarrhea, intestinal bleeding, cramping abdominal pain, and ileus

Diarrhea in acute GHVD is green, mucoid, watery, and mixed with exfoliated cells forming fecal casts. Voluminous secretory diarrhea may persist despite cessation of oral intake.

Upper GI enteric GVHD occurs in approximately 13% of patients who receive HLA-identical transplants and manifests as anorexia and dyspepsia without diarrhea. It is most common in older patients.

Chronic GVHD may be an extension of acute GVHD, may occur de novo in patients who never have clinical evidence of acute GVHD, or may emerge after a quiescent interval after acute GVHD resolves.[3] Manifestations are as follows:

  • Ocular – Burning, irritation, photophobia, and pain from lack of tear secretion

  • Oral and GI – Mouth dryness, sensitivity to acidic or spicy foods, dysphagia, odynophagia, and insidious weight loss

  • Pulmonary – Obstructive lung disease, with symptoms of wheezing, dyspnea, and chronic cough that is usually nonresponsive to bronchodilator therapy

  • Neuromuscular – Generalized or focal weakness, neuropathic pain, vision loss, muscle cramps, myalgia

  • Joints – Arthralgia, arthritis

Physical examination

Skin findings are as follows:

  • Maculopapular exanthema – Red-to-violet lesions that typically first appear on the palms of the hands, soles of the feet, cheeks, neck, ears, and upper trunk, sometimes progressing to involve the whole body; in severe cases, bullae may be observed, and vesicles may form

  • Lichenoid skin lesions or sclerodermatous thickening of the skin, which sometimes causes contractures and limits joint mobility

  • Jaundice from hyperbilirubinemia; patients who subsequently develop pruritus may exhibit excoriations from scratching

Ocular findings may include the following:

  • Acute GVHD – Hemorrhagic conjunctivitis, pseudomembrane formation, and lagophthalmos

  • Chronic GVHD – Keratoconjunctivitis sicca, which may lead to punctate keratopathy

Additional findings are as follows:

  • Oral – Atrophy of the oral mucosa, erythema, and lichenoid lesions of the buccal and labial mucosae in chronic GVHD

  • Pulmonary – Prolonged expiratory breathing phase (wheezes) from bronchiolitis obliterans

  • GI – Diffuse abdominal tenderness with hyperactive bowel sounds may accompany secretory diarrhea of acute GVHD; in severe ileus, the abdomen is silent and appears distended

  • Neuromuscular – Findings of myasthenia gravis, polymyositis, optic neuritis, arthritis may occur in chronic GVHD

  • Vaginitis and vaginal strictures have been described in chronic GVHD

See Presentation for more detail.

Diagnosis

Laboratory study results in GVHD are as follows:

  • CBC – Autoimmune cytopenias (eg, thrombocytopenia, anemia, leukopenia) may be observed with chronic GVHD

  • Liver function tests – Elevation of the alkaline phosphatase level, an early sign of liver involvement by GVHD; hypoalbuminemia is typically due to GVHD-associated intestinal protein leakage and a negative nitrogen balance

  • Serum electrolytes and chemistries (eg, potassium, magnesium, bicarbonate levels) may be altered; massive diarrhea and diminished oral intake can lead to serious electrolyte abnormalities

Other tests

  • Schirmer test – To measure the degree of tear formation by the lacrimal glands in chronic GVHD

  • Pulmonary function tests and arterial blood gas analysis – To identify obstructive pulmonary disease (eg, obliterative bronchiolitis) in chronic GVHD

  • Manometric studies of the esophagus

Imaging studies

  • Hepatic and Doppler sonography

  • Barium swallow study

Procedures

  • Skin punch biopsy

  • Upper GI endoscopy and biopsy in patients with persistent anorexia and vomiting

  • Flexible sigmoidoscopy or colonoscopy with biopsy of sigmoid or colonic lesions in patients with diarrhea

  • Liver biopsy (rarely done, usually only in patients with isolated hepatic findings)

See Workup for more detail.

Management

The criterion standard for primary prophylaxis of acute GVHD is cyclosporine for 6 months and short-course methotrexate in T-cell–replete allogeneic HCT (criterion standard); currently, tacrolimus is often substituted for cyclosporine because of its more potent immunosuppressant capacity and lower risk of nephrotoxicity. Antithymocyte globulin (ATG) is given before HCT in unrelated-donor transplants.

Primary therapy for acute GVHD is as follows:

  • For skin GVHD of stage I or II, observation or a trial of topical corticosteroids (eg, triamcinolone 0.1%) may be used

  • For grade II-IV acute GVHD, continuing the original immunosuppressive prophylaxis and adding methylprednisolone (commonly starting at 2 mg/kg/day in 2 divided doses); in patients who respond to initial therapy, the steroid will be tapered weekly thereafter until off 

  • Other therapies are ATG, cyclosporine, sirolimus [4]  , mycophenolate mofetil (MMF), daclizumab, anti–interleukin-2 (IL-2) receptor, alone or in combination

Secondary therapy for acute GVHD is as follows:

  • ATG or multiple pulses of methylprednisolone (at doses higher than those used in initial therapy)

  • Tacrolimus, for GVHD with cyclosporine resistance or neurotoxicity or nephrotoxicity

  • MMF at 2 g daily, added to the steroid regimen[5]

  • infliximab[6] or etanercept[7]  

  • Psoralen and ultraviolet A irradiation (PUVA), for cutaneous lesions

  • Ruxolitinib 

  • Muromomab-CD3 (Orthoclone OKT3)

  • Humanized anti-Tac antibody to the IL-2 receptor

Primary therapy for chronic GVHD is as follows:

  • Prednisone, 1 mg/kg every day

  • Tacrolimus

  • Cyclosporine, 6 mg given every 12 hours every other day in patients at high risk for GVHD with thrombocytopenia

  • Sirolimus

  • Thalidomide

Secondary therapy for chronic GVHD is as follows:

  • Ibrutinib for adults who failed at least 1 treatment for chronic GVHD[8, 9]

  • MMF, added to standard tacrolimus, cyclosporine, sirolimus, and/or prednisone, for steroid-refractory chronic GVHD

  • Azathioprine, alternating cyclosporine/prednisone, or thalidomide for steroid-refractory chronic GVHD

  • Clofazimine, for treating cutaneous and oral lesions of chronic GVHD and as a steroid-sparing agent

  • PUVA therapy, for refractory cutaneous chronic GVHD

  • Extracorporeal photopheresis (a modification of PUVA treatment)[10]

  • Rituximab, mainly for musculoskeletal and cutaneous chronic GVHD[11]

  • Pentostatin

  • Low-dose (100-cGy) total lymphoid irradiation to thoracoabdominal areas

  • Imatinib[12]

See Treatment and Medication for more detail.

Background

Barnes and Loutit first described (in mice) what is now known as graft versus host disease (GVHD) as a syndrome called secondary disease to differentiate it from primary disease of radiation sickness.[13] Mice that were given allogeneic spleen cells after irradiation developed fatal secondary disease (skin abnormalities and diarrhea), which was a result of introducing immunologically competent cells into an immunoincompetent host.

Human GVHD occurs after allogeneic stem-cell transplantation, with features similar to those observed in animal studies. Acute GVHD describes a distinctive syndrome of dermatitis, hepatitis, and enteritis developing within 100 days of allogeneic hematopoietic-cell transplantation (HCT). Chronic GVHD describes a more diverse syndrome developing after day 100.

Pathophysiology

Several criteria, as first described by Billingham in 1966,[14] are traditionally required to diagnose GVHD, including the following:

  • The graft must contain immunologically competent cells.

  • The host must possess important transplantation alloantigens that are lacking in the donor graft so that the host appears foreign to the graft and can therefore stimulate it antigenically.

  • The host itself must be incapable of mounting an effective immunologic reaction against the graft, or it must at least allow for sufficient time for the latter to manifest its immunologic capabilities (ie, it must have the security of tenure).

Certain patient groups are at risk for GVHD, as outlined below in Table 1.

Table 1. Procedures Associated with a High Risk of GVHD* (Open Table in a new window)

Procedure

Groups at High Risk

Allogeneic HCT

Patients receiving no GVHD prophylaxis

Older patients

Recipients of HLA-nonidentical stem cells

Recipients of grafts from allosensitized donors

Recipients of grafts from unrelated donors

Solid-organ transplantation (organs containing lymphoid tissue)

Recipients of small-bowel transplants

Transfusion of unirradiated blood products

Neonates and fetuses

Patients with congenital immunodeficiency syndromes

Patients receiving immunosuppressive chemoradiotherapy

Patients receiving directed blood donations from partially HLA-identical, HLA-homologous donors

*Modified from Ferrara and Deeg, 1991.[15]

HLA = Human leukocyte antigen.

Current understanding of the biology of GVHD includes the occurrence of autologous GVHD and transfusion-associated GVHD. The former suggests that inappropriate recognition of host self-antigens may occur, and the latter is an example of GVHD in an individual who is immunocompetent (see image below).

Autologous graft versus host disease (GVHD) involv Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.

GVHD is an immune-mediated disease resulting from a complex interaction between donor and recipient adaptive immunity.[1] The main effectors are donor T cells, which are activated in the presence of co-stimulatory molecules by a storm of proinflammatory cytokines[16] (see image below). The successful use of B-cell–targeted therapy such as rituximab in chronic GVHD has sparked an interest in defining the role of B cells in the pathophysiology of GVHD.[17]

Interactive factors involved in the pathogenesis o Interactive factors involved in the pathogenesis of graft versus host disease (GVHD.) Courtesy of Romeo A. Mandanas, MD, FACP.

Chronic GVHD is a syndrome that mimics the autoimmune diseases. Donor T cells play an important role in its development, but humoral immunity is also implicated. The targets of attack may include host non-HLA antigens such as minor histocompatibility antigens. In some studies, host dendritic cells may also be at play. A close relationship exists between the development of chronic GVHD and a helpful graft-versus-tumor/leukemia effect.[3]

Epidemiology

Frequency

United States

Autologous GVHD occasionally occurs after autologous or syngeneic HCT (7-10%). Tissue damage caused by high-dose chemotherapy or secondary cytokine production may expose cryptic self-antigens, which the immune system may newly recognize only after HCT. Mild and usually self-limited episodes of dermal GVHD or even hepatic and GI abnormalities have been described. GVHD-like symptoms and findings can also be induced in autologous recipients after the administration (and withdrawal) of cyclosporine and interleukin (IL)-2.[18]

Transfusion-associated GVHD occurs 4-30 days after transfusion and resembles hyperacute GVHD after allogeneic HCT. Marrow aplasia is a frequent and often fatal complication. This serious complication of transfusion can be prevented by irradiating blood products with at least 2500 cGy before transfusion in individuals at risk. In Japan (where inbred populations share common haplotypes), marrow aplasia is estimated to occur in 1 in 500 open-heart operations in individuals who are immunocompetent.

The occurrence of acute GVHD in patients who receive marrow from HLA-identical siblings varies widely depending on several recognized risk factors. About 19-66% of recipients are affected, depending on their age, on donor-recipient sex matching, and on donor parity. The incidence of GVHD increases with HLA-nonidentical marrow donors who are related or in HLA-matched unrelated donors, with rates of 70-90%.[19]

Chronic GVHD is observed in 33% of HLA-identical sibling transplantations, in 49% of HLA-identical related transplantations, in 64% of matched unrelated donor transplantations. The rate could be as high as 80% in 1-antigen HLA-nonidentical unrelated transplantations.[3]

The source of donor graft affects the incidence of GVHD. Although acute GVHD does not differ significantly among recipients of HLA-identical sibling bone marrow (BM) versus peripheral blood stem cells (PBSC), the cumulative incidence of chronic GVHD (and extensive GVHD) is higher in those who received PBSC (73% vs. 55%).[20, 21] The cumulative incidence of grades III-IV acute and extensive chronic GVHD is much lesser in unrelated cord blood recipients than in either recipients of HLA-identical sibling BM or PBSC transplants.[22]

Mortality/Morbidity

See the list below:

  • The overall grade of acute GVHD is predictive of the patient's outcome, with the highest rates of mortality in those with grade IV, or severe, GVHD.

  • The response to treatment is also predictive of outcomes in GVHD of grades II-IV. Patients with no response or with progression have a mortality rate as high as 75% compared with 20-25% in those with a complete response.[19]

  • In chronic GVHD, mortality rates are increased in patients with extensive disease, progressive onset, thrombocytopenia, and HLA-nonidentical marrow donors. The overall survival rate is 42%, but patients with progressive onset of chronic GVHD have a survival rate of 10%.[23]

 

Presentation

History

Patients at risk for acute graft versus host disease (GVHD) and chronic GVHD are those undergoing allogeneic hematopoietic-cell transplantation (HCT).

Acute GVHD

Acute GVHD may initially appear as a pruritic or painful rash (median onset, day 19 posttransplantation; range, 5-47 d).[2]

A hyperacute form of GVHD has been described as a disorder including fever, generalized erythroderma, and desquamation developing 7-14 days after transplantation.

After the skin, the next most frequently involved target of GVHD is the liver, where the disease causes asymptomatic elevation of bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase levels similar to those observed with cholestatic jaundice. Pruritus ensues, with hyperbilirubinemia. Hepatic coma is rare.

Acute GVHD may involve the distal small bowel and colon, resulting in diarrhea, intestinal bleeding, cramping abdominal pain, and ileus. The diarrhea is green, mucoid, watery, and mixed with exfoliated cells forming fecal casts. Voluminous secretory diarrhea may persist despite cessation of oral intake. Approximately 13% of patients who receive HLA-identical transplants may present with upper gastrointestinal (GI) enteric GVHD manifesting as anorexia and dyspepsia without diarrhea. This is most common in older patients.

Acute GVHD also has been associated with increased risk of infectious and noninfectious pneumonia and sterile effusions, hemorrhagic cystitis with infective agents, thrombocytopenia, and anemia. Hemolytic-uremic syndrome (thrombotic microangiopathy) has been observed in patients given cyclosporine who developed severe GVHD.

Chronic GVHD

Chronic GVHD is viewed as an extension of acute GVHD. However, it also may occur de novo in patients who never have clinical evidence of acute GVHD, or it may emerge after a quiescent interval after acute GVHD resolves.[3] Manifestations are as follows:

  • Ocular manifestations may include burning, irritation, photophobia, and pain due to a lack of tear secretion.

  • Oral and GI manifestations include dryness, sensitivity to acidic or spicy foods, and increasing pain after day 100 (chronic GVHD). Chronic GVHD may affect the esophagus, resulting in symptoms of dysphagia, odynophagia, and insidious weight loss.

  • Obstructive lung disease, with symptoms of wheezing, dyspnea, and chronic cough that is usually nonresponsive to bronchodilator therapy, is a clinical feature of chronic GVHD.

  • Neuromuscular manifestations include weakness, neuropathic pain, and muscle cramps.

Physical

Skin (maculopapular exanthema) findings are as follows:

  • Lesions are red to violet and typically first appear on the palms of the hands, soles of the feet, cheeks, neck, ears, and upper trunk. They can progress to involve the whole body.

  • In severe cases, bullae may be observed, and vesicles may form.

  • Chronic GVHD can lead to lichenoid skin lesions or sclerodermatous thickening of the skin, which sometimes causes contractures and limits joint mobility. See the images below.

    Acute graft versus host disease (GVHD) involving d Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient after allogeneic bone marrow transplantation for myelodysplasia. Courtesy of Romeo A. Mandanas, MD, FACP.
    This boy developed stage III skin involvement with This boy developed stage III skin involvement with acute graft versus host disease (GVHD) despite of receiving prophylaxis with cyclosporin A. The donor was his HLA-matched sister; the sex disparity increased the risk for acute GVHD. Courtesy of Mustafa S. Suterwala, MD.
    Same boy as in previous image progressed to grade Same boy as in previous image progressed to grade IV graft versus host disease (GVHD). High-dose cyclosporin A and methylprednisolone had been administered intravenously. He later died from chronic pulmonary disease due to chronic GVHD. Courtesy of Mustafa S. Suterwala, MD.

Hepatic findings include hyperbilirubinemia, which can manifest as jaundice, cause pruritus, and lead to excoriations from the patient's scratching. Portal hypertension, cirrhosis, and death from hepatic failure are rare.

Ocular findings in patients with acute GVHD include hemorrhagic conjunctivitis, pseudomembrane formation, and lagophthalmos. These complications worsen the prognosis. With chronic GVHD, keratoconjunctivitis sicca is common. Because of the dryness, punctate keratopathy (minimal or severe erosions of the cornea) may ensue.

Oral findings include atrophy of the oral mucosa, erythema, and lichenoid lesions of the buccal and labial mucosae. These are significantly correlated with chronic GVHD. See the image below.

Oral mucosal changes in a patient with chronic gra Oral mucosal changes in a patient with chronic graft versus host disease (GVHD). Note the skin discoloration (vitiligo), which can be a result of GVHD. Courtesy of Romeo A. Mandanas, MD, FACP.

Other findings include the following:

  • Pulmonary findings: Bronchiolitis obliterans causes prolonged expiratory breathing phase (wheezes).

  • GI findings: Diffuse abdominal tenderness with hyperactive bowel sounds may accompany secretory diarrhea of acute GVHD. In severe ileus, the abdomen is silent and appears distended.

  • Neuromuscular findings: Findings of the autoimmune phenomenon of myasthenia gravis or polymyositis are sometimes observed in chronic GVHD.

  • Vaginitis and vaginal strictures have been described in chronic GVHD.

  • Autoimmune thrombocytopenia and anemia have also been described with chronic GVHD.

Acute GVHD is a clinicopathologic syndrome involving the skin, liver, and gut. Staging and grading is important in determining the management and prognosis and for comparing the results of immunosuppressive prophylaxis. See Tables 2 and 3, below.

Table 2. Clinical Staging of Acute GVHD (Open Table in a new window)

Stage

Skin Findings

Liver Findings (Bilirubin Level, mg/dL)

Gut Findings

+

Maculopapular rash on < 25% of body surface

2-3

Diarrhea 500-1000 mL/d or persistent nausea

++

Maculopapular rash on 25-50% of body surface

3-6

Diarrhea 1000-1500 mL/d

+++

Generalized erythroderma

6-15

Diarrhea >1500 mL/d

++++

Desquamation and bullae

>15

Pain with or without ileus

Table 3. Clinical Grading of Acute GVHD (Open Table in a new window)

Overall Grade

Stage

Skin

Liver

Gut

Functional Impairment

0 (None)

0

0

0

0

I (Mild)

+ to ++

0

0

0

II (Moderate)

+ to +++

+

+

+

III (Severe)

++ to +++

++ to +++

++ to +++

++

IV (Life-threatening)

++ to ++++

++ to ++++

++ to ++++

+++

Chronic GVHD has manifestations similar to those of systemic progressive sclerosis, systemic lupus erythematosus, lichen planus, Sjögren syndrome, eosinophilic fasciitis, rheumatoid arthritis, and primary biliary cirrhosis. The median time of diagnosis in HLA-identical sibling recipients is 201 days after transplantation; diagnosis is earlier in patients receiving marrow from HLA-nonidentical related or unrelated donors (159 or 133 d, respectively). Staging and classification helps in predicting the patient's prognosis; see Table 4, below.

Table 4. Clinicopathologic Classification of Chronic GVHD (Open Table in a new window)

Classification

Clinicopathology

Limited

Localized skin involvement and/or hepatic dysfunction due to chronic GVHD

Extensive

Generalized skin involvement or localized skin involvement and/or hepatic dysfunction due to chronic GVHD, plus 1 of the following:

- Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis

- Involvement of the eye (Schirmer test with < 5-mm wetting)

- Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy

- Involvement of any other target organ

Different screening studies have been used to diagnose and stage chronic GVHD. See Table 5, below.

Table 5. Screening Studies for GVHD by Organ or System (Open Table in a new window)

Organ or System

Clinical Findings

Screening Studies

Skin

Dyspigmentation, xerosis, erythema, scleroderma, onychodystrophy, alopecia

Skin biopsy with a 3-mm punch-biopsy sample from the back and forearm areas

Mouth

Lichen planus, xerostomia

Oral biopsy with sample from lower lip

Eyes

Sicca, keratitis

Schirmer test

Liver

Jaundice

Alkaline phosphatase, aspartate aminotransferase, bilirubin determinations

Lungs

Obstructive and/or restrictive lung disease

Pulmonary function studies, arterial blood gas analysis

Vagina

Sicca, atrophy

Gynecologic evaluation

GI (nutrition)

Protein and calorie deficiency

Weight, measurement of muscle and/or fat stores

Multiple (clinical performance)

Contractures, debility

Determination of Karnofsky score and Lansky play index

Causes

Important factors in determining occurrence and severity of GVHD include the following:

  • Donor-host factors
  • Stem cell source
  • Immune modulation
  • High-dose chemotherapy and radiation therapy

Donor-host factors are as follows:

  • The incidence of GVHD increases with unrelated matched donor transplants compared with related matched transplants.

  • With increasing HLA disparity, the incidence and severity of GVHD increases.

  • Sex mismatching and increasing age of both donor and recipient increase the frequency of GVHD.

  • Genetic variations (other than those in the HLA domain), such as in the heparanase gene[24] and genes encoding the natural killer cell receptor,[25] may also play a role in the incidence of acute GVHD.

Stem-cell source factors are as follows:

  • Cryopreservation of marrow before its infusion apparently reduces the rate of GVHD.

  • Use of umbilical-cord blood rather than marrow may also lower the incidence of GVHD.

  • Allogeneic peripheral blood stem cells (PBSC) may increase the incidence of chronic GVHD and prolong follow-up.[26]

Immune modulation factors are as follows:

  • The efficacy of posttransplantational immunosuppressive prophylaxis affects the development of GVHD.[27]

  • Triple therapy with cyclosporine, short-course methotrexate (MTX), and prednisone lowers the incidence of GVHD compared with double therapy with cyclosporine and MTX alone. The addition of sirolimus to tacrolimus and MTX also reduces GVHD incidence compared with double therapy alone.[28]

  • Anti–T-cell globulin, when added to standard immunosuppressive prophylaxis, can decrease the incidence of acute and chronic GVHD in recipients of matched unrelated donor transplants.[29]

  • Statins have been found, in the preclinical setting, to affect or inhibit human antigen-presenting cell (APC) function and to reduce the expression of co-stimulatory molecules and major histocompatibility complex (MHC) class II.[30, 31] In the clinical setting, a retrospective analysis of 567 patients who received allogeneic transplantation from HLA-identical sibling donors for various hematologic malignancies noted that statin use by the donor (but not by the recipient) was associated with a decreased risk of grade 3-4 acute GVHD.[32]

High-dose chemotherapy and radiation therapy have the following effects:

  • After high-dose chemotherapy, levels of circulating cytokines increase; this is known as a cytokine storm. These cytokines are thought to increase the ability of graft immune cells to recognize host antigens.[16]

  • High-dose chemotherapy can also lead to localized tissue damage, exposing cryptic antigens in certain organs (eg, skin, liver, gut).

  • Conditioning regimens that include total-body irradiation are associated with an increased incidence and severity of GVHD compared with chemotherapy alone.[33]

  • Administration of nonmyeloablative but immunosuppressive chemotherapy followed by allogeneic transplants (ie, minidose transplantations, or "transplant-light") decreases the original cytokine storm and tissue damage. This strategy lowers the incidence of GVHD and is aimed at maintaining a graft-versus-tumor effect.[33, 34]

 

DDx

Diagnostic Considerations

Other problems to consider in the differential diagnosis include the following:

  • Acute skin toxicity from radiation (total body irradiation)

  • Hepatobiliary toxicity from chemotherapy (veno-occlusive disease of the liver)

  • Inflammatory or infectious diarrheas

Differential Diagnoses

 

Workup

Laboratory Studies

The workup for graft versus host disease (GVHD) is guided by understanding of the disorder’s characteristics. Acute GVHD usually does not occur until after engraftment. Poor graft function may be a sign of autoimmune cytopenias (eg, thrombocytopenia, anemia, leukopenia) that may be observed with chronic GVHD.

On liver function tests (eg, bilirubin, aspartate aminotransferasealanine [AST], alanine aminotransferase [ALT], alkaline phosphatase, total protein, albumin), elevation of the alkaline phosphatase concentration is an early sign of liver involvement by GVHD. A cholestatic picture is usually observed. Hypoalbuminemia is typically due to GVHD-associated intestinal protein leak and a negative nitrogen balance.

Serum electrolytes and chemistries (eg, potassium, magnesium, bicarbonate levels) may be altered. Massive diarrhea and diminished oral intake can lead to serious electrolyte abnormalities.

Imaging Studies

Hepatic and Doppler sonography can be used to distinguish GVHD from other causes of jaundice or cholestatic liver function abnormalities, such as cholecystitis and veno-occlusive disease of the liver. A barium swallow study can be used to detect esophageal changes of chronic GVHD, such as the following:

  • Web formation
  • Ringlike narrowing
  • Tapering structures of the middle and upper esophagus

Other Tests

See the list below:

  • The Schirmer test is used to measure the degree of tear formation by the lacrimal glands, which can be affected in chronic GVHD.

  • Pulmonary function tests and arterial blood gas analysis can be used to identify obstructive pulmonary disease (eg, obliterative bronchiolitis) in chronic GVHD.

  • Manometric studies of the esophagus can demonstrate poor acid clearance and motor abnormalities that range from aperistalsis to high-amplitude contractions.

  • Genetic polymorphisms, such as those seen in the adhesion molecule CD31 when it is mismatched between donor and recipient, are predictive of an increased risk for GVHD.[35] The IL-10-592A allelic polymorphism is a marker for a favorable outcome after transplantation in recipients of hematopoietic stem cells from HLA-identical siblings.[36]

  • Low numbers of circulating dendritic cells at the time of myeloid engraftment significantly increase the risk of relapse and acute GVHD and are predictive of death after allogeneic HCT.[37]

  • A biomarker panel (4 proteins: interleukin-2 receptor-α, tumor necrosis factor receptor 1, interleukin-8, and hepatocyte growth factor) measured in the serum by sequential enzyme linked immunosorbent assay (ELISA) at the onset of clinical symptoms was able to confirm GVHD with 95% specificity.[38, 39] If validated in prospective studies, this high-risk biomarker profile may eliminate the need for an invasive biopsy procedure to confirm the diagnosis of GVHD.

Procedures

See the list below:

  • Findings on skin punch biopsy help establish the diagnosis of GVHD when the patient's clinical features are consistent with the syndrome.

  • Upper-GI endoscopy and biopsy, when performed in patients with persistent anorexia and vomiting, may reveal a variety of diagnoses, including GVHD, peptic ulceration, or mycotic or viral infection.

  • On gastroduodenal biopsy, alterations in endothelial cells in the absence of signs of infections may be predictive of the severity of GVHD. These alterations include rupture of capillary basement membranes and extravasated red blood cells.

  • Flexible sigmoidoscopy or colonoscopy with biopsy of sigmoid or colonic lesions may be helpful. In patients with diarrhea, GVHD may involve the colonic mucosa.

  • Liver biopsy is rarely performed, usually only in patients with isolated hepatic findings.

Histologic Findings

Characteristic findings on histologic examination of skin (eg, eosinophilic bodies), liver (eg, necrosis of the bile duct), and gut (eg, crypt-cell degeneration) soon after transplantation may be difficult to distinguish from the effects of the conditioning chemoradiotherapy. Serial biopsy and observation help establish the diagnosis and severity of acute GVHD.

On histology, mononuclear-cell infiltration and inflammation of affected epithelium is more subtle in chronic GVHD than in acute GVHD. Dermal fibrosis and inflammation of sweat glands can be used to distinguish chronic GVHD of skin from acute GVHD. Fibrosis of the submucosa and serosa is observed when chronic GVHD involves the GI tract. See the image below.

Acute graft versus host disease (GVHD). Hematoxyli Acute graft versus host disease (GVHD). Hematoxylin and eosin–stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. Moderate superficial dermal and perivascular lymphocytic infiltrate are also observed. Courtesy of Melanie K. Kuechler, MD.
 

Treatment

Medical Care

Acute GVHD

Primary prophylaxis for acute GVHD includes the following:

  • The criterion standard for prophylaxis is cyclosporine for 6 months and short-course methotrexate (MTX) in T-cell–replete allogeneic hematopoietic cell transplantation (HCT); cyclosporine levels should be kept above 200 ng/mL.

  • Tacrolimus is frequently substituted for cyclosporine, especially in unrelated-donor transplantation, because it may improve the control of GVHD, though not survival. The addition of prednisone to the prophylactic regimen also reduces the incidence of GVHD but does not change overall survival.[40]

  • Antithymocyte globulin (ATG) given before HCT significantly reduces the risk of grade III or IV acute GVHD and extensive chronic GVHD, but it does not alter survival, possibly because of the increased risk of infection.[41] Ex-vivo depletion of T-cells has also been tried (in the 1980s), but transplantation-related mortality was not reduced compared with standard treatments in patients receiving HLA-matched grafts.

  • Other agents that have been studied for GVHD prophylaxis include combinations with or substitutions by other agents such as mycophenolate mofetil,[5] sirolimus,[28] pentostatin, alemtuzumab[42] keratinocyte growth factor (KGF), cyclophosphamide,[43] and suberoylanilide hydroxamic acid (SAHA).

  • Extracorporeal photopheresis (ECP) is an immunomodulatory procedure in which lymphocytes are collected and mixed with 8-methoxypsoralen (which intercalates into the DNA of the lymphocytes), rendering them susceptible apoptosis when exposed to ultraviolet light. The lymphocytes are then returned to the patient. ECP has been used as part of a conditioning regimen together with pentostatin and total body irradiation, with very promising results.[23]

Primary therapy for acute GVHD includes the following:

  • For skin GVHD of stage I or II, observation or a trial of topical corticosteroids (eg, triamcinolone 0.1%) may be used.

  • Begin systemic treatment in patients with grade II-IV acute GVHD. Treatment consists of continuing the original immunosuppressive prophylaxis (cyclosporine or tacrolimus [FK506]) and adding methylprednisolone. Doses have been in the range of 1-60 mg/kg, but the most common starting dosage is 2 mg/kg/d given in 2 divided doses. Median time to resolution of acute GVHD is 30-42 days. In patients who respond to initial therapy, short-term tapering treatment with prednisone to a cumulative dose of 2000 mg/m2 is effective and expected to minimize steroid-related complications.

  • Other therapies are ATG, sirolimus[4, 44] , mycophenolate mofetil, anti–interleukin-2 (IL-2) receptor, anti-CD5–specific immunotoxin, and a pan T-cell ricin A-chain immunotoxin (XomaZyme). These agents can be used alone or in combination. No data from well-conducted controlled trials have shown the superiority of any of those over any other therapies.

  • Novel therapies have included the addition of ex vivo cultured mesenchymal cells derived from unrelated donors to conventional steroid therapy; this approach produced initial response rates of 90%, although 31% of patients required a second-line agent to control the disease.[45]

Failure of initial therapy is defined as any of the following:

  • Progression of acute GVHD after 3 days
  • No change after 7 days
  • Incomplete response after 14 days of treatment with methylprednisolone

Secondary therapy is usually initiated in steroid-refractory cases. Secondary therapy for acute GVHD includes the following:

  • ATG or multiple pulses of methylprednisolone (at doses higher than those used in initial therapy) have a response rate of about 40%.

  • Sirolimus [44]

  • Infliximab (an IgG1 murine-human chimeric monoclonal antibody that binds the soluble subunit and the membrane-bound precursor of tumor necrosis factor–alpha [TNF-α]) has a high response rate, but opportunistic infections (especially noncandidal invasive fungal infections) result in a high mortality rate.[6, 7]

  • Etanercept (a soluble dimeric TNF-α receptor 2 that can be given as a subcutaneous injection) competes for TNF-α binding, thus rendering it inactive. Higher response rates are seen with etanercept plus steroids (82%) versus steroids alone (66%) as primary therapy for acute GVHD).[46, 47]

  • Mycophenolate mofetil (MMF) at 2 g daily, when added to the steroid regimen, caused an overall response rate of 62%.[5]

  • Ruxolitinib [48]

  • Psoralen and ultraviolet A irradiation (PUVA) may be beneficial for cutaneous lesions of GVHD and may improve survival in some patients with steroid-resistant GVHD. ECP, in a phase II study, achieved a 60% response in steroid-refractory GVHD 3 months following the initiation of treatment. More responses were observed in patients with skin involvement only than in patients with liver or gut involvement.[10]

  • Approximately 12% of patients with GVHD resistant to cyclosporine may respond to conversion to tacrolimus. In patients who develop cyclosporine-related neurotoxicity, therapy can be switched and maintained with tacrolimus, which stabilizes and resolves neurologic abnormalities.

Other therapies for acute GVHD includes the following:

  • ABX-CBL is an immunoglobulin (Ig) M (IgM) murine monoclonal antibody that recognizes CD147 and initiates killing by means of complement-mediated lysis. ABX-CBL induced complete responses in 13 of 26 subjects with corticosteroid-refractory GVHD.[49]

  • Visilizumab is a humanized anti-CD3 monoclonal antibody with a mutated IgG2 isotype and selective apoptotic activity in activated T cells. It has produced promising responses in many patients, but posttransplantational lymphoproliferative disease is a problem.

  • Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, was associated with a worse 100-day and 1-year survival than a control arm because of increased relapse and infection. It was withdrawn from the United States market because of diminished use and emergence of other effective therapies.

  • Muromomab-CD3 (Orthoclone OKT3) monoclonal antibody has shown some benefit, but it is associated with a 24% incidence of Epstein-Barr–associated lymphoproliferative syndrome.

  • Humanized anti-Tac antibody to the IL-2 receptor showed a 40% clinical response rate in clinical trials. IL-1 receptor or IL-1 receptor antagonists have yielded response rates of 57-63% in pilot trials. Monoclonal antibodies against the efferent arm of GVHD, such as those for TNF-α, have produced responses. Partial responses are reported, but in all cases GVHD returned after treatment was discontinued.

  • Pentostatin has shown limited benefit in steroid-refractory acute GVHD[50]

  • Denileukin diftitox (product discontinued from market in January 2014) is a recombinant protein composed of IL-2 fused to diphtheria toxin and has selective toxicity against activated lymphocytes. In studies, it elicited a 50% complete and 21% partial response in corticosteroid-refractory GVHD.[51] Hepatic transaminase elevation was the dose-limiting toxicity.

Chronic GVHD

The following measures can substantially reduce the risk of chronic GVHD[52] :

  • Administration of rabbit ATG or alemtuzumab in the conditioning regimen before hematopoietic cell transplantation (HCT)
  • Administration of high-dose cyclophosphamide on days 3 and 4 after HCT

If chronic GVHD does develop, early recognition and treatment, before disability ensues, is critical. Used alone, prednisone 1 mg/kg every other day decreases treatment-related mortality rates (21% vs 40%) compared with prednisone combined with azathioprine, which is associated with a survival rate of 61% in patients with standard-risk chronic GVHD (no thrombocytopenia).

The addition of cyclosporine 6 mg given every 12 hours every other day in patients at high risk for GVHD with thrombocytopenia may improve survival rates from 26% to 52%. It may also improve functional performance to near-normal in long-term survivors by significantly decreasing the incidence of disabling scleroderma. However, infections are a frequent cause of morbidity and mortality in patients with high-risk chronic GVHD.

The addition of tacrolimus to steroids was associated with a high response rate of 72%. However, it led to a high chronic-GVHD–related mortality (34%) and a significant need for salvage therapy (47%).

Thalidomide has been reported as effective primary treatment for chronic GVHD because of its TNF-modulating effect. The 3-year survival rate is about 48%, with a diminished incidence of infection in long-term survivors.

Secondary therapy for chronic GVHD includes the following:

  • In August 2017, the FDA approved ibrutinib as the first drug for chronic GVHD in adults who have failed at least 1 systemic treatment. Ibrutinib is a Bruton’s tyrosin kinase (BTK) inhibitor. Inhibition of BTK enzymatic activity diminishes signaling to B-cell surface receptors that activate B-cell trafficking, chemotaxis, and adhesion.

    Approval of ibrutinib was based on a single-arm trial in 42 patients with chronic GVHD whose symptoms persisted despite standard treatment with corticosteroids. Results showed GVHD symptoms improved in 67% of patients after ibrutinib treatment, and in 48% of patients, the improvement of symptoms lasted for up to 5 months or longer.[8, 9]

  • Steroid-refractory chronic GVHD has been treated with azathioprine, alternating cyclosporine/prednisone, or thalidomide, with approximately similar survival rates. Clofazimine, an antileprosy agent, has also been effective in treating cutaneous and oral lesions of chronic GVHD and may be useful as a steroid-sparing agent because adverse effects and infections appear to be minimal.

  • MMF is now the most commonly used agent used to treat steroid-refractory chronic GVHD. Responses of 90% and 75% in first and second line settings are seen when MMF is added to standard tacrolimus, cyclosporine, and/or prednisone treatments. MMF does not seem to increase the rate of infections or relapse.[5]

  • PUVA therapy plays a role in patients with refractory cutaneous chronic GVHD. In 1 study, it resulted in a 78% response rate and improvement in a few extracutaneous sites.

  • Extracorporeal photopheresis, a modification of PUVA treatment, has also shown benefit, with best responses in the skin (59%), liver (71%), eye (67%), and oral mucosa (77%).[10]

  • The anti-CD20 monoclonal antibody rituximab produced a clinical response rate of 70% mainly for musculoskeletal and cutaneous chronic GVHD. These responses were durable through 1 year after initiation of therapy and allowed a 75% reduction in steroid doses.[11]

  • Ruxolitinib[48]

  • Pentostatin at a dose of 4 mg/m2 IV every 2 weeks for 6 months produced 50% response rates in patients with chronic GVHD who failed 2 prior immunosuppressive regimens. Aggressive infection prophylaxis was necessary with steroid tapering, antibiotics, antifungals, and antiviral agents.

  • Low-dose (100-cGy) total lymphoid irradiation to thoracoabdominal areas can lead to partial or complete improvement in some patients.

  • Imatinib has shown an overall response rate of 79% at 6 months for patients with refractory GVHD with fibrotic features where antibodies activating the platelet-derived growth factor receptor pathway have been reported.[12]

Other supportive care for chronic GVHD includes the following:

  • Pain control with analgesics for patients with painful mouth sores allows for oral intake. Oral beclomethasone may improve oral intake, nausea, and diarrhea without causing systemic or local toxicity.

  • Octreotide can control secretory diarrhea in enteric GVHD.

  • Antiviral prophylaxis (eg, for herpes simplex, cytomegalovirus [CMV]) can prevent oropharyngeal infection and interstitial pneumonia in patients with refractory GVHD.

  • Antifungal agents (eg, new triazoles, liposomal amphotericin B) may be useful for preventing and treating serious mycotic infections. Posaconazole is approved for prophylaxis against invasive aspergillosis in patients undergoing treatment for GVHD.[53]

  • Retinoic acid is used for ocular sicca syndrome, and pilocarpine (Salagen), for oral sicca manifestations.

  • Clonazepam is used to treat neuromuscular manifestations (eg, muscular aches, cramping, carpal spasm).

  • Ursodeoxycholic acid treatment for abnormalities in liver function can result in improvement of hepatic chronic GVHD; it can reduce elevated bilirubin levels by as much as 30%.

  • Patients receiving chronic corticosteroid therapy are at risk for osteoporosis and fractures. For women, estrogen replacement, calcium supplements, and antiosteoporosis agents (eg, Fosamax, calcitonin) should be considered.

  • Patients with stage IV skin GVHD are best treated in the burn unit, where the staff should pay meticulous attention to skin and wound care, nutrition, and infection control.

Surgical Care

Surgical consultations are required mainly for the insertion of central venous access devices, such as infusion ports and pheresis catheters.

Consultations

See the list below:

  • In patients with severe dermal involvement of chronic GVHD, burn care speeds re-epithelialization and closure of the portals of infection.

  • Plastic surgery may be necessary for skin allografting from the marrow donor in certain severe cases of dermal involvement due to chronic GVHD.

  • Patients with eye manifestations of chronic GVHD require ophthalmologic examination, follow-up, and treatment.

Diet

Institute gut rest and hyperalimentation for patients with acute GVHD and severe diarrhea. Patients should slowly advance to a bland diet or to the bananas, rice cereal, applesauce, and toast (BRAT) diet as tolerated.

Activity

Encourage patients who are receiving corticosteroid therapy to maintain an active lifestyle and to participate in a mild-to-moderate exercise program.

 

Medication

Medication Summary

Therapy includes immunosuppressive agents, antimetabolite and/or chemotherapeutic agents, antibodies and/or immunoglobulins, immunomodulating agents, and photoactive agents.

Immunosuppressive agents

Class Summary

Corticosteroids are the mainstay for treatment of GVHD. Corticosteroids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. Complications associated with glucocorticoid therapy depend on the dose and duration of treatment. A risk-benefit decision is made to determine the dose, duration, and frequency (daily or intermittent) of treatment.

The lowest possible dose of corticosteroid is used to control the condition and then gradually reduced when possible. Most patients undergoing allogeneic stem-cell transplantation are receiving prophylaxis for GVHD with CSP or tacrolimus in combination with methotrexate (MTX) and/or prednisone. Acute GVHD is treated with IV methylprednisolone for as long as 14 days. Subsequent tapering of the dose or switching to an oral agent is continued over several weeks to months. Chronic GVHD is treated with oral prednisone alone or in combination with CSP. If the response is positive, it is continued and tapered over 6-9 months.

Methylprednisolone (Solu-Medrol, Depo-Medrol, Medrol)

Synthetic analog of naturally occurring glucocorticoids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Greater anti-inflammatory potency than that of prednisolone and less likely than prednisolone to induce sodium and water retention.

Prednisone (Rayos)

Synthetic analog of naturally occurring glucocorticoids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.

Cyclosporine (Sandimmune, Neoral, Gengraf)

Cyclic polypeptide. Suppresses some humoral immunity and more so cell-mediated immune reactions. Dosages for children and adults based on ideal body weight. Sandimmune and Neoral not bioequivalent.

Sirolimus (Rapamune)

Inhibits lymphocyte proliferation by interfering with signal-transduction pathways. Binds to immunophilin FKBP to block action of mammalian target of rapamycin (mTOR). Approved by Food and Drug Administration for prophylaxis of organ rejection in patients receiving allogeneic renal allografts. Prolonged survival of allografts (kidney, heart, skin, islet, small bowel, pancreaticoduodenal, bone marrow) in mice, rats, pigs, and primates. Reversed acute rejection of heart and kidney allografts in rats and prolonged graft survival in presensitized rats. Immunosuppressive effect may last up to 6 mo after discontinuation. Tolerization effect is alloantigen specific. Also used for treatment of GVHD and for prophylaxis in combination with tacrolimus and/or MTX.

Tacrolimus (Prograf, Astagraf XL, Envarsus XR)

Previously known as FK506. Macrolide immunosuppressant produced by Streptomyces tsukubaensis. Prolonged host and transplant survival in animal models. Adults should receive doses at low end of dosing range. Concomitant adrenal corticosteroid therapy recommended early after transplantation.

Mycophenolate mofetil (CellCept, Myfortic)

The 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent. Inhibits purine synthesis and proliferation of human lymphocytes. Prolonged survival of allogeneic transplants in animal models.

Azathioprine (Imuran, Azasan)

Imidazolyl derivative of 6-mercaptopurine. Many of its biologic effects similar to those of the parent compound. Suppresses hypersensitivities of cell-mediated type and variably alters antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity suppressed more than antibody responses. Considered slow-acting drug, and effects may persist after discontinuation.

Immunomodulating agents

Class Summary

Thalidomide exerts an immunologic effect. Its effectiveness is thought to be due to suppression of excessive TNF-alpha production and downmodulation of selected cell-surface adhesion molecules involved in leukocyte migration.

Thalidomide (Thalomid)

Immunologic effects vary substantially in different conditions but may be related to suppression of excessive TNF-alpha production and downmodulation of selected cell-surface adhesion molecules involved in leukocyte migration.

Photoactive agents

Class Summary

Methoxsalen, a psoralen, and PUVA may be beneficial in treating cutaneous lesions of GVHD and may improve survival in some patients with steroid-resistant GVHD.

Methoxsalen (Oxsoralen Ultra)

Naturally occurring photoactive substance that acts as photosensitizer. Subsequent exposure to UVA can cause cell injury. PO dose reaches skin by blood, and UVA penetrates well into skin. If sufficient cell injury occurs in skin, inflammatory reaction occurs. Most obvious manifestation is erythema, which may not begin for several h and peaks at 48-72 h. Over days to weeks, inflammation followed by repair manifested by increased melanization of epidermis and thickening of stratum corneum.

Exact mechanism of action with epidermal melanocytes and keratinocytes not known. Best-known biochemical reaction is with DNA. On photoactivation, conjugates and forms covalent bonds with DNA, which leads to formation of monofunctional (addition to single strand of DNA) and bifunctional adducts (cross-linking of psoralen to both strands of DNA).

Antineoplastic agents

Class Summary

These agents inhibit cell growth and proliferation.

MTX is used to treat certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. A short-course MTX is administered for the prophylaxis of acute GVHD. It is used in combination with CSP or tacrolimus.

Newer antineoplastic treatments include novel fusion proteins carrying a toxin or chemotherapeutic agents are engulfed into target cells, delivering a highly toxic molecule and leading to cell death.

Pentostatin (Nipent)

Inhibits adenosine deaminase resulting in deoxyadenosine and deoxyadenosine 5+-triphosphate accumulation that may inhibit DNA or RNA synthesis causing cell death.

Methotrexate (Trexall)

Formerly amethopterin. Antimetabolite used to treat certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues (eg, malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, cells of urinary bladder) generally most sensitive to this effect. May impair malignant growth without irreversible damage to healthy tissues when cellular proliferation in malignant tissues is greater than that of most healthy tissues. Preservative formulation contains benzol alcohol and must not be used for intrathecal or high-dose therapy.

Ruxolitinib (Jakafi)

Kinase inhibitor inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2. JAK signaling involves recruitment of STATs (signal transducers and activation of transcriptions). JAK-STAT signaling pathways play a role in regulating development, proliferation, and activation of several immune cells types imperative for GVHD pathogenesis. In a mouse model of acute GvHD, oral ruxolitinib was associated with decreased expression of inflammatory cytokines in colon homogenates and reduced immune-cel infiltration in the colon. Indicated for treatment of steroid-refractory acute GvHD in adult and pediatric patients aged 12 years or older.

Antineoplastics, Tyrosine Kinase Inhibitor

Class Summary

Ibrutinib is the first drug approved by the FDA for chronic GVHD.

Ibrutinib (Imbruvica)

Ibrutinib is a Bruton’s tyrosin kinase (BTK) inhibitor. Inhibition of BTK enzymatic activity diminishes signaling to B-cell surface receptors that activate B-cell trafficking, chemotaxis, and adhesion. It is indicated for chronic GVHD in adults who have failed at least 1 systemic treatment.

Monoclonal Antibody

Class Summary

These agents are monoclonal antibody directed against specific antigens found on surface of normal and/or malignant cells. They may also be directed against specific molecules to render them inactive.

Newer monoclonal antibodies directed against particular targets such as cytokines or antigens on cells that may have a role in GVHD initiation and propagation include alemtuzumab, infliximab, and other agents being investigated.

Infliximab (Remicade, Inflectra, Renflexis)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-α and inhibits its binding to TNF-α receptor. Reduces infiltration of inflammatory cells and TNF-α production in inflamed areas.

Rituximab (Rituxan)

Antibody genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of normal and malignant B lymphocytes. Antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy- chain variable region sequences and human constant region sequences.

Alemtuzumab (Campath, Lemtrada)

Monoclonal antibody against CD52, antigen found on B-cells, T-cells, and almost all chronic lymphocytic leukemia (CLL) cells. Binds to CD52 receptor of lymphocytes, which slows proliferation of leukocytes.

Antibodies and/or immunoglobulins

Class Summary

Antithymocyte globulin-equine (Equine, Atgam) is an Ig-containing immunosuppressive agent that principally inhibits cell-mediated immune responses and inhibits humoral immune response to an extent.

IVIG (human) is a sterile, highly purified polyvalent antibody product containing, in concentrated form, all the IgG antibodies that regularly occur in the donor population.

Antithymocyte globulin-equine (Atgam)

Ig-containing immunosuppressive agent. Immunosuppressive action generally similar to that of other antilymphocyte preparations. May differ qualitatively and/or quantitatively in extent of specific effects, partly because of factors such as source of antigenic material, animal used to produce antiserum, and method of production.

Intravenous immune globulin, human (Sandoglobulin, Gammagard, Octagam, Gamunex-C)

Sterile, highly purified polyvalent antibody product containing, in concentrated form, all IgG antibodies that regularly occur in donor population. Do not mix with other medications or fluids; administer in separate infusion line.

Tumor Necrosis Factor Inhibitor

Class Summary

Preclinical studies have shown the importance of tumor necrosis factor-α (TNF α) as an effector of experimental GVHD. TNF inhibition can be accomplished by either antibodies against soluble and membrane-bound TNF α or by competitive binding using soluble TNF α receptors (such as etanercept) to render the molecule inactive.

Etanercept (Enbrel)

A dimeric fusion protein made up of the extracellular ligand-binding portion of tumor necrosis factor receptor linked to the Fc portion of human IgG1. It binds specifically to TNF and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine involved in normal inflammatory and immune responses. It is also implicated in mediating GVHD both through amplification of donor immune response to host tissues as well as direct toxicity to target organs.

 

Follow-up

Further Inpatient Care

See the list below:

  • Manage severe diarrhea with octreotide, intravenous hydration to prevent dehydration, and total parenteral nutrition in patients with severe malabsorption.

  • Treat infections and prescribe prophylactic antibiotics, antiviral agents, and antifungals.

  • Grade IV skin lesions (ie, bullae, vesicles) require meticulous care, which may be similar to the care for second-degree burns.

Deterrence/Prevention

To minimize graft versus host disease (GVHD), donor and host factors should be addressed, as follows:

  • Refinement of methods to select the donor based on molecular characterization of HLA class I and II antigens may minimize HLA disparity between the donor and recipient and therefore decrease the incidence of GVHD; for example, Japanese researchers recommend that reported that mismatched HLA-C*14:02 should be considered a non-permissive HLA-C mismatch in donor selection for unrelated donor hematopoietic stem cell transplantation, as it is a potent risk factor for severe acute GVHD and mortality[54]

  • Use of a cytomegalovirus (CMV)-seronegative donor for a CMV-seronegative patient appears to reduce the risk of both CMV infection and GVHD in the recipient

  • Laminar airflow protective isolation with gut decontamination can decrease the incidence of GVHD and improve survival in patients with aplastic anemia undergoing bone marrow transplantation

Posttransplantational immunosuppressive prophylaxis

Single agents or combinations of agents have been used to prevent acute GVHD. The most common effective regimen consists of cyclosporine administered for 180 days combined with a short course of methotrexate administered on days 1, 3, 6, and 11. The combination is better than either agent administered alone. In one study, the addition of prednisone on days 7-180 further reduced the incidence of acute GVHD from 23% to 9%.

Tacrolimus, a more potent immunosuppressant than cyclosporine, is also being used in combination with methotrexate and appears to be more effective than cyclosporine at preventing acute graft versus host disease (GVHD), especially in patients receiving a transplant from an unrelated donor. The cumulative incidence of chronic GVHD also seems to be less with the tacrolimus-methotrexate combination (48%) than with the cyclosporine-methotrexate combination (64%).[40] Prolonged immunosuppression (extending beyond the usual day 180) may be indicated for patients at high risk for chronic GVHD (ie, patients who have had acute GVHD).

Antibody prophylaxis with intravenous immunoglobulin (IVIG), when administered weekly through day 90 after transplantation, reduces the incidence and mortality rate of acute GVHD. Continuing IVIG treatment from day 90 to day 360 after transplantation did not seem to change the cumulative incidence of chronic GVHD in treated patients compared with a control group that was not receiving IVIG.[55]

In a prospective, multicenter, open-label, randomized phase 3 study, the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG.[56]

Marrow T-cell depletion by in vitro methods (eg, soybean-lectin agglutination, counterflow centrifugation, use of antibodies against T lymphocytes or their subsets) can substantially reduce the incidence and severity of acute and chronic GVHD (50% in T cell–depleted HLA-identical marrows). However, the overall survival rate is not improved because of increased incidence of graft failure and recurrent leukemia. In long-term survivors who received T cell–depleted unrelated donor marrows, chronic GVHD still occurred in 85%.

In vivo T-cell depletion by the addition of anti–T-cell globulin to standard cyclosporine-methotrexate prophylaxis decreased the incidence of both acute and chronic GVHD without affecting relapse or nonrelapse mortality or compromising overall survival in recipients of matched unrelated donor transplants in a randomized, open-label, multicenter, phase 3 trial.[29]

Prevention is the most important aspect in managing transfusion-associated GVHD. Encourage the hospital's blood bank to automatically irradiate all blood products that may be transfused into high-risk patients.

Complications

Late infections are possible. Multiple immune defects are observed in patients with chronic GVHD, such as impaired mucosal defense, chemotactic defects, functional asplenia, T-cell alloreactivity, and qualitative and quantitative B-cell abnormalities. Bacteremia and sinopulmonary infections due to Streptococcus pneumoniae and Haemophilus influenzae can occur.[57] The incidence of pulmonary infections after day 100 is 50% in patients with chronic GVHD versus 21% in those without GVHD.

In patients who undergo unrelated donor transplantation, the risk of bacteremia and septicemia due to chronic GVHD and HLA-nonidentity is increased, and hypogammaglobulinemia occurs frequently.

Other complications include the following:

  • Treatment of patients with chronic GVHD with azathioprine is associated with an increased risk of secondary neoplasms, such as squamous cell carcinomas of the skin and buccal mucosa.
  • Sclerodermatous lesions can lead to joint contractures, impairing mobility and the patient's ability to perform certain routine body movements.

Prognosis

The overall grade of acute GVHD correlates well with outcome, as well as response to treatment, as follows:

  • Patients achieving a complete response have approximately a 22% mortality rate, compared with a 75% mortality rate in patients who have progressive GVHD or no change with treatment.

  • Factors associated with impaired survival are HLA-nonidentical marrow donors, liver abnormalities in addition to GVHD, and early time to onset and treatment of GVHD.

For chronic GVHD, the 6-year survival rate is about 42% and is worst (10%) in patients with progressive onset. Other factors linked to high mortality rates are as follows:

  • Extensive disease
  • Thrombocytopenia
  • HLA-nonidentical marrow donors
  • Elevated bilirubin value at 2 mg/dL or greater
  • Lichenoid histology on skin biopsy
  • Failure to taper prednisone treatment for acute GVHD before the onset of progressive chronic GVHD

Patient Education

See the list below:

  • To decrease the incidence of sunburn, which can exacerbate GVHD reactions, patients should avoid excessive exposure to the sun by using sunblock lotion, sun-blocking headgear, and appropriate garments.

  • Patients should pay attention to good skin care, using moisturizing lotions or creams to prevent skin breakdown.

  • While receiving corticosteroid therapy, patients should be encouraged to preserve muscle tone and mass by avoiding sedentary activity and by exercising regularly.

  • Patients should avoid unnecessary exposure to potentially hazardous infections while they are receiving highly immunosuppressive treatment for GVHD. Examples of unnecessary exposure are the inhalation of fungal spores from the soil while gardening, working on farms, and working with animal excreta.