Chronic Graft Versus Host Disease

Chronic graft versus host disease is a serious complication that can occur after a stem cell transplant, when the donated immune cells begin attacking the recipient’s own organs and tissues, creating a condition that may require years of treatment and significantly impact daily life.

Table of contents

• What Is Chronic Graft Versus Host Disease?
• Signs and Symptoms
• What Causes Chronic GVHD?
• Risk Factors
• Diagnosis
• Organs and Tissues Affected
• Treatment Options
• How Long Does Chronic GVHD Last?
• Coping with the Emotional Challenges
• Self-Monitoring and Early Detection

What Is Chronic Graft Versus Host Disease?

Chronic graft versus host disease (cGVHD) is a complication that can develop after an allogeneic transplant, a procedure in which a patient receives hematopoietic stem cells (immature blood cells) from a donor. These transplants are often needed to treat serious blood cancers such as leukemia or lymphoma, or other conditions like aplastic anemia.^[1]

In chronic GVHD, the donated stem cells—called the graft—view the recipient’s body (the host) as a foreign threat. As a result, the donor cells attack the recipient’s own tissues and organs. This is why the condition is named “graft” versus “host.”^[1]

Chronic GVHD is different from acute GVHD. While acute GVHD typically occurs within the first 100 days after transplant, chronic GVHD can appear at any time, though most cases develop within the first two years after transplant.^[1] Chronic GVHD tends to develop more slowly than acute GVHD and can affect many more organs and tissues throughout the body.^[4]

Signs and Symptoms

Symptoms of chronic GVHD can range from mild to severe and may affect multiple parts of the body. Because some symptoms resemble those of other health conditions, it’s important to report any unusual changes to your healthcare provider.^[4]

Common symptoms include:^[1][4]

• Rash and itching of the skin
• Skin tightness and swelling
• Hair loss on the head and body
• Dry mouth and mouth sores
• Gum disease
• Dry or gritty feeling in the eyes
• Vision changes
• Diarrhea, nausea, and vomiting
• Yellow discoloration of the skin and eyes (jaundice)
• Shortness of breath and persistent dry cough
• Fatigue
• Muscle weakness, cramping, or pain
• Decreased range of motion in joints
• Vaginal dryness, itchiness, or pain with intercourse
• Itchy penis or scrotum, or pain with intercourse

Some effects of chronic GVHD include tissue thickening and scarring, known as fibrosis. These symptoms are similar to those caused by certain autoimmune diseases—conditions where the body’s immune system mistakenly attacks healthy organs.^[4]

What Causes Chronic GVHD?

The development of chronic GVHD involves a complex, multistep process. It begins with early inflammation and tissue injury, followed by chronic inflammation, abnormal tissue repair, and fibrosis.^[8]

Normally, blood cells in your immune system protect you from infection by fighting invaders like viruses and bacteria. These blood cells recognize a protein on your body’s cells called human leukocyte antigen (HLA), which signals that the cells belong to you.^[1]

During an allogeneic transplant, the donor’s stem cells have slightly different HLA proteins. When these donor cells mature and develop into immune cells, they may recognize the recipient’s tissues as foreign and attack them, leading to GVHD.^[2]

Risk Factors

Certain factors increase the likelihood of developing chronic GVHD. Patients are at higher risk if they:^[3]

• Previously had acute GVHD
• Are older in age
• Received cells from an unrelated donor or a donor who was not a perfect match
• Were transplanted with stem cells collected from the bloodstream (peripheral blood stem cells) rather than bone marrow or cord blood
• Are male and received cells from a female donor
• Are male or female and received cells from a female donor who had previously borne children

Diagnosis

Because chronic GVHD symptoms can be confused with other health conditions, healthcare providers typically perform a thorough physical exam and various tests to confirm the diagnosis. This helps ensure that symptoms are caused by chronic GVHD and not something else.^[4]

Healthcare providers now diagnose chronic GVHD based on symptoms and clinical signs (such as test results or imaging) in addition to the timing of symptom onset, rather than relying solely on when symptoms appear.^[1]

Organs and Tissues Affected

Chronic GVHD most commonly affects the skin, liver, gastrointestinal tract, and lungs, but it can affect virtually any part of the body.^[1]

The condition most often impacts:^[3]

• Skin and nails
• Eyes
• Mouth
• Liver

Less frequently, chronic GVHD affects:^[3]

• Lungs
• Intestines
• Joints
• Genitals
• Muscles
• Nervous system

Treatment Options

How healthcare providers manage chronic GVHD depends on which organs and tissues are affected, the severity of symptoms, and the impact the condition is having on daily life.^[3]

If chronic GVHD is affecting only one or two organs or tissues, doctors may choose a localized therapy, such as a skin ointment. However, if it is affecting many different parts of the body or if symptoms are severe and cannot be managed by localized therapy, doctors may prescribe drugs that suppress the immune system (systemic therapy).^[3]

Systemic corticosteroids remain the first line of treatment for chronic GVHD.^[7][9] Common initial treatments include:^[3]

• Prednisone alone
• Prednisone combined with cyclosporine
• Prednisone combined with tacrolimus
• Sirolimus

In the past decade, significant advances have been made in the treatment of chronic GVHD. Three novel agents have been approved for the management of chronic GVHD, all showing activity and quality-of-life benefits.^[9] For patients whose chronic GVHD does not respond to initial treatments, doctors may try other drugs such as:^[3]

• Ibrutinib
• Ruxolitinib
• Belumosudil
• Methotrexate
• Mycophenolate mofetil
• Sirolimus
• Extracorporeal photopheresis
• Low-dose interleukin-2
• Abatacept

Ibrutinib was the first agent approved for the management of steroid-refractory chronic GVHD in 2017.^[9] In 2021, ibrutinib received FDA approval for the treatment of adults with chronic GVHD after failure of one or more lines of therapy, making it the first drug to be FDA approved specifically for chronic GVHD.^[5]

It’s important to continue taking prescribed medications even when symptoms improve. Stopping medication too early can cause chronic GVHD to flare up again or worsen.^[3]

Timely diagnosis, multidisciplinary working, and good supportive care, including infection prevention measures, are clearly important in optimizing response and survival.^[7] A multidisciplinary team approach that focuses on individual needs and quality of life is strongly encouraged.^[8]

How Long Does Chronic GVHD Last?

The length of time patients have chronic GVHD varies. Many people see gradual improvement over a few months, but for some it can last longer. The average duration is between one and three years, though some people may have it for a longer period.^[14]

Patients with chronic GVHD usually require treatment for three to five years. Approximately 15 percent of patients require treatment for a longer period and, in rare cases, may need lifelong immunosuppressive drugs.^[3] Although most patients need many years of treatment, active chronic GVHD most often resolves within five to eight years, though not always without permanent damage.^[5]

Most cases of chronic GVHD are mild or moderate. However, 10 to 15 percent of patients develop symptoms that are more severe.^[3]

Coping with the Emotional Challenges

Living with chronic GVHD can be emotionally difficult for both patients and their families. After transplant, everyone wants to resume a normal life, but chronic GVHD can make that challenging for a time.^[10]

Chronic GVHD can be particularly hard to cope with, especially after going through extensive treatment. Patients may have been free of symptoms before their transplant, so dealing with long-term, uncomfortable symptoms afterward can be difficult to accept.^[14]

It’s normal to feel sad or anxious while dealing with chronic GVHD. Physical changes, some of the drugs used to treat the condition, fatigue, and sleep problems can cause depression, confusion, anxiety, mood swings, and exaggerated feelings of anger, excitement, or sadness.^[10]

Living with chronic GVHD can bring challenges with physical functioning, fatigue, general health, social functioning, and psychological distress including depression and anxiety.^[13] Chronic GVHD of the muscles and joints can be painful and affect mobility. Patients might also feel very tired and lethargic, or breathless if chronic GVHD affects the lungs.^[14]

It’s important to let your doctor know if you are experiencing any emotional symptoms. Sometimes medications are offered to stabilize mood swings and reduce anxiety. Short-term use of these drugs is common and does not mean long-term dependence.^[10]

Finding an outlet to express and process feelings can decrease stress, facilitate problem-solving, and help patients move forward in a healthy manner. Talking with a social worker, psychologist, psychiatrist, or pastoral counselor often helps, especially those who have experience working with patients who live with chronic GVHD and their caregivers.^[10]

Talking with others who have traveled the same path can be especially helpful. Speaking with other survivors who understand the experience may make patients feel less alone. Support groups offer a safe, private space to network with others living with chronic GVHD.^[10]

Many patients find that meditation, guided imagery, and relaxation techniques help them cope with the stress of living with chronic GVHD. Practicing mindfulness—living in the moment and acknowledging and accepting feelings—can be beneficial.^[10]

Helpful coping strategies include:^[10]

• Taking each day as it comes, one day at a time
• Focusing on what you can do, rather than what you can’t
• Building flexibility into plans since you don’t always know how you will feel
• Noticing small things that bring joy and pleasure
• Engaging in non-medical activities that help maintain a sense of normalcy

Self-Monitoring and Early Detection

Because chronic GVHD usually develops more than 100 days after transplant when patients no longer have weekly visits with the transplant team, self-monitoring becomes especially important. Patients should carefully examine their body weekly for signs of chronic GVHD.^[3]

It’s crucial to inspect the mouth, eyes, skin, joints, and genitals for any changes. Subtle changes should not be ignored, and anything unusual should be reported to a doctor immediately.^[3] Finding symptoms early is vital, as certain problems such as dry eyes may become permanent if not treated promptly.^[5]

Patients should not be afraid to ask questions. If they notice a change, they should not assume it’s nothing to worry about and should consult their care team to be sure.^[3]