Graft Versus Host Disease (GVHD): What You Need To Know About Having A Bone Marrow Transplant
If you have ever had a Bone Marrow Transplant or Allogeneic Stem Cell Transplant (any transfer of stem cells from a healthy person (the donor) to your body after high-intensity chemotherapy or radiation), you will always need to be followed yearly to be sure you do not develope Graft Versus Host Disease (GVHD).
Things you need to know about GVHD.
1. Definition: GVHD develops when the donor’s immune cells mistakenly attack the patient’s normal cells. GVHD can be mild, moderate or severe — even life threatening. Its symptoms can include:
- Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body
- Blistering, causing the exposed skin surface to flake off in severe cases
- Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected
- Jaundice, or a yellowing of the skin, which can indicate that your liver is damaged
- Excessive dryness of the mouth and throat, leading to ulcers
- Dryness of the eyes lungs, vagina and other surfaces
2. The older the person, the higher the risk for GVHD.
3. Dry Eyes can be one of the first symptoms of GVHD. If you feel your eyes, see your EyeMD and tell them you have a history of a transplant.
4. GVHD can be acute or chronic. Its severity depends on the differences in tissue type between patient and donor. The older the patient, the more frequent and serious the reaction may be.
Here is more information:
Monitor Yourself for Symptoms of GVHD
Like many conditions, chronic GVHD is easier to treat if detected early. Contact your doctor if you develop any of the following symptoms:
- Skin: rash, discoloration, tightness or changes in texture
- Hair: thinning
- Nails: changes in texture, brittleness or ridges
- Eyes: irritation, dryness, blurred vision, a gritty feeling
- Mouth: dryness, sensitivity to foods or toothpaste
- Vagina: dryness, irritation, tightening
- Penis: irritation
- Digestive System: nausea, vomiting, diarrhea, loss of appetite, unexplained weight loss
- Lungs: chronic cough, wheezing, shortness of breath
- Joints: difficulty fully extending fingers, wrists, elbows, knees or ankles
- Low grade fever
These symptoms may also be caused by something other than chronic GVHD, but you should report them to your doctor immediately so that you can be evaluated.
One to two days before your stem cell infusion, you’ll take a regimen of drugs to help prevent GVHD. It may include:
- Cyclosporine and methotrexate
- Tacrolimus (Prograf®) and methotrexate
- Tacrolimus and mycophenolate mofetil (CellCept®)
- Prograf and sirolimus (Rapamune®)
These regimens suppress the immune system. You may need to continue to take them for many months after transplantation.
To diagnose GVHD, your doctor will likely biopsy one of your affected organs. He or she will assess GVHD a grade from I (mildest) to IV (most severe).
Acute GVHD can occur soon after the transplanted cells begin to appear in the recipient. Acute GVHD ranges from mild, moderate or severe, and can be life-threatening if its effects are not controlled.
Chronic GVHD usually occurs at about three months post-transplant, although in some cases it may not develop for a year or more after the transplant. It’s more likely to occur in patients who previously have had acute GVHD, but it may still appear without prior acute GVHD.
Chronic GVHD can be mild (with later improvement) or more severe, persistent and incapacitating. Most patients with chronic GVHD experience skin problems that may start with a rash and itching. The skin may also become scaly. As the reaction becomes more severe, so do the symptoms, which may include one or more of the following:
- Patches of skin may be lost.
- Skin color may deepen and texture may become hard.
- The skin may heal by scarring, causing the motion of nearby joints, such as the fingers, to become restricted.
- Hair loss may accompany skin injury.
- The drying and scarring effects of the attack by the donor cells can affect the inside of the mouth and the esophagus (from the throat to the stomach), causing them to become excessively dry and damaged. This reaction can result in ulcers.
- The tendency to drying can lead to loss of tear formation and general eye redness and irritation. Dryness of the vagina and other surfaces may also occur.
- The lungs may also show effects of drying and scarring.
- Liver injury can result in liver failure and diminished bile flow.
- Bile may back up into the blood and cause jaundice.
In some cases, damage to internal organs may not immediately be obvious, but can be detected by blood chemistry measurements.
Several drugs have been developed to prevent or lessen GVHD. These drugs, in addition to early detection and advances in understanding the disease, have resulted in a significant reduction in serious or fatal outcomes from GVHD. However, GVHD doesn’t always respond to these treatments. It can still result in fatal outcomes. Many deaths related to GVHD occur because of infections that develop in patients with suppressed immune systems.
Several advances in transplantation techniques have helped to reduce the risk of developing acute GVHD:
- More precise HLA tissue matching
- Immunosuppressive drugs
- Depletion of T lymphocytes from the donor graft
- The use of umbilical cord blood as the source of donor cells
Types of Drugs Used to Treat GVHD
Glucocorticoids such as methylprednisolone or prednisone combined with cyclosporine are used to treat acute GVDH. New drugs and strategies available now or in clinical trials can supplement standard treatment. They include:
- Antithymocyte globulin (rabbit ATG; Thymoglobulin®)
- Denileukin diftitox (Ontak®)
- Monoclonal antibodies such as daclizumab (Zenapax®); infliximab (Remicade®); or, more rarely, alemtuzumab (Campath®)
- Mycophenolate mofetil (CellCept®)
- Sirolimus (Rapamune®)
- Tacrolimus (Prograf®)
- Oral nonabsorbable corticosteroids such as budesonide or beclomethasone dipropionate
- Intra—arterial corticosteroids
- Pentostatin (Nipent®)
- Extracorporeal photopheresis (a procedure under study that removes, treats and reinfuses the patient’s blood)
- Infusions of mesenchymal stem cells (experimental only)
Corticosteroids are the primary therapy used for chronic GVHD. Cyclosporine may be combined with prednisone. Clinical trials investigating GVHD that doesn’t respond to steroid treatment have reported some success for the following treatments:
- Daclizumab (Zenapax®)
- Etanercept (Enbrel®)
- Extracorporeal photopheresis
- Infliximab (Remicade®)
- Mycophenolate mofetil (CellCept®)
- Pentostatin (Nipent®)
- Rituximab (Rituxan®; experimental only)
- Tacrolimus (Prograf®)
- Thalidomide (Thalomid®)
- Imatinib mesylate (Gleevec®) for some skin changes
Patients must pay attention to nutrition and take supportive care measures for their skin, eyes, mouth, vaginal mucosa and lungs. Because both the disease and its treatments suppress the immune system, it’s important that your doctor monitors you for and treats infections. If GVHD stabilizes or improves, your doctor may taper drug dosages or eventually stop medication.
Typically, after a year or so, your body will form new T lymphocytes from the engrafted donor cells. The newly formed lymphocytes won’t attack your cells, and immunosuppressive therapy can be stopped. Your immune system can work efficiently to protect against infections, and your risk of infection begins to approach that of a healthy person. This “state of tolerance” between the donor immune cells and your cells is important for long-term transplant success.
Allogeneic stem cell transplantation involves transferring the stem cells from a healthy person (the donor) to your body after high-intensity chemotherapy or radiation.
Allogeneic stem cell transplantation is used to cure some patients who:
- Are at high risk of relapse
- Don’t respond fully to treatment
- Relapse after prior successful treatment
Allogeneic stem cell transplantation can be a high-risk procedure. The high-conditioning regimens are meant to severely or completely impair your ability to make stem cells and you will likely experience side effects during the days you receive high-dose conditioning radiation or chemotherapy. The goals of high-conditioning therapy are to:
treat the remaining cancer cells intensively, thereby making a cancer recurrence less likely
inactivate the immune system to reduce the chance of stem cell graft rejection
enable donor cells to travel to the marrow (engraftment), produce blood cells and bring about graft versus tumor effect
Possible Adverse Effects
The immune system and the blood system are closely linked and can’t be separated from each other. Because of this, allogeneic transplantation means that not only the donor’s blood system but also his or her immune system is transferred. As a result, these adverse effects are possible:
- Immune rejection of the donated stem cells by the recipient (host-versus-graft effect)
- Immune reaction by the donor cells against the recipient’s tissues (graft-versus-host disease [GVHD])
The immune reaction, or GVHD, is treated by administering drugs to the patient after the transplant that reduce the ability of the donated immune cells to attack and injure the patient’s tissues. See Graft Versus Host Disease.
Allogeneic stem cell transplants for patients who are older or have overall poor health are relatively uncommon. This is because the pre-transplant conditioning therapy is generally not well tolerated by such patients, especially those with poorly functioning internal organs. However, reduced intensity allogeneic stem cell transplants may be an appropriate treatment for some older or sicker patients.
One goal of allogeneic stem cell transplant is to cause the T lymphocytes in the donor’s blood or marrow to take hold (engraft) and grow in the patient’s marrow. Sometimes the T lymphocytes attack the cancer cells. When this happens, it’s called graft versus tumor (GVT) effect (also called graft versus cancer effect). The attack makes it less likely that the disease will return. This effect is more common in myeloid leukemias than it is in other blood cancers.
Unfortunately, T lymphocytes are the same cells that cause graft versus host disease (GVHD). Because of this serious and sometimes life-threatening side effect, doctors in certain cases want to decrease the number of T lymphocytes to be infused with the stem cells. This procedure, called T-lymphocyte depletion, is currently being studied by researchers. The technique involves treating the stem cells collected for transplant with agents that reduce the number of T lymphocytes.
The aim of T-lymphocyte depletion is to lessen GVHD’s incidence and severity. However, it can also cause increased rates of graft rejection, a decreased GVT effect and a slower immune recovery. Doctors must be careful about the number of T lymphocytes removed when using this technique.
Stem Cell Selection
Stem cell selection is another technique being studied in clinical trials that can reduce the number of T lymphocytes that a patient receives. Because of specific features on the outer coat of stem cells, doctors can selectively remove stem cells from a cell mixture. This technique produces a large number of stem cells and fewer other cells, including T lymphocytes.
Finding a Donor
If you’re considering allogeneic stem cell transplantation, you’ll need a bone marrow donor. First, you and your siblings, if any, will have your blood or a scraping from your inside cheek tested to determine tissue type. A sibling has the potential to match you most closely because you both received your genes from the same parents.
A lab technician examines the surface of the sample tissue cells to identify the proteins that give everyone his or her own unique tissue type, called human leukocyte antigens (HLAs). If the HLA on the donor cells are identical (from identical twins, for example) or similar (such as those from siblings), the transplant is more likely to be successful. On average, you have a one in four chance of having the same HLA type as a sibling. Many patients, therefore, don’t have a sibling with the same tissue type.
If a brother or sister doesn’t provide a match, your doctor will search registries of volunteer donors such as the National Marrow Donor Program for an unrelated donor that matches your tissue type. A donor who’s not related to you but who has a similar tissue type is called a matched unrelated donor (MUD).
Collecting Stem Cells
Stem cells for transplantation are collected from three sources:
- Bone marrow
- Placental and umbilical cord blood
Before stem cells are collected from blood or bone marrow, the donor must undergo a thorough physical exam and blood testing for hepatitis viruses, human immunodeficiency disease (HIV) and other infectious agents or viruses.
The most common source of stem cells for transplant is peripheral blood, the blood that flows throughout our veins and arteries.
Bone marrow normally releases a small number of peripheral blood stem cells (PBSCs) into the bloodstream. To obtain enough PBSCs for a transplant, the donor takes a white cell growth factor, such as granulocyte–colony stimulating factor (G-CSF) drug, which increases the number of stem cells by drawing them out of the marrow and into the bloodstream. When a patient’s own stem cells are used, both G-CSF and the chemotherapy used to treat the disease usually increase PBSCs. In patients who have myeloma and non-Hodgkin lymphoma, the drug plerixafor (Mozobil®) can be used to mobilize their own stem cells.
The blood is removed from the donor and the cells collected using a process called apheresis, which involves placing a needle in the donor’s vein, usually in the arm, similar to administering a blood test. The donor’s blood is pumped through an apheresis machine, which separates the blood into four components: red cells, plasma, white cells and platelets. The white cells and platelets, which contain the stem cells, are collected, while the red cells and plasma are returned to the donor. It can take one to two sessions of apheresis to collect enough blood from a MUD. If you are your own donor, it may take more than two sessions.
If enough stem cells can’t be retrieved from apheresis, they can be removed directly from the bone marrow. This requires the donor to undergo a minor outpatient surgical procedure.
While the donor is under anesthesia, the surgeon inserts a hollow needle into the donor’s pelvic bones just below the waist and removes liquid marrow. This is done a number of times until several pints of marrow are collected. The donor can expect to stay in the hospital for six to eight hours after the procedure to recover from the anesthesia and the acute pain at the needle insertion sites. He or she may feel some lower back soreness for a few days afterward. The donor’s body naturally replaces the marrow soon after the procedure. Red cells are also removed, and the donor may experience anemia, which is often treated with iron supplements.
The marrow that’s removed (harvested) passes through a series of filters to remove bone or tissue fragments and is then placed in a plastic bag from which it can be infused into the recipient’s vein. The marrow is usually given to the patient within a few hours and almost always within 24 hours. If necessary, however, marrow can be frozen and stored and will remain suitable for use for years. If the transplant is autologous, the marrow is usually frozen while the patient undergoes intensive chemotherapy.
Placental and Umbilical Cord Blood
A rich source of stem cells for blood cancer patients are the stored stem cells collected from the umbilical cord and placenta after a baby is born, called the cord blood unit. Parents may choose to have the cord blood unit collected after delivery. Healthy parents with healthy children and no transplant candidate in the family can choose to donate their newborn’s cord blood to cord blood banks or research programs at participating hospitals. Parents with a child or a family member who could be a candidate for transplantationshould discuss with their doctor the potential benefits of saving their newborn’s cord blood for possible family use.
Advantages of Using Cord Blood
The advantages of using cord blood stem cells instead of donor peripheral blood or donor marrow stem cells include:
- Availability. Cord blood stored in a public cord blood bank has been prescreened, tested and frozen and is ready to use; on the other hand, it can take several months to find and confirm a marrow or peripheral blood donor.
- HLA matching. A close match between the patient and the cord blood unit can improve outcome.
- Graft-versus-host disease. Patients who undergo cord blood stem cell transplant are less likely to develop graft-versus-host disease (GVHD) or experience less severe complications from GVHD than patients who have bone marrow or peripheral blood transplants.
- Diversity. Donated cord blood units collected from hospitals where births from varied ethnic backgrounds are well represented have the potential to provide a racially diversity source of stem cells.
- Infectious disease transmission. Cord blood stem cell transplants carry less risk of transmission of blood-borne infectious diseases compared with stem cells from the peripheral blood or marrow of related or unrelated donors.
Disadvantages of Using Cord Blood
There can be disadvantages of using cord blood stem cells as well:
- Clinical data. Genetic diseases may be present but not apparent at the time of birth and could be transplanted to a patient via donor cord blood stem cells. Procedures to track this possibility require follow-up until the donor infant is months or even years old, and such follow-up has proven difficult. A partial solution used by many public cord blood banks is to obtain a detailed health history from potential donors in advance of cord blood collection — similar to standard procedures used to screen volunteer blood donors.
- Storage. Researchers don’t know how long cord blood can be frozen and stored before it loses its effectiveness. However, cord blood samples have been preserved for as long as 10 years and have still been successfully transplanted.
- Engraftment. The number of cells needed to give a transplant patient the best chance for engraftment and for surviving the transplant is based on his or her weight, age and disease status. A cord blood unit might contain too few stem cells for the recipient’s size. Because of the smaller number of stem cells, cord blood stem cell transplants engraft more slowly than stem cells from marrow or peripheral blood. Until engraftment occurs, patients are at risk of developing life-threatening infections. This means that cord blood transplant recipients may be vulnerable to infections for up to one to two months longer than marrow and peripheral blood stem cell recipients.
The decrease in marrow function often begins to take effect by the second or third day after an allogeneic stem cell infusion. You’ll be kept in a protected environment to reduce contact with infectious agents. Generally within two to four weeks after the transplant, the engraftment of donated cells will be apparent from the appearance of normal white cells in your blood. You’ll receive periodic transfusions of red cells and platelets until your marrow function has been restored by the transplanted stem cells.
Your doctor will carefully monitor you with physical exams, blood chemistry tests, imaging studies and other tests to ensure that your heart, lungs, kidneys, liver and other major organs are functioning normally. You’ll need drugs to prevent GVHD, in addition to blood transfusions. If you’re suffering from a poor appetite or diarrhea, you may need to be fed intravenously or through a duodenal tube (called hyperalimentation) to ensure you get adequate nutrition.