Almost every patient with cGVHD receives some form of combination therapy because the disease is difficult to treat. Those with refractory cGVHD either do not have an adequate response to steroids or are unable to taper the steroids without a recurrence. These patients are typically receiving steroids and other medications, often a calcineurin inhibitor, plus an additional therapy. 

Currently, ibrutinib, ruxolitinib, and belumosudil are the only drugs that are approved by the US Food and Drug Administration for steroid-refractory cGVHD. The challenge with treating patients with refractory or steroid-resistant cGVHD is knowing what the optimal combination is.

Since steroids with or without calcineurin inhibitors constitute the first line of therapy, we often think of these second- or subsequent-line medications as steroid-sparing agents, as they may allow us to taper the steroids. Steroids are excellent for the treatment of cGVHD in the near-term; however, the long-term use of steroids is associated with well-known toxicities. We try to get the steroid dose below a certain threshold where the patient is not experiencing those problems. In general terms, we aim to get the steroid dose below approximately 0.15 mg/kg, and then we assess the patient to determine whether we are still achieving the desired effect. 

However, for many patients with cGVHD, we cannot reduce the steroid dose, and that is often a reason for adding another drug to their treatment regimen, such as one of the approved therapies for refractory or steroid-resistant cGVHD. Ibrutinib, ruxolitinib, and belumosudil are all used to try to achieve a deeper response, for example, and may allow for the use of steroids at a lower dose. 

Ultimately, there has to be a balance between managing the medication-related complications, managing the cGVHD-related complications, and trying to find that sweet spot where the patients are adequately controlled with minimal medication doses. Arguably, the most active drugs we have are ibrutinib, ruxolitinib, and belumosudil; however, data on specific combinations of these drugs are still limited.

When using combination therapies for patients with cGVHD, we try to avoid overlapping toxicities and excessive immunosuppression, as this may increase the risk of infection. All of these agents are immunosuppressive to some extent, which may increase the risk of opportunistic infections. We also worry about more specific organ-overlapping toxicities, especially in the lung, kidneys, and liver. The severity of the cGVHD does serve as a guide on therapeutic intensity, and the question of whether the severity of the cGVHD manifestations warrants the side effects of the drug(s) is a relevant one. However, there are also some manifestations of cGVHD that people generally do not feel at first but are perhaps a bit more ominous, including lung cGVHD. Many patients with cGVHD are not that physically active, so they are not really taxing their cardiovascular systems. Sometimes, the threshold between feeling fine and having significant debility can be rather narrow. Additionally, many patients with cGVHD live hundreds of miles away from the center at which they initially received care. This is one of the reasons why it is so important for patients in the community to be monitored (eg, pulmonary function tests, chemistries, and hematological tests). Infection as a side effect of therapy is a concern for all patients, particularly in the context of lung cGVHD, so there is a lot of art that goes into the treatment of patients with cGVHD.