Chronic Graft-versus-Host Disease (cGVHD): Advances in Targeted Immunomodulatory Therapies

Chronic Graft-versus-Host Disease (cGVHD) is a complex, immune-mediated complication that arises in patients following allogeneic stem cell transplantation. It occurs when donor-derived immune cells recognize the recipient & tissues as foreign and initiate a prolonged immune attack, leading to multi-organ damage.

cGVHD is the most common long-term complication of stem cell transplantation, affecting 30–70% of survivors. It can involve the skin, liver, eyes, lungs, gastrointestinal tract, and joints, significantly impairing quality of life and increasing the risk of morbidity and mortality. Symptoms can range from mild to severe, often mimicking autoimmune disorders like scleroderma or Sjögren’s syndrome.

Targeted Therapies: Jakafi, Rezurock, Niktimvo

Until recently, treatment options were limited to corticosteroids and broad immunosuppressants. However, the development of targeted immunomodulatory agents has transformed the management of steroid-refractory cGVHD.

Jakafi® (ruxolitinib)

Jakafi is an oral JAK1/2 inhibitor originally approved for myelofibrosis and polycythemia vera. It became the first FDA-approved treatment for steroid-refractory cGVHD in 2021. Ruxolitinib works by blocking key inflammatory cytokine pathways involved in immune cell activation and tissue damage.

In the REACH3 trial, Jakafi demonstrated superior overall response rates, greater symptom improvement, and longer failure-free survival compared to best available therapy in patients with moderate to severe cGVHD.

Rezurock® (belumosudil)

Rezurock is a selective ROCK2 (Rho-associated coiled-coil-containing protein kinase 2) inhibitor that modulates both inflammatory and fibrotic pathways. It was approved for adults and pediatric patients aged ≥12 with cGVHD after failure of at least two prior lines of systemic therapy.

Belumosudil has shown durable responses and significant improvement in joint and skin manifestations, two of the most debilitating aspects of cGVHD. It also offers once-daily oral dosing and a favorable safety profile.

Niktimvo™ (axatilimab)

Niktimvo (axatilimab) is a CSF-1R (colony-stimulating factor-1 receptor) inhibitor, approved for adult patients with chronic Graft-versus-Host Disease (cGVHD) after failure of at least two prior lines of systemic therapy. Unlike BTK inhibitors, axatilimab targets monocyte-derived macrophages, which are central to the fibrotic and inflammatory processes of cGVHD. By depleting pathogenic macrophages in affected tissues, Niktimvo addresses both inflammation and organ fibrosis.

Niktimvo has shown particular promise in patients with skin, lung, and liver involvement. It is generally well tolerated, with adverse events including elevated liver enzymes, fatigue, and gastrointestinal symptoms. Careful monitoring is required during treatment, but it offers a novel, non-immunosuppressive approach for patients with refractory cGVHD.

Diagnostic Considerations

cGVHD is diagnosed based on clinical features and supported by histologic, radiologic, and functional testing. Common signs include:

• ●  Skin thickening, rash, or pigment changes
• ●  Dry eyes and mouth
• ●  Lung function decline (BOOP/bronchiolitis obliterans)
• ●  Joint stiffness or contractures
• ●  Elevated liver enzymes
•  

Organ scoring and symptom burden assessments help guide treatment intensity and monitor response over time.

Future Directions in cGVHD Treatment

The emergence of Jakafi, Rezurock, and Niktimvo represents a major shift from nonspecific immunosuppression to precision-targeted immunotherapy in cGVHD. As research advances, new strategies are being explored, including:

• ●  Combination therapies with complementary mechanisms
• ●  Biomarkers to predict treatment response and relapse
• ●  Cellular therapies to restore immune tolerance
•  

With these innovations, cGVHD is transitioning from a chronic, debilitating complication to a more manageable condition with individualized, disease-modifying treatment options.