Corticosteroids (steroids) are often considered the main treatment for chronic graft-versus-host disease (GVHD) — a condition where the donated immune cells attack a transplant recipient’s body. Steroids help treat chronic GVHD by suppressing (calming) the immune system and decreasing inflammation.

However, for about 30 percent to 60 percent of people with GVHD, steroids don’t work or stop working well. If this occurs, it’s known as steroid-refractory GVHD (meaning the disease doesn’t respond to steroid treatment).

If you or a loved one develops steroid-refractory GVHD, you should know there are still various treatment options available. In this article, we’ll explain what steroid-refractory GVHD is and explore the treatment options doctors may recommend.

What Is Steroid-Refractory GVHD?

The word “refractory” means “resistant” or “unresponsive.” If you have steroid-refractory GVHD, it means that the disease isn’t responding to steroids, which are the first-choice treatment for GVHD (like prednisone).

Steroid-refractory GVHD can occur in people with acute or chronic GVHD. Acute GVHD is often considered steroid-refractory if symptoms get worse or don’t improve within a few days of starting steroid treatment.

Chronic GVHD may be considered steroid-refractory if any of the following apply:

• Symptoms worsen after two weeks of steroid treatment.
• There’s no improvement after four to six weeks of steroid treatment.
• Symptoms return when tapering (lowering the dose) of steroids.
• Serious side effects make it unsafe to continue steroids.

Researchers don’t completely understand why some people with chronic GVHD develop steroid resistance, but it’s common. After two years of steroid treatment for chronic GVHD, more than half of people need an alternate treatment.

What Are the Symptoms of Steroid-Refractory Chronic GVHD?

Symptoms of steroid-refractory chronic GVHD vary from person to person. They depend on which organs are affected and at what stage the condition is. Some people can also experience side effects from long-term steroid use.

Common Symptoms of Chronic GVHD

Following are the organs most commonly affected by chronic GVHD and the symptoms that may develop:

• Skin — Rash, itching, thickened or tight skin, or sores
• Nails — Brittleness, changes in texture, or nail loss
• Eyes — Blurred vision, dry eyes, or vision loss
• Mouth — Dry mouth, difficulty eating and swallowing, or mouth sores
• Liver — Jaundice (yellowing of the skin and eyes) abdominal (stomach) swelling, or liver damage

Other organs that may be affected include:

• Digestive system (stomach and intestines) — Nausea, diarrhea, or weight loss
• Lungs — Shortness of breath, cough, or wheezing
• Muscles and joints — Stiffness, pain, or weakness
• Genitals — Vaginal dryness, pain, or scarring
• Nervous system — Numbness, tingling, or nerve pain

Organ damage due to chronic GVHD may become permanent in people with steroid resistance. Many eye, skin, and lung problems related to chronic GVHD don’t respond to other types of immunosuppression.

No matter which organ is affected by chronic GVHD, studies have found that people living with this complication have worse quality of life. More severe disease is linked with a further decline in quality of life.

Steroid Side Effects

Even if steroids are helping with GVHD, some people may still need a different treatment if they develop serious side effects (also called steroid toxicity). Long-term steroid use can cause:

• High blood sugar and diabetes
• Weight gain
• Fluid retention, leading to swelling in the hands, feet, or face
• High blood pressure, which can increase the risk of heart disease
• Osteoporosis (weakened bones that break more easily)
• Eye problems, like cataracts or glaucoma
• Mood changes, including depression or anxiety

Medications for Steroid-Refractory Chronic GVHD

Steroids are considered a first-line treatment for chronic GVHD. Any treatments tried after the first-line treatment doesn’t work are considered second-line or third-line treatments.

There’s no single standard treatment for steroid-refractory chronic GVHD. People with moderate to severe chronic GVHD usually need systemic (whole-body) therapy. Systemic therapy involves taking a medication — either by mouth or infused into your bloodstream — that affects your whole body. This can include oral medications (taken by mouth) or intravenous (IV) medications given directly into the bloodstream

The Leukemia & Lymphoma Society encourages people with steroid-refractory GVHD to enroll in a clinical trial, which is a type of study that potentially gives a person access to newer treatments.

There are several medications currently approved by the U.S. Food and Drug Administration (FDA) to treat steroid-refractory chronic GVHD. We’ll discuss each below.

Ruxolitinib

Ruxolitinib (Jakafi) is a JAK inhibitor, a type of medication that blocks JAK1 and JAK2 — proteins involved in inflammation. By targeting these proteins, ruxolitinib helps reduce the immune system’s attack on the body in chronic graft-versus-host disease.

A 2021 study looked at the effect of ruxolitinib in people with steroid-refractory chronic GVHD. Researchers found that compared to other treatments, people taking ruxolitinib had a greater response to treatment, lived longer without transplant failure, and had improved symptoms. Results from clinical trials with ruxolitinib have led to some health specialists recommending this drug as the first treatment recommended for people with steroid-refractory chronic GVHD.

Ruxolitinib is FDA-approved to treat both acute and chronic GVHD after at least one other systemic treatment (such as steroids) has been tried.

Ibrutinib

Ibrutinib (Imbruvica) is a Bruton’s tyrosine kinase (BTK) inhibitor. It works by blocking the BTK protein, which activates B cells, a type of white blood cell (WBC) involved in inflammation in chronic GVHD.

It’s FDA-approved as a second-line treatment for adults and children with chronic GVHD. In a 2024 study, researchers found that about 45 percent of people who took ibrutinib for steroid-refractory chronic GVHD responded to the drug within six months.

Belumosudil

Belumosudil (Rezurock) is a ROCK1 and ROCK2 inhibitor. These proteins help regulate T cells, a type of white blood cell involved in inflammation. By blocking ROCK1 and ROCK2, belumosudil reduces harmful immune responses that contribute to chronic graft-versus-host disease.

Belumosudil FDA-approved for people with chronic GVHD who’ve previously tried at least two other systemic treatments. In clinical trials, about 74 percent of people with chronic GVHD responded to belumosudil, with about 60 percent of people seeing improved symptoms.

Although belumosudil is specifically FDA-approved for chronic GVHD, a 2024 real-world study found that the drug demonstrated good treatment response and promising survival outcomes in people with steroid-refractory GVHD.

Axatilimab-Csfr

Axatilimab-csfr (Niktimvo) is a colony-stimulating factor-1 receptor (CSF-1R)- blocker. This medication targets macrophages — a WBC that can become overactive in graft-versus-host disease. By blocking CSF-1R, axatilimab helps reduce inflammation and tissue damage in chronic GVHD.

Axatilimab-csfr is FDA-approved to treat chronic GVHD in people who have tried at least two other treatments. In clinical trials, about 75 percent of people with chronic GVHD have a positive overall response to this treatment.

Remestemcel-L-Rknd

Remestemcel-L (Ryoncil) is a cell therapy made from healthy donor bone marrow. It contains special cells called mesenchymal stromal cells (MSCs) that help calm an overactive immune system. In steroid-refractory acute GVHD, the donor’s immune cells attack the recipient’s body. Ryoncil works by reducing inflammation and protecting healthy tissues from damage.

Remestemcel-L-rknd was approved by the FDA in 2024 to treat steroid-refractory GVHD in children as young as two months old who haven’t improved with steroids. It is given through an IV and offers a new treatment option for a serious condition that can happen after a stem cell transplant.

Off-Label Treatments

Off-label treatments are medications or therapies that the FDA has approved for one condition but are also used for other conditions based on medical research and professional recommendations. Your healthcare provider may prescribe an off-label treatment if they believe it is safe and effective for your specific situation, considering which organ is affected, how severe your symptoms are, and your overall health.

Some off-label treatments for steroid-refractory chronic GVHD include:

• Abatacept (Orencia)
• Alemtuzumab (Lemtrada)
• Etanercept (Enbrel)
• Hydroxychloroquine (Plaquenil, Sovuna)
• Imatinib (Gleevec, Imkeldi)
• Interleukin-2 (IL-2)
• Methotrexate (Trexall, Jylamvo, Otrexup, Rasuvo)
• Mycophenolate mofetil (CellCept)
• Pentostatin (Nipent)
• Rituximab (Rituxan)
• Sirolimus (Rapamune)
• Tacrolimus (Prograf, Astagraf XL, Envarsus XR)

Extracorporeal Photopheresis

Extracorporeal photopheresis (ECP) is a treatment for steroid-refractory GVHD that helps regulate the immune system’s response. It works by reducing the activity of immune cells that cause inflammation and tissue damage. When starting ECP, most people receive treatment twice per week.

During this procedure, a small amount of blood is drawn, and white blood cells are separated and mixed with a medication called 8-methoxypsoralen. This drug becomes active when exposed to ultraviolet A (UVA) light, which modifies the WBCs before they are returned into the body. This process helps reduce the immune response that drives GVHD symptoms.

Although researchers don’t know exactly how ECP works, it appears to calm down the immune response that causes symptoms in chronic GVHD. ECP is generally considered safe, with most people experiencing only minimal side effects, such as fatigue, mild fever, or low blood pressure after treatment.

Research shows that this treatment works best for people with chronic GVHD affecting the skin, liver, lungs, and mouth.

Talk With Others Who Understand

On myGVHDteam, the site for people with graft-versus-host disease and their loved ones, people come together to ask questions, give advice, and share their stories with others who understand life with the condition.

Do you or a loved one have steroid-refractory GVHD? How was it treated? Share your experience in the comments below, or start a conversation by posting on your Activities page.