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Review 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: drprasad.svss@gmail.com
doi: 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 toT-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
3. Graft-versus-host disease Review Article 39
© 2012, Indraprastha Medical Corporation Ltd
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 loss
Chronic 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 ANDTREATMENT
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
4. 40 Apollo Medicine 2012 March; Vol. 9, No. 1 Prasad
© 2012, Indraprastha Medical Corporation Ltd
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.