Graft versus-host disease

Graft-versus-host disease

Apollo Medicine 2012 MarchReview Article

Volume 9, Number 1; pp. 38–40

© 2012, Indraprastha Medical Corporation Ltd

Graft-versus-host disease

SVSS Prasad**Senior Consultant, Department of Medical Oncology, Apollo Cancer Institute, Apollo Health City, Jubili Hills, Hyderabad, India.

ABSTRACT

Graft-versus-host disease (GVHD) is a complication seen in allogeneic stem cell transplantation. The incidence and severity is more in T-cell replete allograft (stem cells), donor T-cells being the principal mediators of GVHD. Acute GVHD is seen within 90 days post transplant and chronic GVHD after 90 days. Cyclosporin A (CsA) and methotrexate combination is used in prevention of acute GVHD. Corticosteroids and CsA combination is used in treatment of both acute and chronic GVHD.

Key words: Allogeneic stem-cell transplantation, GVHD, T-cells

Correspondence: Dr. SVSS Prasad, E-mail: [email protected]: 10.1016/S0976-0016(12)60118-5

Graft-versus-host disease (GVHD) is a complication occur-ring in the stem-cell or bone marrow transplantation. Allogeneic hematopoietic stem-cell transplantation (HSCT) is a therapeutic modality for curing certain diseases or can-cers which are resistant to standard treatments. This modal-ity uses the delivery of high enough doses of cytotoxic agents (high-dose chemotherapy [HDCT]) which results in permanent eradication of recipient bone marrow. The donor hematopoietic progenitor (stem) cells (graft) are infused to rescue the patient (host) from the ensuing bone marrow aplasia. Apart from this dose-intensive tumor killing, a pow-erful immune reaction generated from transplanted donor T-cells against residual leukemia called graft-versus-leukemia (GVL) effect helps in achieving durable disease-free sur-vival.1 This GVL is part of GVHD that occurs in HSCT. The GVHD is the consequence of immunocompetent donor T-cells targeting recipient tissues that possess antigens absent from the donor. As GVHD sets in a disease process, sometimes with disastrous consequences, it is an unwanted complication of allogeneic HSCT. Graft-versus-host disease, therefore, needs prevention and treatment once manifest.

PATHOPHYSIOLOGY

Donor T-cells are the principal mediators of GVHD. The antigens in the recipient that are different from that in the

donor stem cells are the targets for the GVHD. In the human leukocyte antigens (HLA)-identical transplant setting, these are known as minor histocompatibility antigens. The disparity in these antigens is more in matched unrelated donor (MUD) transplants and hence incidence of GVHD is 60–80% here compared with 30–40% among related donors and recipients.

The development of GVHD is a multistep process in which recipient tissues are recognized as foreign by the donor immune system; antigen-presenting cells present recipient alloantigens to donor T-cells, resulting in the acti-vation and expansion of GVHD effector populations, ulti-mately leading to T-cell-mediated cytotoxic damage of target tissues.2,3

The incidence and severity of GVHD is more in T-cell-replete allograft compared with T-cell-depleted allo-graft. It also increases with age and also depends on the intensity of conditioning regimen, being more in nonmyelo-ablative regimens.

TYPES OF GRAFT-VERSUS-HOST DISEASE

Graft-versus-host disease is either acute (AGVHD) or chronic (CGVHD). Acute GVHD is seen within the first 90 days post transplant. Chronic GVHD usually occurs between 90 days and 2 years after transplant and lasts for months to years, sometimes lifelong. Risk factors for CGVHD include

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Graft-versus-host disease Review Article 39


prior AGVHD, older patient age, use of mismatched or unre-lated donors, history of donor lymphocyte infusions (DLI) for relapsed malignancy, and use of peripheral blood stem cells (PBSC) compared with bone marrow stem cells.

SYMPTOMS

Common AGVHD symptoms are as follows:• Fever• Vomiting• Abdominal pain or cramps• Diarrhea• Jaundice• Skin rash• Weight lossChronic GVHD symptoms are as follows:• Hair loss• Dry eyes• Dry mouth, lichenoid buccal changes• Dry vagina• Hepatitis• Gastrointestinal tract disorders—diarrhea, malabsorption• Lung disorders—bronchiolitis obliterans• Skin rash and skin thickening, friable nails• Pancytopenia.

Patient is susceptible to infections in both acute and chronic GVHD.

DIAGNOSIS

The GVHD is diagnosed based on the clinical symptoms and on laboratory tests, namely• Gastrointestinal endoscopy and biopsy• Liver function tests (enzymes and bilirubin levels are

elevated)• Liver biopsy (in patients with only liver symptoms)• Chest radiographs• Skin biopsy

PREVENTION AND TREATMENT

Acute GVHD is prevented using prophylactic immunosup-pressive agents and use of allografts in which donor T-cells are partially or completely depleted.

Combined use of cyclosporin A (CsA) and methotrexate is the best immunosuppressive combination. Prednisolone addition to this combination is of no additional benefit. Also, longer use of CsA (>6 months) is of no benefit.

T-cell depletion using CD34 selection (in vitro) or drugs (in vivo) is the most effective method for preventing GVHD, but increases the risk of graft rejection, opportunis-tic viral infection, and leukemic relapse. T-cell-depleted HSCT followed by DLI decreases GVHD and also do not increase leukemic relapse.4,5

Treatment of AGVHD is done with corticosteroids in combination with CsA or tacrolimus. Patients (40–60%) respond to these and such a response indicates a good prog-nosis. Nonresponders have a poor prognosis and 60–80% of them die of GVHD-related causes. There is no first line standard therapy for such nonresponders. Antithymocyte globulin (ATG), extracorporeal photophoresis, monoclonal antibodies like daclizumab and infliximab are being tried. Bone marrow-derived mesenchymal stem cells (MSC) usage is showing good results in refractory liver and gas-trointestinal GVHD.

Chronic GVHD reduces the risk of relapse. Therefore, it offsets the deleterious effects of the complication on sur-vival. These patients are severely immunocompromised due to the immunosuppressive therapy used and from the under-lying immune deregulation associated with the disease process. Chronic GVHD is lethal in 20% of cases and death is usually due to infection. Hepatic involvement and throm-bocytopenia carry a poor prognosis. Chronic GVHD is classified as either limited or extensive; limited, when localized skin involvement with mild hepatic involvement is seen and extensive, when generalized skin involvement with or without other target organ involvement is seen. Treatment depends on the extent of the disease. In systemic disease, alternate day CsA or tacrolimus with low-dose steroids is used and 70–80% patients respond allowing for eventual discontinuation of the therapy. Patients not responding to the standard therapy are subjected to:• Micophenolate mofetil• Psoralen• Ultraviolet A light (for skin involvement)• Thalidomide (oral)• Imatinib• Extracorporeal photophoresis.

Monoclonal antibodies targeting tumor necrosis factor and activation antigens on T-cells:• Rituximab targeting CD20 on B-cells• Prophylaxis for organisms such as pneumocystis and

encapsulated bacteria is necessary during this prolonged systemic immunosuppressive therapy.6


40 Apollo Medicine 2012 March; Vol. 9, No. 1 Prasad


Graft-versus-host disease is therefore a complication which is frequent in allogeneic stem cell transplantation, has a positive effect in the form of reducing disease relapse, but needs active management to prevent the risk to life of the recipient (patient).

REFERENCES

1. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-

leukemia reactions after bone marrow transplantation. Blood

1990;75:555.

2. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention

of graft versus host disease by inactivation of host antigen-

presenting cells. Science 1999;285:412.

3. Matte-Martone C, Wang X, Anderson B, et al. Recipient B cells are not required for GVHD induction. Biol Blood Marrow Transplant 2010;16:1222–30.

4. Soiffer RJ, Alyea EP, Hochberg E, et al. Randomized trial of CD8+ T-cell depletion in the prevention of graft-versus-host disease associated with donor lymphocyte infusion. Biol Blood Marrow Transplant 2002;8:625.

5. Elmaagacli AH, Peceny R, Steckel N, et al. Outcome of trans-plantation of highly purified peripheral blood CD34+ cells with T-cell add-back compared with unmanipulated bone marrow or peripheral blood stem cells from HLA-identical sibling donors in patients with first chronic phase chronic myeloid leukemia. Blood 2003;101:446.

6. DeVita, Hellman. Allogeneic stem cell transplantation. In: Rosenberg’s CANCER Principles & Practice of Oncology 9th edn. Philadelphia: Lippincott Williams & Wilkins publishers 2011:2249–50.


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Graft versus-host disease

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