Chronic GVHD Treatment Options: 5 Second- and Third-Line Therapies

Medically reviewed by Fatima Sharif, MBBS, FCPS

Written by Puttatida Chetwong, M.D.

Posted on June 26, 2026

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Key Takeaways

When steroids do not work well enough for chronic graft-versus-host disease (GVHD), finding a second- or third-line treatment becomes an important next step toward improving quality of life.

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What happens if steroids don’t work well enough for chronic graft-versus-host disease (GVHD)? Corticosteroids are usually the first-line treatment for chronic GVHD, but they can cause significant side effects, especially when used for long periods.

When steroids don’t work, or when the side effects become too much to handle, finding the right second- or third-line therapy is the next big step toward getting your quality of life back.

Research suggests more than half of people with chronic GVHD eventually need treatment beyond steroids. The good news is that treatment options for chronic GVHD have expanded. Four U.S. Food and Drug Administration (FDA)-approved medications and one well-established nondrug approach are available for people whose disease does not respond adequately to steroids.

This article explains what second- and third-line treatments are and describes five options a healthcare provider may consider for chronic GVHD.

What Does ‘Second-Line’ or ‘Third-Line’ Chronic GVHD Treatment Mean?

Second-line therapy is the next step a doctor may recommend when the standard first-line treatment — steroids, with or without other immunosuppressive medications (drugs that calm the immune system) — isn’t controlling symptoms well enough or is causing side effects that make it hard to continue.

Third-line treatment may be considered when a second option also doesn’t work well enough or causes difficult side effects.

How Do Doctors Know It’s Time To Try Something New?

Two patterns may tell a care team it’s time to change course.

The first is steroid-refractory GVHD, meaning GVHD gets worse despite steroid treatment or stays the same despite an adequate steroid dose for a set period of time.

The second is steroid-dependent disease, meaning symptoms come back or get worse each time the steroid dose is lowered.

Care teams also watch how GVHD affects everyday activities. If GVHD is still affecting a person’s ability to eat, move, breathe, or return to work or daily routines while they’re taking steroids, that may be a sign the treatment plan needs to change.

Long-term steroid use carries important risks, including bone loss, blood glucose (blood sugar) changes, and a higher chance of infection. One real-world study found that, after newer chronic GVHD medications became available, people had fewer hospital admissions and were more likely to return to work sooner.

However, the study was small and looked back at past records, so more research is needed to confirm these findings.

What Are the Main Chronic GVHD Treatment Options After Steroids?

The five options often considered after steroids don’t work well enough or cause difficult side effects are:

Axatilimab (Niktimvo)
Belumosudil (Rezurock)
Extracorporeal photopheresis (ECP), a treatment that filters and treats blood cells with light before returning them to the body
Ibrutinib (Imbruvica)
Ruxolitinib (Jakafi)

Each works through a different mechanism and suits different situations.

Axatilimab

Axatilimab is the most recently FDA-approved option for chronic GVHD. It was approved in August 2024 for adults and children weighing at least 40 kilograms (about 88 pounds) with chronic GVHD after failure of at least two prior lines of systemic therapy (treatment that affects the whole body).

Axatilimab works by blocking a protein called CSF1R. This protein activates macrophages, immune cells that can contribute to inflammation and scarring in chronic GVHD. Unlike treatments taken orally (by mouth), axatilimab is given as an IV infusion (through a vein). It’s typically given every two weeks, usually at a clinic or infusion center.

Research showed a high overall response rate across skin, mouth, lungs, and other organs, with a favorable safety profile. It may suit people who haven’t responded to other medications or have health conditions that make other treatments harder to tolerate.

Belumosudil

The FDA approved belumosudil in 2021 for adults and children ages 12 and older with chronic GVHD after at least two prior lines of systemic therapy have not worked well enough.

The drug targets a protein called ROCK2, which plays a role in both inflammation and fibrosis (the buildup of scarlike tissue) in chronic GVHD.

Fibrosis can be especially challenging because it may tighten the skin, limit joint movement, and reduce lung function over time. Because belumosudil affects pathways involved in both inflammation and fibrosis, it has shown activity in chronic GVHD affecting the skin, joints, mouth, lungs, and gastrointestinal (GI) tract.

Belumosudil is an oral tablet that is typically taken once daily with food. In the clinical trial that supported its approval, more than 70 percent of participants had a response to treatment.

Extracorporeal Photopheresis

Extracorporeal photopheresis is a procedure, not a medication. During ECP, blood is drawn from the body. Some white blood cells are separated, treated with a light-activated medication and ultraviolet (UV) light, and then returned to the body. This process may help calm or “reset” parts of the immune system so it attacks the body’s tissues less.

ECP has been studied for decades in steroid-refractory chronic GVHD. It may be particularly helpful for GVHD affecting the skin, mouth, and lungs, including bronchiolitis obliterans syndrome (airway scarring that can make breathing harder).

One advantage of ECP is that it generally has less risk of weakening the immune system than some medications. ECP is usually done in a clinic or treatment center over multiple sessions and is often used with other chronic GVHD treatments rather than by itself.

Ibrutinib

Ibrutinib was the first medication approved by the FDA for chronic GVHD. It received approval in 2017 for adults and children with chronic GVHD after one or more prior lines of systemic therapy have not worked well enough.

Ibrutinib works by blocking a protein called Bruton’s tyrosine kinase (BTK). BTK helps activate certain immune cells, including B cells, that may contribute to chronic GVHD. By blocking this protein, ibrutinib may help reduce harmful immune activity.

Ibrutinib is an oral medication, typically taken once a day. In the clinical trial that supported its approval, many participants had improvements in chronic GVHD symptoms, including those affecting the skin, mouth, and GI tract.

Clinical data from the approval study showed responses in several organs affected by chronic GVHD, including the skin, mouth, GI tract, and liver.

Some clinicians have observed that ibrutinib may be more helpful in people with more inflammatory forms of chronic GVHD, although research is still evolving. During treatment, healthcare providers monitor for side effects, including thrombocytopenia (low platelet counts), bleeding, infections, and changes in heart rhythm.

Ruxolitinib

Ruxolitinib was approved by the FDA in 2021 for adults and children ages 12 and older with chronic GVHD after one or two prior lines of systemic therapy have not worked well enough. It has become a commonly used treatment option for chronic GVHD that persists despite earlier therapies.

Ruxolitinib works by blocking two proteins called Janus kinase 1 (JAK1) and JAK2. These proteins act like “on” switches, keeping immune cells — particularly T cells — in a constant attacking state. Turning those switches off may help calm the immune response driving chronic GVHD.

Ruxolitinib is taken as an oral tablet, typically twice daily. Clinical studies have shown that it can help people with chronic GVHD affecting the skin, mouth, lungs, liver, and other organs.

In the large clinical trial that led to its approval, around 50 percent of people responded to ruxolitinib, compared with about 26 percent who received standard supportive care.

During treatment, healthcare providers usually monitor blood counts because ruxolitinib can sometimes lower levels of red blood cells, white blood cells, or platelets.

Why Is Chronic GVHD Treatment Different for Everyone?

No two cases of chronic GVHD look the same, and neither do the treatment plans. Which organs are affected — skin, mouth, eyes, lungs, liver, the gastrointestinal tract, or joints — shapes which options are most likely to help.

Symptom severity, past treatments, side effects from earlier treatments, and other health conditions can also affect whether a medication is a good fit.

Practical preferences are part of the conversation too. For example, some people may prefer a daily oral tablet, while others may be comfortable with scheduled clinic infusions.

Treatment is often adjusted as chronic GVHD changes. The goal is to find an approach that helps control the condition, lowers the need for steroids when possible, and fits the person’s overall health and goals.

Why Consider a Clinical Trial?

Clinical trials are research studies that test whether new treatments, or new ways of using existing treatments, are safe and effective. People who join clinical trials are monitored closely by a research and care team.

Clinical trials may offer access to new treatments for chronic GVHD — or combinations of treatments — that aren’t yet widely available. Researchers are actively studying new targets and approaches, including agents that work through different pathways and combinations of already-approved therapies.

Asking your transplant or chronic GVHD care team whether a trial may be appropriate is a worthwhile step, especially if you’ve tried multiple lines of treatment or your symptoms still aren’t well controlled. Your care team can help you understand what participation involves and whether a study is a good match.

Your Action Plan

Navigating chronic GVHD can feel overwhelming, especially when a first-line therapy stops working. It may help to know that there are more treatment options beyond steroids than ever before.

To help find the best path forward, try keeping a brief record of how your symptoms impact your day-to-day life. Before your next appointment, jot down the specific challenges that bother you the most. It can also help to prepare a guiding question in advance, such as, “What would we need to see to decide it’s time to try a different treatment?”

Your care team is there to partner with you to find the therapy that fits your unique situation right now. It’s always OK to bring your questions to the table and share what matters most to your quality of life. Finding the right approach is a process, and your care plan can always be adjusted as your needs change.