Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is a potentially serious complication of allogeneic stem cell transplantation and reduced-intensity allogeneic stem cell transplantation. In this treatment, a patient’s own damaged or diseased blood-forming stem cells are destroyed. Then they are replaced with healthy stem cells from a donor.

GVHD occurs when the donor stem cells (“the graft”) attack healthy cells in the patient (“the host”), causing the condition “graft-versus-host disease” or GVHD.There are two main categories of GVHD:

Each type affects different organs and tissues and has different signs and symptoms. Patients may develop one type, both types, or neither type.

Importance of Human Leukocyte Antigen (HLA) Typing

Before an allogenic stem cell transplant, the patient and the potential donor are tested to see if the donor’s stem cells are a good match for the patient. Human leukocyte antigen (HLA) typing, also called “tissue typing,” is a test done to identify proteins called HLAs found on the surface of most cells in the body. There are many HLA markers, and different people have different patterns of markers. Except for identical twins, everyone has different HLA markers. 

HLA markers play an important role in the body’s immune response to foreign substances such as bacteria and viruses. They tell white blood cells in the immune system which cells belong in the body and which ones do not.

These white blood cells know which pattern of HLA markers is normal for a person’s body. If they find cells with a different pattern of markers, they will attack and kill those cells. That is why it is important for the donor’s stem cells to have HLA markers that are as similar to the patient’s as possible—to prevent the donor’s cells from attacking the patient’s cells, leading to GVHD.

Acute GVHD

Acute GVHD usually develops within the first 100 days after transplantation, but it can occur later. It can affect the skin, the liver and the gastrointestinal (GI) tract (stomach, intestines and colon). Somewhere between 30 to 70 percent of transplant recipients develop acute GVHD. 

Risk Factors

The following risk factors are usually associated with an increased change of moderate to severe acute GVHD:

  • HLA mismatch—receiving stem cells from a related donor who is not a perfect HLA match
  • Unrelated donor—receiving stem cells from an unrelated donor even if the donor is a perfect HLA match
  • Older age of the donor or recipient
  • Female donor for male recipient y Intensity of the transplant conditioning regimen
  • Receiving total body irradiation as part of the conditioning regimen

Symptoms of Acute GVHD

Signs and symptoms of acute GVHD most often affect the skin, gastrointestinal (GI) tract or liver. Some may be mild, and some can be severe and even life-threatening.

Patients must be aware of the symptoms of acute GVHD. Call your transplant team immediately if you have any of these symptoms. Early detection and treatment may help limit the severity of GVHD.

Skin
  • Rash is the most common symptom of GVHD of the skin.
  • Rash often starts as a faint redness that may appear anywhere, including the palms of the hands and the soles of the feet.
  • Rash may spread to cover the entire body.
  • Mild rash may be slightly sore or itchy and look like a minor sunburn.
  • More severe rash may include blistering or peeling skin.
Gastrointestinal (GI) Tract
  • The most classic symptom of GVHD of the GI tract is diarrhea, caused by inflammation of the colon. Diarrhea can be as severe as several liters of stool each day.
  • Other symptoms include:
    • Blood in the stool
    • Nausea
    • Loss of appetite
    • Vomiting
Liver
  • Acute GVHD of the liver most commonly has no symptoms. It can only be identified by blood tests that show higher than normal liver enzymes, indicating damage to the liver.
  • Acute liver GVHD can appear as jaundice (yellowing of the skin or eyes) from liver damage and inability to excrete a substance called bilirubin (bilirubin is produced when the liver breaks down old red blood cells).
  • Some patients develop liver failure, with symptoms of bleeding, confusion or ascites (excess fluid in the abdomen).

Low blood counts are not necessarily classic signs of acute GVHD, but it is extremely common for patients with GVHD to develop low blood counts. This is the body’s response to the immune system’s attack on organs.

Diagnosis and Staging 

Patients with signs and symptoms of acute GVHD may need to have tests to confirm the diagnosis and rule out other conditions that may mimic acute GVHD, such as drug reactions and infections.

Acute GVHD may be mild, moderate or severe. Doctors classify the severity of acute GVHD according to the number of organs involved and the degree to which they are affected.

Each organ is staged individually, with each stage ranging between 1 (mildest) to 4 (most severe). The skin is given a stage based on the amount of body surface area involved. The gastrointestinal (GI) tract is staged based on the amount of diarrhea or bowel movements a patient has per day. The liver is given a stage based on the rise in bilirubin level in the blood. Bilirubin is a yellowish substance found in bile, a fluid made by the liver. If the liver is not working as well as it should, there may be too much bilirubin in the blood. This can cause jaundice, a condition that causes the skin and eyes to turn yellow.

Once each organ is given a stage, the doctor is able to group these organs into an overall grade. Acute GVHD is also graded from 1 (mildest) to 4 (most severe). Patients with grade 3/4 acute GVHD tend to have poorer outcomes and decreased survival.

Chronic GVHD

Chronic GVHD may occur at any time after transplantation, but it typically develops at least 100 days after the day of transplant. Chronic GVHD may involve a single organ or possibly many organs. It affects approximately 40 to 50 percent of patients receiving an allogeneic stem cell transplantation. Since GVHD is a chronic condition, it can last for years or even a lifetime. Symptoms range from mild to life-threatening.

Risk Factors 

The following risk factors are associated with higher rates of chronic GVHD:

  • HLA mismatch or unrelated donor
  • Older patient age y Older donor age
  • Female donor for male recipient (the risk increases if the female donor has ever been pregnant)
  • Stem cell source
    • Stem cells retrieved from peripheral blood have a higher risk of causing chronic GVHD than stem cells retrieved from bone marrow
    • Stem cells retrieved from cord blood have the lowest risk of causing chronic GVHD
  • Prior acute GVHD

Symptoms of Chronic GVHD

Eyes
  • Dry, painful, itchy eyes
  • Difficulty tolerating bright lights
  • Blurred vision
  • Blindness
Mouth
  • Very dry mouth
  • Sensitivity to hot, cold, spicy and acidic foods, mint (often in toothpaste), and carbonated drinks
  • Painful mouth sores that may extend down the throat
  • Difficulty eating
  • Gum disease and tooth decay
  • Trouble swallowing
Skin
  • Rash
  • Dry, tight, itchy skin
  • Thickening of the skin which may result in restriction of joint movement
  • Change in skin color
  • Intolerance to temperature changes caused by damaged sweat glands
  • Ulcers (sores) that do not heal
Nails
  • Changes in nail texture
  • Hard, brittle nails
  • Nail loss
Scalp and Body Hair
  • Loss of hair on the head
  • Premature gray hair
  • Loss of body hair
Gastrointestinal (GI) Tract
  • Loss of appetite
  • Unexplained weight loss
  • Feeling like food is stuck after swallowing
  • Nausea
  • Vomiting
  • Diarrhea
  • Stomach pain
Lungs
  • Shortness of breath and difficulty breathing
  • Persistent cough that does not go away
  • Wheezing
Liver
  • Abdominal swelling
  • Jaundice (yellow discoloration of the skin and/or eyes)
Muscles and Joints
  • Muscle weakness and cramps
  • Joint stiffness or difficulty fully extending fingers, wrists, elbows, knees and ankles
Genitals and Sex Organs 
  • Vaginal dryness, itching and pain
  • Vaginal ulcerations and scarring
  • Narrowing of the vagina
  • Difficult or painful intercourse
  • Itching or scarring on the penis and scrotum
  • Irritation of the penis
  • Narrowing or scarring of the urethra

In rare cases, symptoms of chronic GVHD may also affect the kidneys or nervous system, or cause fluid around the heart or lungs.

Since chronic GVHD can also occur months to years after transplant, you may no longer have weekly appointments with your transplant team. It is important to examine your body, in particular your mouth, eyes, skin, genitals and joints, for symptoms of chronic GVHD. If you have any symptoms, contact your doctor immediately. Although a symptom may be caused by something other than chronic GVHD, a doctor needs to evaluate it. Early detection and treatment may help limit the severity of the disease.

Preventing GVHD

Doctors try to take every precaution to prevent GVHD before and after the transplant. Strategies to prevent GVHD disease include the following: 

Finding the Best Donor Match 

GVHD can develop when the donor and the recipient have different tissue types. The patient’s transplant team will try to find a donor who closely matches the patient. A close match between a patient’s and donor’s HLA markers is essential to reduce the risk of GVHD. There are many HLA markers. HLA matching, however, is usually based on either eight or ten HLA markers. The more markers the donor and patient share, the greater the chance that the new immune system established by the donor cells will not attack the patient’s healthy cells.

Medication 

Doctors try to prevent GVHD by treating patients with immunosuppressive drugs to suppress donor T-cell function. The drugs are given before and after the stem cell infusion. There is no standard regimen for preventing GVHD, and different combinations of medications are given at different institutions.

Some of the medications used to prevent GVHD may also be used to treat it. These include:

  • Chemotherapy drugs that eliminate certain donor T cells:
    • Cyclophosphamide (Cytoxan®)–IV infusion
    • Methotrexate (Trexall®)–IV infusion, oral administration
  • Calcineurin inhibitors that suppress enzymes that activate the immune system:
    • Cyclosporine (Neoral®)–IV infusion, oral administration
    • Tacrolimus (Prograf®)–IV infusion, oral administration
  • Immunosuppressants that lower the body’s immune response:
    • Mycophenolate mofetil (CellCept®)–IV infusion, oral administration
    • Sirolimus (Rapamune®)–oral administration
    • Corticosteroids that weaken the body’s immune response and reduce inflammation: Methylprednisolone or prednisone–IV infusion or oral administration
  • Biologics that stop or slow inflammation:
    • Abatacept (Orencia®)–IV infusion
    • Antithymocyte globulin (ATG)–IV infusion
    • Alemtuzumab (Campath®)–IV infusion
    • Tocilizumab (Actemra®)–IV infusion

For information about the drugs listed on this page, visit Drug Listings.

T-Cell Depletion

Often transplanted stem cells from a donor also contains T cells (a type of white blood cell) from the donor. T cells can increase a patient’s risk of developing GVHD. To prevent GVHD in some patients, the transplant team will remove some of the T cells from the donor stem cells before they are infused into the patient. This procedure is called a “T-cell depleted allogeneic stem cell transplant.” Eliminating T cells from the donor cells may reduce the risk of GVHD. There are two methods:

  • In vivo (within the body) T-cell depletion consists of giving medications like ATG or alemtuzumab to the recipient just before or just after transplant. In vivo T-cell depletion is typically added to another immune suppressant regimen to reduce the risk of GVHD.
  • Ex vivo (outside the body) T-cell depletion uses a machine to remove T cells from the stem cells before the stem cells are given to the patient. This procedure removes more of the T cells than the in vivo method.

Treating GVHD

The goals of treatment for GVHD are to manage symptoms and to prevent further damage to the body’s organs. Immunosuppression (suppression of the body’s immune system and its ability to fight infections and other diseases) with corticosteroids forms the basis of therapy in both acute and chronic GVHD. Other medications that lower the immune response are also used. Treatment may be either outpatient or inpatient. Treatment decisions are determined by the severity of the patient's symptoms and concerns about complications. 

Treatment for Acute GVHD

Patients who develop stage 1 mild skin-only acute GVHD are usually treated with non-systemic therapy including topical steroid creams.

Patients with more severe symptoms typically require systemic or “whole-system” treatment, which travels in the bloodstream and reaches cells throughout the entire body. Treatment for patients with grade 2-4 acute GVHD usually consists of continuing the original immunosuppressive prevention and adding a corticosteroid such as methylprednisolone or prednisone taken orally (by mouth). For patients who respond to the corticosteroids, the dose is gradually tapered over time. Patients not responding to the corticosteroids, are considered “steroid refractory,” and second-line treatments are needed.

Treatment for Chronic GVHD

Patients with mild symptoms limited to a single organ or site can often be managed with close observation or with local therapies. For example, patients with mild chronic GVHD of the skin may be treated with topical steroid ointments, and others with chronic GVHD of the eye (ocular GVHD) may be treated with steroid eye drops.

Patients with more severe symptoms or multi-organ involvement typically require systemic or “whole-system” treatment, which travels in the bloodstream and reaches cells throughout the entire body. Prednisone is the standard first-line systemic therapy for chronic GVHD. For patients who do not respond to steroid treatment, second-line treatments are available.

It is important for patients to continue taking their medication, even if they start to feel better. Stopping medication too soon may cause chronic GVHD to flare up or worsen, which may result in permanent damage. Once chronic GVHD begins to stabilize and improve, doctors may consider tapering the medications over time, and eventually the drugs may be discontinued.

Options for Steroid-Refractory GVHD

Patients whose acute or chronic GVHD does not improve with corticosteroids are considered to have “steroid-refractory” GVHD. Doctors will try second-line therapies. Patients with steroid-refractory GVHD are encouraged to participate in clinical trials, which may offer access to new drugs or better administration of current drugs.

Systemic Therapy

Systemic therapy is treatment that affects the whole body. It is usually given orally (by mouth) or infused through an IV to reach cells throughout the body. 

The FDA has currently approved three drugs for the treatment of steroid-refractory GVHD.

  • Ruxolitinib (Jakafi®)
  • Ibrutinib (Imbruvica®)
  • Belumosudil (Rezurock®)

Drugs that are not FDA-approved to treat GVHD can be used as “off-label” treatments. “Off-label” prescribing is when a doctor gives a drug that is FDA-approved to treat one condition for another condition, if the doctor feels it will benefit the patient. This is a common practice.

See the Graft-Versus-Host Disease fact sheet for a list of drugs recommended by the National Comprehensive Cancer Network (NCCN) for the treatment of steroid-refractory GVHD.

Extracorporeal photopheresis

Extracorporeal photopheresis (ECP) treatment uses light to treat acute and chronic GVHD that has not improved after steroid treatment. This procedure requires central venous access through a special port and biweekly visits when starting. In this procedure, blood is removed from the patient’s body and enters a machine that separates the lymphocytes from the blood. The blood is returned to the patient without the lymphocytes. The lymphocytes are exposed to a photosensitizing agent, 8-methoxypsoralen, and then treated with ultraviolet light. The treatment of lymphocytes alters their function, and the altered lymphocytes are returned to the body. Researchers do not know exactly how extracorporeal photopheresis works. One theory suggests that it decreases swelling and inflammation in the body.

Supportive Treatments for GVHD

Common supportive therapies include:

  • TPN (total parenteral nutrition), also called intravenous feeding, for acute GVHD of the bowel, to prevent malnutrition and keep patients from getting weaker
  • Antimicrobials (medicines against bacteria, viruses and fungi) to prevent additional risks of infection from the added immunosuppressants used to prevent and treat GVHD
  • Bone-strengthening agents to prevent bone loss from steroids Taking these medications as prescribed may be as important for patient health as the medicines for GVHD.

 

For more information, download or order the free fact sheet, Graft-Versus-Host Disease.

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