AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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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. 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 1966,¹ 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 in Table 1.

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. Image 4 shows the interactive factors involved in the pathogenesis of GVHD.

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 like 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.

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 cyclosporin (CSP) and interleukin (IL)-2.

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%.

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.

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%). 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.

Mortality/Morbidity

• 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.
• 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%.

CLINICAL

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History

Patients at risk for acute GVHD and chronic GVHD are those undergoing allogeneic HCT.

• Acute GVHD
• • Acute GVHD may initially appear as a pruritic or painful rash (median onset, day 19 posttransplantation; range, 5-47 d).
  • A hyperacute form of GVHD has been described as 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-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 CSP A 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.
  • 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
• • 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.
• Hepatic findings: Hyperbilirubinemia 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: Acute GVHD may also cause 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: Atrophy of the oral mucosa, erythema, and lichenoid lesions of the buccal and labial mucosae are significantly correlated with chronic GVHD.
• 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 autoimmune phenomenon of myasthenia gravis or polymyositis are sometimes observed in chronic GVHD.
• Other findings: 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.

  Table 2. Clinical Staging of Acute GVHD

  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

  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 day of diagnosis in HLA-identical sibling recipients is 201 days after transplant; 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.

  Table 4. Clinicopathologic Classification of Chronic GVHD

  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.

  Table 5. Screening Studies for GVHD by Organ or System

  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, AST, 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 are listed below.

• Donor-host factors
• • 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.
• Stem-cell source
• • 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.
• Immune modulation
• • The efficacy of posttransplantational immunosuppressive prophylaxis affects the development of GVHD.
  • Triple therapy with CSP, short-course methotrexate (MTX), and prednisone lowers the incidence of GVHD compared with double therapy with CSA and MTX alone.
• High-dose chemotherapy and radiation therapy
• • 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.
  • High-dose chemotherapy can also lead to localized tissue damage, exposing cryptic antigens in certain organs (eg, skin, liver, gut).
  • Conditioning regimens including total-body irradiation are associated with an increased incidence and severity of GVHD compared with chemotherapy alone.
  • 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.

DIFFERENTIALS

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Other Problems to be Considered

Acute skin toxicity from radiation (total body irradiation)
Hepatobiliary toxicity from chemotherapy (veno-occlusive disease of the liver)
Inflammatory or infectious diarrheas

WORKUP

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Lab Studies

• Complete blood count
• • Acute GVHD usually does not occur until after engraftment during transplantation.
  • Poor graft function may be a sign of autoimmune cytopenias (eg, thrombocytopenia, anemia, leukopenia) that may be observed with chronic GVHD.
• Liver function tests (eg, bilirubin, AST, ALT, alkaline phosphatase, total protein, and albumin measurements)
• • Elevation of the alkaline phosphatase concentration is 1 of the early signs 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.
• Barium swallow study can be used to detect esophageal changes of chronic GVHD, such as web formation, ringlike narrowing, and tapering structures of the middle and upper esophagus.

Other Tests

• 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. 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.
• 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.

Procedures

• 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.

TREATMENT

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Medical Care

Acute GVHD

• Primary prophylaxis
• • The criterion standard for prophylaxis is CSP A for 6 months and short course MTX in T-cell–replete allogeneic HCT. CSP levels should be kept above 200 ng/mL.
  • Substitution of tacrolimus for CSP A is frequently used, 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.
  • 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. Ex-vivo depletion of T-cells has also been tried (in the 1980s), but transplantation-related mortality was not reduced compared to 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, sirolimus, pentostatin, Campath-1H, keratinocyte growth factor (KGF), and suberoylanilide hydroxamic acid (SAHA).
  • Extracorporeal photopheresis (ECP) is an immunomodulatory procedure that collects lymphocytes and mixes them with 8-methoxypsoralen (which intercalates into the DNA of the lymphocytes), rendering them susceptible to ultraviolet light radiation effects that cause apoptosis. 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.
• Primary therapy
• • 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 (CSP A or tacrolimus [FK506]) and adding methylprednisolone. Doses have been in the range of 1-60 mg/kg, but the most common starting dose 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, CSP alone, mycophenolate mofetil, daclizumab, anti–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 1 over any other.
  • Novel therapies like the addition of ex vivo cultured mesenchymal cells derived from unrelated donors to conventional steroid therapy showed initial response rates of 90%, although 31% of patients required a second-line agent to control the disease.
• Secondary therapy
• • Failure of initial therapy is defined as the progression of acute GVHD after 3 days, no change after 7 days, or incomplete response after 14 days of treatment with methylprednisolone. Secondary therapy is usually initiated in steroid-refractory cases.
  • ATG or multiple pulses of methylprednisolone (at doses higher than those used in initial therapy) have a response rate of about 40%.
  • Mycophenolate mofetil (MMF) at 2 g daily, when added to the steroid regimen, caused and overall response rate of 62%.
  • 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 tumor necrosis factor–alpha (TNF-alpha), have produced responses. Partial responses are reported, but in all cases GVHD returned after treatment was discontinued.
  • 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 responders were observed in patients with skin involvement only than in patients with liver or gut involvement.
  • Approximately 12% of patients with GVHD resistant to CSP may respond to a conversion to FK506. In patients who develop CSP-related neurotoxicity, therapy can be switched and maintained with FK506, which stabilizes and resolves neurologic abnormalities.
• Newer therapies
• • 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.
  • 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.
  • Infliximab is a genetically constructed IgG1 murine-human chimeric monoclonal antibody that binds the soluble subunit and the membrane-bound precursor of TNF-alpha. It causes a high response rate, but opportunistic infections (especially noncandidal invasive fungal infections) result in a high mortality rate.
  • Denileukin diftitox 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. Hepatic transaminase elevation was the dose-limiting toxicity.
  • Pentostatin at 1.5 mg/m² produced a complete and partial response rate of 64% and 14%, respectively, and was also effective in patients who were retreated at progression.

Chronic GVHD

• Primary therapy
• • Recognizing and treating chronic GVHD early, 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 CSP 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% but 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
• • Steroid-refractory chronic GVHD has been treated with azathioprine, alternating CSP/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 its 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.³
  • 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%).
  • 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.
  • 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.
• Other supportive care
• • 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.
  • 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 female patients, 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 Infuse-A-Port devices and pheresis catheters.

Consultations

• In patients with severe dermal involvement of chronic GVHD, burn care speeds reepithelialization 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

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

Drug Category: Immunosuppressive agents

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.

Drug Category: Immunomodulating agents

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.

Drug Category: Photoactive agents

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.

Drug Category: Antineoplastic agents

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.

Azathioprine is an antimetabolite that suppresses cell-mediated hypersensitivities and causes variable alterations in antibody production. It is used in combination with steroids and CSP to treat chronic GVHD.

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.

Drug Category: Monoclonal Antibody

These agents are monoclonal antibody directed against specific antigens found on surface of normal and/or malignant cells.

Drug Category: Antibodies and/or immunoglobulins

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.

Muromonab-CD3 is a murine monoclonal antibody to the CD3 antigen of human T cells that functions as an immunosuppressant. It is thought to reverse graft rejection by blocking the function of T cells that play a major role in acute allograft rejection.

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, daclizumab, infliximab, and other agents being investigated.