Pediatric Graft Versus Host Disease 

Updated: Jun 03, 2019
Author: Phillip Ruiz, Jr, MD, PhD; Chief Editor: Harumi Jyonouchi, MD 

Overview

Background

The occurrence of an immunologically mediated and injurious set of reactions by cells genetically disparate to their host, otherwise known as graft versus host disease (GVHD), is a phenomenon that has been described as the age of bone marrow and solid organ transplantation has emerged. In 1962, Barnes and Loutit first described GVHD in mice.[1] Simonsen introduced the term graft-versus-host reaction in the 1960s to describe the direction of the immunological damage caused by introduction of immunologically competent cells into an immunocompromised host.[2] In 1966, Billingham proposed 3 conditions required for the development of GVHD, as follows: (1) the graft must contain immunologically competent cells, (2) the host must possess important transplant alloantigens that are lacking in the donor graft so that the host appears foreign to the graft, and (3) the host itself must be incapable of mounting an effective immunologic reaction against the graft.[3] See the image below.

Autologous graft versus host disease (GVHD) involv Autologous graft versus host disease (GVHD) involving the skin of a patient's arm shortly after showing signs of engraftment after an autologous peripheral blood stem cell transplant for ovarian cancer. Image courtesy of Romeo A. Mandanas, MD, FACP.

According to the accepted definition, the immunologic assault itself and its consequences are referred to as GVHD. In both experimental and clinical scenarios, acute GVHD, as shown below, describes a syndrome consisting of dermatitis, enteritis, and hepatitis occurring within the first 100 days, but typically within 30-40 days, following a bone marrow transplant (BMT). Chronic GVHD usually develops after 100 days and describes an autoimmunelike syndrome consisting of impairment of multiple organs or organ systems.[4] However, the timing of GVHD occurrence to define the acute versus chronic is arbitrary.

Acute graft versus host disease (GVHD) involving d Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient following allogeneic bone marrow transplantation for myelodysplasia. Image courtesy of Romeo A. Mandanas, MD, FACP.

With the advances of transplant practice, the clinical manifestations are now better defined than timing alone. The National Institutes of Health (NIH) published consensus criteria for the diagnosis of GVHD and proposed 2 subcategories for acute GVHD (classic acute and late acute) and chronic GVHD (classic chronic and overlap syndrome), taking an organ-functional impact into the account.[5] However, the feasibility of the NIH consensus criteria to replace the old grading system of chronic GVHD (limited versus extensive) is still under evaluation.[6]

Pathophysiology

GVHD can develop in the course of (1) BMT or peripheral blood progenitor (hematopoietic stem cell) transplantation; (2) transfusion of unirradiated blood products (transfusion-associated GVHD), especially in immunocompromised individuals; or (3) solid organ transplantation involving organs containing lymphoid tissue. GVHD from passive transmission of immunocompetent maternal cells has also been described in neonates with severe immunodeficiency.

Graft-versus-host reaction occurs when donor immune cells recognize disparate host antigens. These differences are governed by genetic polymorphisms of human leukocyte antigen (HLA)-dependent factors (ie, major and minor histocompatibility antigens) and non-HLA–dependent factors (ie, cytokine gene polymorphisms, nucleotide-binding oligomerization domains [NOD2] genes, and killer immunoglobin receptor [KIR] family of natural killer [NK] receptors).[7]

The immunopathologic characteristics of acute GVHD have often been separated into different phases (1-3), which describes the creation of a suitable host environment with the conditioning regimens intended to remove particular host cell populations, and immune-based sensitizing and efferent (effector) phases (see image below).[8, 9]

Pathophysiological pathways and mechanisms of acut Pathophysiological pathways and mechanisms of acute GVHD.

During phase 1 (Afferent phase), tissue injured by chemotherapy and irradiation releases proinflammatory cytokines such as tumor necrosis factor (TNF) alpha and interleukin (IL)-1, which subsequently increases expression of adhesion molecules, major histocompatibility complex (MHC) molecules, and costimulatory molecules. These cytokines further activate host antigen-presenting cells (APCs).

In phase 2 (Donor-T-cell activation, differentiation, and migration), the infused donor T lymphocytes are responsible for triggering GVHD and proliferate after activation by the recipient antigens expressed on host cells. APCs, such as dendritic cells or macrophages, present the antigen to CD4+ T cells, which recognize antigens in association with MHC class II molecules.[10] IL-1 produced by monocytes and other factors stimulates the T-helper cells. The T-helper cells, in turn, release compounds such as IL-2 and interferon (IFN)-γ; the latter enhances the expression of MHC class II on epithelial cells, macrophages, and dendritic cells, further stimulating the activation of T cells and NK cells.

IL-2 activates cytotoxic CD8-positive T cells, which react with MHC class I-positive targets. In addition, NK cells and macrophages appear to participate in the development of GVHD, although their roles are not well defined. Among the variables determining the extent to which GVHD develops are the types and properties of the transplanted T cells, the degree of MHC antigen mismatching, and the degree of interactions between T cells and the endothelial cells.

The final phase (3) of acute GVHD, is where immune effector cells and cytokines enact end-organ damage and contribute to a possible loss of self-tolerance. This injury is clinically manifested as the symptoms seen in GVHD and may be a contributing factor to the development of chronic GVHD.

As mentioned before, chronic GVHD develops after day 100 from transplantation and, like acute GVHD, appears dependent on alloreactivity for it to develop. Chronic GVHD has features similar to naturally occurring autoimmune disease with a wider range of involved organs. Clinical manifestations can include sclerodermatous lesions, liver failure, autoantibody production, and immune complex disease (including glomerulonephritis).

Host-recipient differences in MHC antigens or minor histocompatibility antigens can lead to this syndrome, albeit with slightly different kinetics. Alterations in thymic function with decreased thymopoiesis likely contribute to this syndrome with a breakdown of normal self-tolerance mechanisms. The donor CD4+ T-cell population is necessary for human chronic GVHD to develop; Th2 cells are the predominant subpopulation in the chronic GVHD, although the mechanisms of the disease progress remains poorly defined.

Epidemiology

Frequency

United States

Incidence and frequency of acute GVHD in transplanted or transfused populations is related to the presence of several risk factors, as follows:[11]

  • Histocompatibility: The most important factor correlating with incidence and severity of GVHD is the degree of HLA (MHC molecules in humans) disparity. With HLA-identical siblings used as bone marrow donors, the incidence of moderate-to-severe acute GVHD ranges from less than 10% to 60%, depending on prophylaxis and other risk factors (see images below). Incidence of grades II-IV acute GVHD increases to 70-75% with one HLA antigen mismatch and as much as 90% with 2-3 HLA antigen mismatch. Incidence of grades II-IV GVHD of as much as 70% have been reported in unrelated donors; a difference was noted between those receiving marrow from an HLA-identical donor or from an HLA-mismatched donor.

    This boy developed stage III skin involvement with This boy developed stage III skin involvement with acute graft versus host disease (GVHD) in spite of receiving prophylaxis with cyclosporin A. The donor was an human leukocyte antigen (HLA)-matched sister; however, the sex disparity increased the risk for acute GVHD. Image courtesy of Mustafa S. Suterwala, MD.
    This photo depicts the same boy who has progressed This photo depicts the same boy who has progressed to grade IV graft versus host disease (GVHD). Both cyclosporin A and methylprednisolone had been administered in high dose intravenously. He later died with chronic pulmonary disease caused by chronic GVHD. Image courtesy of Mustafa S. Suterwala, MD.
  • Graft cell composition: T-cell depletion of the bone marrow decreases the risk of GVHD but increases a risk of graft failure as well as leukemic relapse, which is due to a loss of a graft-versus-leukemia effect. Umbilical cord blood cells, when used as the source of hematopoietic stem cells, cause reduced incidence of GVHD, but the same is not true of peripheral blood stem cells.

  • Age and sex: Older patients have a significantly higher risk of acute GVHD, with an incidence of approximately 20% in the pediatric population and rising to 30% in patients aged 20-50 years and to 70% in patients aged 51-62 years. An increased risk of GVHD exists in recipients of gender-mismatched marrow, possibly because of HLA association with the Y chromosome.

  • Microenvironment: Host environment is important for the development of GVHD. Patients with aplastic anemia who are undergoing BMT and are treated with antibiotics, who are treated with skin and gut decontamination, and who are placed in a protective environment with laminar airflow units have reduced incidence of GVHD.

  • Chronic disease: Chronic GVHD develops in 30-50% of long-term survivors after BMT.[12] HLA disparity, prior acute GVHD, older age, and viral infections (especially herpesvirus group) are associated with increased risk of chronic GVHD. Chronic GVHD is also known to occur at a higher rate in survivors of transplant for aplastic anemia.

  • Type of transplantation: Acute GVHD in stem cell transplantation develops in 30-60% of recipients of sibling matched allografts. The incidence of GVHD after intestinal transplantation and liver transplantation is reported to be 5% and 0.1-1%, respectively.[13] Transfusion-associated GVHD often presents with marrow aplasia; in Japan, this is estimated to occur in 1 in 500 open-heart operations in individuals who are immunocompetent.

Mortality/Morbidity

The survival rate is 90% in grade 0-I, 60% in grade II-III, and 0 in grade IV of acute GVHD. Fatality mainly results from infections, hemorrhages, and hepatic failure. Acute GVHD can have an antileukemic effect. In chronic GVHD, the overall survival rate is 42%, with the mortality rates increased in patients with more extensive disease and thrombocytopenia.

Sex

An increased risk of GVHD is noted in recipients of sex-mismatched marrow, possibly because of HLA association with the Y chromosome.

 

Presentation

History

See the list below:

  • Acute graft versus host disease (GVHD): The clinical presentation is often a triad of dermatitis, hepatitis, and gastroenteritis, although symptoms may occur alone or in different combinations. Other tissues that may be involved include mucous membranes, conjunctiva, exocrine glands, bronchial tree, and urinary bladder.

    • Skin: Maculopapular rash may present with the onset occurring within 5-47 days after transplantation.[14] Pruritus involving the palms and soles may precede the rash. In the early stage, the rash is confined to the nape of the neck, shoulder, palms, or soles. It may be confluent and involve the entire integument. In severe cases, bullous lesions similar to third-degree burns may develop.

    • Liver: The liver is the second most common organ involved. GVHD first manifests as elevated liver transaminases. Cholestatic jaundice is common, but hepatic failure with encephalopathy is unusual. Hepatic and GI involvement manifest with or following skin involvement.

    • GI: GVHD of the distal bowel and colon results in profuse diarrhea; intestinal bleeding; cramping, abdominal pain; and paralytic ileus. Diarrhea is greenish mucoid, watery, and secretory in nature. Upper GI involvement without enteric manifestation has been described in 13% of adults. Common symptoms are anorexia, nausea, vomiting, and dyspepsia.

    • Grading: Acute GVHD is graded in 5 steps from 0-IV based on involvement of the skin, liver, and GI tract. Grade 0 indicates no clinical evidence of disease. Grades I-IV are graded functionally. Grade I indicates rash on less than 50% of skin and no gut or liver involvement. Grade II indicates rash covering more than 50% of skin, bilirubin level of 2-3 mg/dL, diarrhea of 10-15 mL/kg/d, or persistent nausea. Grade III or IV indicates generalized erythroderma with bullous formation, bilirubin level of more than 3 mg/dL, or diarrhea of more than 16 mL/kg/d.

  • Chronic GVHD: This is a more pleiotropic syndrome that develops after day 100. The syndrome resembles autoimmune systemic collagen vascular disease with protean manifestations, involving essentially every organ.[15] Systemic manifestations include recurrent infections with immunodeficiency, weight loss, sicca syndrome, and failure to thrive (children) or debility and weight loss (adults).

    • Chronic GVHD can present with 2 forms of skin involvement. An early phase resembles lichen planus; these lesions may be sparse and transitory, ranging from papules to more typical lesions. Poikiloderma can be present in the later phase, which is extra pigmentation of the skin demonstrating various shades and associated with telangiectasia in the affected area.

    • Hair manifestations present as alopecia.

    • The mouth may present with sicca syndrome, depapillation of the tongue with variegations, scalloping of lateral margins, lichen planus, oral ulcers, and angular tightness. 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 result from GVHD. Image courtesy of Romeo A. Mandanas, MD, FACP.
    • Joints exhibit decreased range of movements with associated myositis and tendinitis.

    • Manifestations of the eyes include decreased tearing, injected sclera, and conjunctivitis.

    • The liver involvement typically presents as cholestasis and cirrhosis.

    • GI presentations include esophageal stricture, malabsorption, and chronic diarrhea.

    • Pulmonary presentations include cough, dyspnea, wheezing, rales, pneumothorax, and, finally, bronchiolitis obliterans.

    • Hematological manifestations include refractory thrombocytopenia and eosinophilia.

    • Spleen involvement may present with functional asplenia.

    • Chronic GVHD has 2 stages. Limited chronic GVHD presents with localized skin involvement, hepatic dysfunction caused by chronic GVHD, or both. Extensive chronic GVHD presents with the following:

      • Generalized skin involvement, or localized skin involvement and/or hepatic dysfunction caused by chronic GVHD

      • Liver histologic findings showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis

      • Eye involvement - Schirmer test (< 5 mm wetting)

      • Involvement of minor salivary glands or oral mucosa demonstrated by buccal/labial biopsy

      • Involvement of any other target organ

Physical

See the list below:

  • See History.

 

DDx

Diagnostic Considerations

Acute graft versus host disease

  • Skin

    • Chemoradiotherapy toxicity

    • Drug reaction

    • Viral exanthema

  • Liver

    • Venoocclusive disease

    • Viral hepatitis

    • Drug toxicity

    • Septicemia

    • Total parental nutrition complications

  • GI

    • Clostridium difficile

    • Gastroenteritis, especially cytomegalovirus

    • Chemoradiotherapy

Chronic graft versus host disease

  • Autoimmune diseases

  • Gastroenteritis, especially cytomegalovirus

  • Chemoradiotherapy

 

Workup

Laboratory Studies

See the list below:

  • The diagnosis of graft versus host disease (GVHD) is established by clinical judgment, imaging studies, laboratory workup, and biopsy results.

  • Anemia and thrombocytopenia are observed early in acute GVHD or in chronic GVHD.

  • Eosinophilia (see Eosinophils) and Howell-Jolly bodies are observed on peripheral smear in chronic GVHD.

  • In hepatic involvement, elevation of transaminase levels is observed early and followed by an increase in bilirubin and, finally, cholestatic picture with increased alkaline phosphatase and glucose tolerance.

  • A panel of 4 biomarkers in the serum, including interleukin (IL)-2 receptor-α, tumor necrosis factor (TNF)-receptor-1, IL-8, and hepatocyte growth factor, have been reported to be useful to confirm the diagnosis of GVHD in patients at onset of clinical symptoms.[16, 17]

    Acute graft versus host disease (GVHD). Hematoxyli Acute graft versus host disease (GVHD). Hematoxylin-stained and eosin-stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. A moderate superficial dermal and perivascular lymphocytic infiltrate is also seen in this case. Image courtesy of Melanie K. Kuechler, MD.

Imaging Studies

See the list below:

  • Pulmonary fibrosis resulting from irradiation or chemotherapeutic agents

  • Bronchiolitis obliterans on radiograph or CT scan observed in chronic GVHD

  • Ultrasonography, CT scanning, and Doppler studies: These may be used to distinguish GVHD from other causes of jaundice or cholestatic liver function abnormalities.[18]

  • Endoscopic studies of small bowel: These may reveal atrophy of the villi, ulceration, and bleeding. Barium swallow study may reveal the changes of chronic GVHD, such as ringlike narrowing and web formation.

Procedures

See the list below:

  • Although a biopsy is not routinely performed, it can be very helpful to distinguish changes of GVHD from drug toxicity in skin and liver. Biopsy findings are necessary for confirming the diagnosis of chronic GVHD.

  • Upper GI endoscopy is currently routinely performed in older patients with nausea, anorexia, and dyspeptic symptoms. This study is useful in grading.

Histologic Findings

See the list below:

  • Acute GVHD

    • The skin demonstrates epidermal basal vacuolization, followed by epidermal basal cell apoptotic death with lymphoid infiltration. Eosinophilic bodies may be observed with increased severity. Bullous formation with epidermal separation and necrosis is observed in later stages.

    • Liver tissue undergoing acute GVHD can demonstrate damage to more than 50% of bile ducts with vacuolated cytoplasm, with duct cell nuclear pleomorphism and necrosis of individual cells (apoptosis). A lymphocytic infiltrate of portal tracts with endothelialitis (veins with lifting of endothelium from its basement membrane) is observed along with ballooning degeneration of hepatocytes and/or acidophil bodies.

    • GI biopsy specimens reveal diffuse edema and mucosal swelling followed by variable crypt cell apoptosis (eg, "exploding" crypts), a mixed chronic and predominantly lymphoplasmacytic infiltrate, and possibly crypt dropout.

  • Chronic GVHD: Skin biopsy specimens can reveal epithelial acanthosis, dyskeratosis, and hyperkeratosis with a mononuclear infiltrate at the dermal-epidermal junction and in adnexal structures. This inflammatory process can evolve to dermal fibrosis and epidermal atrophy. Similarly, a mononuclear infiltrate is seen in the salivary glands on lip biopsy findings. The liver shows a portal mononuclear infiltrate with damage to the bile ducts and eventually ductopenia, changes that can be seen in the absence of clinical manifestations. GI findings of crypt destruction, increase in lymphoplasmacytic infiltrate with single cell drop out, and fibrosis of lamina propria are observed.

Staging

See the list below:

  • Acute GVHD is traditionally graded in 5 stages (0-IV), based on involvement of the skin, liver, and GI tract. Grades I-IV are graded functionally.

    • Grade 0 indicates no clinical evidence of disease.

    • Grade I indicates rash on less than 50% of skin and has no gut or liver involvement.

    • Grade II indicates rash covering more than 50% of skin, bilirubin level of 2-3 mg/dL, diarrhea of 10-15 mL/kg/d, or persistent nausea.

    • Grade III or IV indicates generalized erythroderma with bullous formation, bilirubin level of more than 3 mg/dL, or diarrhea of more than 16 mL/kg/d.

      • Use the "Rule of Nines" or burn chart to determine the range of skin involvement. Downgrade one stage if an additional cause of elevated bilirubin level has been documented.

      • Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body surface area. Gut staging criteria for pediatric patients were not discussed at the consensus conference. Downgrade one stage if an additional cause of diarrhea has been documented.

      • Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.

      • Criteria for grading are given as the minimum degree of organ involvement required to confer that grade.

      • Grade IV may also include lesser organ involvement but with extreme decrease in performance status.

 

Treatment

Medical Care

Prevention and treatment of acute graft versus host disease

Successful therapeutic intervention of life-threatening graft versus host disease (GVHD) is possible, although the consequence can be the development of fatal opportunistic infections. Therefore, the best approach to manage GVHD should be its prevention. Effective prevention against GVHD includes the use of histocompatible donor and recipient combinations.[19, 20, 21]

Primary prophylaxis

Interference of T-cell activation/function using immunosuppressive therapy. The calcineurin inhibitors (cyclosporine and tacrolimus) are the principal drugs used to prevent GVHD. They are not found to be very effective and have additional toxicity that reduces their use. Corticosteroids can also interfere with T-cell activation and function but are uncommonly used in prophylactic regimens because they seem to increase mortality from infection. Over the last few years, great attention has been focused on the potential of regulatory T cells (Tregs) for inhibiting the division, expansion and differentiation of donor T cells specific for host antigens. However, the potential use of this approach in humans is still not established.

Removal of T cells by T–cell depletion ex vivo or T-cell depletion in vivo. The in vivo host lymphocyte depletion has the advantage of reducing the risk of graft rejection, but both techniques are associated with a reduction in graft-versus-leukemia (GVL) effects and a concomitant increase in risk of leukemia relapse.

  • T–cell depletion ex vivo: Removing T cells from the graft is very effective in preventing GVHD without affecting the graft survival, disease-free survival, and treatment-related mortality rates. The number of infused T cells should not exceed 5 × 104 cells/kg of recipient body weight. This procedure increases a risk of graft rejection.

  • T-cell depletion in vivo: Adding T-cell antibodies to the conventional conditioning regimen has the following 2 side effects: (1) it can reduce the host response, which improves engraftment, and (2) it affects mature donor T cells in the graft. This can be accomplished with such agents as alemtuzumab (Campath) or antithymocyte globulin (ATG). These long-lived agents can be directly administered to the patient, a tactic that depletes host and donor-derived T cells. Alternatively, the T cells (in the donor bone marrow) can be eliminated in vitro using monoclonal antibodies and using physical methods such as elutriation, or using immunotoxins.

Inhibition of T-cell proliferation. Drugs often used for this therapy include methotrexate and mycophenolate (MMF). Methotrexate has been the primary drug in this indication for decades, and, although effective, it is also associated with delayed engraftment, mucositis, and transplant-associated toxicity. MMF inhibits T-cell purine salvage pathways and appears to have less toxicity than methotrexate and can be used with a calcineurin inhibitor.[22]

Interference of cytokine function (although this approach is relatively new and still experimental). Moreover, agents such as corticosteroids definitely reduce inflammatory cytokine levels, but, as noted above, for the most part they have not been helpful in GVHD prophylaxis.

Removal of host antigen-presenting cells (APCs) using extracorporeal photopheresis (ECP).[23] ECP is pheresis of approximately 5 × 109 leukocytes that are treated with a photoactive compound 8-methoxypsoralen and ultraviolet A light and re-infused to the patients. This therapy induces lymphocytes undergoing apoptosis. Those apoptotic cells are taken up by host APCs, thereby triggering certain tolerance mechanisms, which results in lower incidence of GVHD.

Increase in host immune activity using reduced-intensity conditioning regimens. This was defined as a conditioning regimen in which the dosage of chemotherapy and/or total body irradiation (TBI) was reduced to 50%. These changes may result in less toxicity and less severe GVHD due to the persistence of host T cells.

Housing the patient in a pathogen-poor protected environment can be very helpful to reduce the risk of infections.

Treatment

Many different therapies have been used in the treatment of acute GVHD. Unfortunately, control of GVHD does not translate into improved survival in many patients because of the subsequent development of opportunistic infections.

First-line treatment

Steroids in conjunction with cyclosporine or tacrolimus are considered standard therapy. Treatment is required for established grades II-IV GVHD and often consists of continuation of original immunosuppressive agents used for GVHD prophylaxis and the addition of methylprednisolone at 2 mg/kg/d in divided doses for 10-14 days or until GVHD is controlled, followed by steroid taper. Patients who have not received cyclosporine or tacrolimus as part of their GVHD prophylaxis may benefit by combining it with corticosteroids. Combination triple therapy with cyclosporine, prednisone, and antithymocyte globulin has been found to be equally efficacious but more toxic in children. Successful treatment of GVHD with this initial intervention is only seen in about 25-40% of patients after donor transplantation; thus, 60-75% of patients with clinically significant GVHD require therapy in addition to corticosteroids.

Steroid-refractory GVHD

For steroid-refractory GVHD, rituximab along with other sporadically tried drugs have been studied. ATG has activity in steroid refractory GVHD, especially in the skin. Overall responses are seen in 20-60% of patients, but overall survival has not improved, and 1-year mortality rates approach 90%. 

A 2011 study noted that in patients with chronic GVHD refractory to glucocorticoid therapy, daily low-dose subcutaneous interleukin-2 was found to increase regulatory T cells in vivo, suppress clinical manifestations, and permit glucocorticoid tapering by a mean of 60%.[24, 25]

In May 2019, ruxolitinib was FDA-approved for the treatment of steroid-refractory acute GvHD in patients aged 12 years or older. Approval was based on data from REACH1, an open-label, multicenter trial, which studied ruxolitinib in combination with corticosteroids in patients with steroid-refractory acute GVHD. Patients with steroid refractory acute GVHD treated with ruxolitinib had an overall response rate was 59% and a complete response of 31%.[26]

Cytokine blockade

This has been attempted with blocking actions of IL-1 by preventing it binding to IL-1 receptor either by soluble IL-1 receptor or by IL-1 receptor antagonist, anakinra [Kineret]. This approach has not been extensively pursued. The anti-TNF alpha antibody infliximab (Remicade) has been effective in steroid-resistant GVHD but with increased subsequent infection. To date, it has shown benefit over steroids alone.

Cytotoxic therapy

MMF and the inosine monophosphate dehydrogenase (IMPDH) inhibitor, pentostatin, are cytotoxic reagents tried on acute GVHD. The latter drug appears to be highly active in acute GVHD in a single institution experience. The response rate was approximately 65%, but long-term survival was only 26%. Several small studies of MMF have shown therapeutic efficacy in the range of 40-70%, with survival rates ranging from 16-37%. As with other reagents, opportunistic infections mandate careful dosing.

Newer therapies

A murine monoclonal antibody against CD147, which is a neurothelion member of the immunoglobulin superfamily and up-regulated on activated B cells and T cells, induced 50% response in steroid-resistant acute GVHD. Moderate-to-severe myalgia occurred in 28-60% of cases and was dose limiting. Visilizumab is a humanized anti-CD3 antibody that selectively induces apoptosis of activated T-cells. A phase I study demonstrated that all patients affected by severe acute GVHD and treated with visilizumab improved. However, posttransplant lymphoproliferative disease (PTLD) was a major concern. Also, extracorporeal photopheresis has been used to treat resistant, acute GVHD; the patients who responded had a significantly better outcome.

Prevention and treatment of chronic graft versus host disease

The best prophylaxis against chronic GVHD is prevention of acute GVHD because de novo chronic GVHD is less common compared with incidence in patients with acute GVHD. Limited chronic GVHD may spontaneously resolve without specific therapy. Treatment of extensive chronic GVHD involves oral prednisone, which may be used simultaneously or on an alternate day schedule with cyclosporine or tacrolimus. Azathioprine may be used as a corticosteroid-sparing agent.

Numerous therapies, including psoralen plus ultraviolet radiation, thalidomide, and clofazimine, have been tried. MMF is an immunosuppressive agent used for prophylaxis for acute GVHD. In the treatment of steroid-refractory chronic GVHD, responses of 90% and 75% in first-line and second-line settings have been reported when MMF is added to standard tacrolimus, cyclosporine, and/or prednisone treatments.[27]

Supportive therapy and symptomatic management is equally important, including ursodeoxycholic acid for cholestasis, artificial tears and saliva for sicca syndrome, physiotherapy to prevent contractures, and immunoglobulin replacement and infection prophylaxis against opportunistic infections.

Surgical Care

Surgical care is restricted to insertion of a central line to aid in parental nutrition and intravenous treatments.

Diet

During acute GVHD, persistent diarrhea requires total parenteral nutrition until symptoms have subsided.

Activity

Activity is restricted depending on the patient's conditions, and isolation for infection control may be necessary.

 

Medication

Immunosuppressive agents

Class Summary

Methotrexate is a folate antagonist and a potent inhibitor of the cell-mediated immune system. Selective inhibitors of T-cell lymphocytes (eg, cyclosporine) suppress early cellular response to antigenic and regulatory stimuli.

Traditionally, high-dose steroids were thought to be lympholytic, but recent studies have suggested that steroids may inhibit T-cell proliferation and T-cell dependent gene expression of cytokines. They produce nonspecific anti-inflammatory effects and anti-adhesion effects that contribute to immune suppression.

Methotrexate (Trexall)

Prevents T-cell proliferation. Acts on purine and pyrimidine synthesis and has been employed as an immunosuppressive agent.

Cyclosporine (Sandimmune, Neoral)

Inhibits calcineurin activity. A serine-threonine phosphatase whose activity is essential for T-cell cytokine transcription.

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

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Tacrolimus (Prograf)

Previously known as FK506. Macrolide immunosuppressant produced by Streptomyces tsukubaensis. Reported to prolong survival of the host and transplanted graft in some animal transplant models.

Sirolimus (Rapamune)

Inhibits lymphocyte proliferation by interfering with signal transduction pathways. Binds to immunophilin FKBP to block action of mTOR.

Alemtuzumab (Campath)

Monoclonal antibody against CD52, an antigen found on B-cells, T-cells, and almost all CLL cells. Binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes.

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 has been demonstrated in experimental animal models.

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-cell infiltration in the colon. Indicated for treatment of steroid-refractory acute GvHD in adult and pediatric patients aged 12 years or older.

Antithymocyte globulin, rabbit (Thymoglobulin)

Purified concentrated gamma-globulin (primarily monomeric IgG) from hyperimmune horses immunized with human thymic lymphocytes. Mechanism of action is thought to be its effect on lymphocytes responsible in part for cell-mediated immunity and lymphocytes involved in cell immunity.

Immunosuppressive action generally is similar to other antilymphocyte preparations. However, they may differ qualitatively and/or quantitatively in extent to which they produce specific effects, in part because of factors such as source of antigenic material used, type of animal used to produce antiserum, and method of production.

A hematologist or another physician with extensive experience must be involved in the administration and monitoring of antilymphocyte serum because of the many complications and adverse effects of this therapy. Dose and duration of therapy vary with different investigational protocols.

 

Follow-up

Further Outpatient Care

Regular follow-up with monitoring of immunosuppressive therapy is needed, as well as vigilance for developing chronic GVHD.

Further Inpatient Care

Further inpatient care of graft versus host disease (GVHD) depends on initial response.

Maintenance immunosuppression with close monitoring is required.

Opportunistic infections may become severe and require intravenous (IV) antibiotics and supportive care.

Deterrence/Prevention

Effective prevention against GVHD includes the following:

  • Use of histocompatible donor and recipients

  • Use of immunosuppressive agents after bone marrow infusion (Most bone marrow transplant [BMT] teams currently use cyclosporine plus a brief course of methotrexate as the standard GVHD prophylaxis regimen. Adding steroids has been proven beneficial in some trials. Other drugs used alone or in combination include tacrolimus, antithymocyte globulin [ATG], and sirolimus.)

  • In vitro manipulation of the donor graft, such as marrow T-cell depletion

  • Possibly housing the patient in a pathogen-poor protected environment

The best prophylaxis against chronic GVHD is prevention of acute GVHD because de novo chronic GVHD is less common compared with incidence in patients with acute GVHD.

Prognosis

Severe acute GVHD is the important cause of treatment failure after BMT. Survival rates vary from 90% in stage I, 60% in stage II or III, to almost 0% in stage IV. Death is often caused by infections, hemorrhage, and hepatic failure.

Severe chronic GVHD is associated with a higher mortality rate, mostly because of infection complications. Survivors are often severely disabled. The survival rate after onset of chronic GVHD is approximately 42%. Factors that predict death are progressive presentation (ie, acute GVHD followed by chronic GVHD), lichenoid skin changes on biopsy, and elevated serum bilirubin. A patient with one or more of these factors has a projected 6-year survival rate of 60%.

Mild chronic GVHD as with mild acute GVHD is associated with improved outcome in patients with leukemia because of graft-versus-leukemia (GVL) effect.