Steroid therapy is often the first choice for treating graft-versus-host disease (GVHD). Nearly half of people with GVHD eventually stop responding to this treatment.

Steroid-refractory GVHD is diagnosed when your symptoms worsen or don’t improve enough even with steroid therapy. Your doctor will likely recommend progressing to another treatment, also called second-line therapy. The decision depends on your symptoms and your overall health.

This article will cover steroid-refractory GVHD and what health experts say about when it’s time to progress to a different therapy. We’ll also discuss your treatment options once GVHD stops responding to steroids alone.

What Is Steroid-Refractory GVHD?

GVHD can be a serious complication that occurs following allogeneic hematopoietic stem cell transplantation — a transplant that uses stem cells from a donor. The donated cells form a new immune system. You may also hear this called a bone marrow transplant.

In GVHD, your new immune system attacks your body’s tissues. This causes systemic (bodywide) inflammation.

There are two types of GVHD — acute and chronic. Corticosteroids (steroids) are often the first-line treatment for both acute and chronic GVHD. Prednisone is a common steroid medication used to treat GVHD.

High-dose steroids help control inflammation and suppress the immune system. These medications reduce attacks on your tissues.

Unfortunately, many people who develop GVHD don’t respond well to steroid treatment. This is known as steroid-resistant or steroid-refractory GVHD.

Steroid-refractory GVHD is associated with worse outcomes. Earlier treatment can prevent end-organ damage (serious damage to vital organs) — a severe complication of GVHD.

Steroid-Refractory Acute GVHD

Steroid-refractory GVHD can also be acute or chronic. Doctors may diagnose the acute type if your GVHD symptoms:

• Get worse or progress after three days of steroid treatment, or
• Stay the same or don’t get better after about a week of steroid treatment

Studies show that 30 percent to 50 percent of people with acute GVHD don’t respond well to steroid treatment.

Steroid-Refractory Chronic GVHD

Steroid-refractory chronic graft-versus-host disease is diagnosed when your symptoms:

• Get worse while you’re taking a high-dose steroid for one to two weeks, or
• Stabilize but don’t improve enough while you’re taking steroids for one to two months

Most people taking steroids for chronic GVHD become resistant to them within two years.

Steroid-Dependent GVHD

Some people with GVHD develop steroid-dependent GVHD. This means steroids can help control their symptoms. However, if they stop taking them or take a lower dose, their symptoms get worse again.

Long-term steroid treatment typically comes with many side effects. According to the Mayo Clinic, you may develop:

• Vision problems
• Osteoporosis (thinning of bones)
• Hyperglycemia (high blood sugar levels)
• Insomnia (difficulty sleeping)
• Mood swings

If you have steroid-dependent GVHD, your doctor will likely recommend trying other medications.

What Causes Steroid-Refractory GVHD?

Researchers aren’t exactly sure what causes steroid-refractory GVHD. They think it may be related to how donor immune cells react to the body and how immune cells communicate with one another.

The immune system uses proteins called cytokines to send signals between cells. When cytokine signals become too active, they can increase inflammation and tissue damage.

Studies also show that long-term steroid use can make inflammation rebound and become worse. Doctors try to taper down steroids slowly to avoid unwanted side effects and reduce the risk of a flare.

Certain factors can raise your risk of developing steroid-refractory GVHD, such as older age and symptoms affecting your gastrointestinal (GI) tract, which includes the stomach and intestines.

When Do You Start Progression Therapy for Steroid-Refractory GVHD?

If you have steroid-refractory GVHD, your doctor will likely recommend starting progression therapy. Progression therapy means moving to a second-line treatment with another medication.

Currently, there aren’t clear guidelines for the exact time to start progression therapy. Doctors start treating GVHD with steroids and adjust the treatment plan from there.

If your symptoms are stable after starting steroid treatment, then your doctor will likely keep the therapy as is.

If your symptoms start worsening, or if another organ becomes affected by GVHD, then you may have steroid-refractory GVHD. Doctors typically recommend trying another line of therapy at this point.

The choice to move to progression therapy also depends on your steroid dose. High-dose steroids are prescribed based on your body weight. Taking more than 1 milligram of medication per 1 kilogram of your body weight is considered a high dose.

According to one GVHD specialist, increasing the steroid dose above 1 milligram per kilogram has not been shown to significantly change outcomes. At that point, GVHD may be considered steroid-refractory.

Some doctors start steroid therapy for GVHD and monitor your symptoms over time. If you don’t improve within a few weeks to a month, you may start progression therapy.

In an interview with Cancer Network, Dr. Yi-Bin Chen, a hematologist-oncologist, explained, “Practically, if I start systemic steroids for a patient with chronic graft-versus-host disease and at a month’s time in follow-up, they haven’t improved, then I’ll start a second-line agent.”

Other GVHD specialists may use different benchmarks for when to start progression therapy.

Which Medications Treat Steroid-Refractory GVHD?

Treatment for steroid-refractory GVHD depends on your individual case. There aren’t any widely agreed-upon guidelines. Instead, your doctor will choose treatment based on the course of your GVHD, medication tolerance, and other health conditions you have.

The U.S. Food and Drug Administration (FDA) has approved several treatment options for steroid-refractory GVHD. These treatments were studied in clinical trials to evaluate their safety and effectiveness.

Medications for chronic GVHD are systemic therapies. This means they act throughout the body to control inflammation. Some are taken orally (by mouth) and others are infused into your bloodstream.

Ibrutinib

Ibrutinib (Imbruvica) was the first FDA-approved treatment for steroid-refractory chronic GVHD. This medication works by blocking a protein called BTK.

BTK protein helps specialized immune cells called B cells grow and divide. B cells make antibodies that help fight infections. However, in GVHD, these antibodies cause inflammation and damage.

Clinical trials showed that the best overall response rate (ORR) with ibrutinib treatment was 69 percent. This means that 69 percent of people responded to the medication at some point in the study. Among all study participants, 31 percent had a complete response to treatment, meaning signs of GVHD went away.

Side effects of ibrutinib include:

• Diarrhea
• Nausea
• Fatigue
• Muscle spasms
• Bruising

Ruxolitinib

Ruxolitinib (Jakafi) is also approved for steroid-refractory GVHD. It works by blocking Janus kinase (JAK) proteins, which help send signals that activate immune cells. This helps calm the immune response that drives GVHD.

Several studies show that ruxolitinib works well for treating both acute and chronic steroid-refractory GVHD. In studies, people treated with ruxolitinib had higher response rates than those who received other available treatments.

Potential side effects of ruxolitinib include low blood cell counts and infections.

Belumosudil

Belumosudil (Rezurock) is another FDA-approved treatment option for steroid refractory chronic GVHD. The medication is a ROCK1/ROCK2 inhibitor, which means it blocks proteins involved in inflammation and fibrosis (tissue scarring). Researchers think that blocking these pathways may help reduce inflammation and slow GVHD-related tissue damage.

Studies showed that belumosudil improved GVHD symptoms in up to 62 percent of people. The best overall response rate was 74 percent to 77 percent, depending on the dose studied.

This medication also helped some people who had already tried other medications, such as ibrutinib.

Side effects seen in clinical trials included pneumonia, hypertension (high blood pressure), and high blood sugar levels.

Axatilimab-Csfr

Axatilimab-csfr (Niktimvo) is a newer FDA-approved treatment option for steroid-refractory chronic GVHD. It works by blocking CSF1R, a protein found on certain immune cells involved in inflammation and fibrosis.

You may be prescribed axatilimab-csfr if chronic GVHD hasn’t responded after at least two prior lines of systemic therapy. Both children and adults who weigh at least 40 kilograms (around 88 pounds) can take this medication.

In a clinical trial, 75 percent of people treated with the recommended dose of axatilimab-csfr responded to treatment.

Common side effects of axatilimab-csfr include:

• Fatigue
• Headache
• Muscle, bone, or joint pain
• Nausea or diarrhea
• Fever
• Infections

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