Clinically, what really distinguishes acute GVHD from cGVHD is the presence of significant fibrosis in the latter. While active inflammation is still a central component of cGVHD, it is associated with constant tissue injury, remodeling, and fibrosis. 

Patients with cGVHD can have tightness and fasciitis, as well as restrictions that limit normal tissue functions and ranges of motion. For example, fibrosis can limit a person’s ability to eat a full meal when the stomach cannot distend properly. It is important to emphasize just how central fibrosis is in cGVHD. In patients who develop bronchiolitis obliterans, increasing degrees of fibrosis and fixed obstruction of the respiratory tract can lead to a relentless decline in FEV1 that, in some cases, may ultimately be fatal.

It is fascinating how much of the etiopathogenesis has now been molecularly dissected by our colleagues on the experimental side, including by Dr Negrin and colleagues. The ROCK2 pathway is important and is involved in cGVHD-associated fibrosis. ROCK2 inhibition drives the pathway away from proinflammatory effector T cells toward regulatory T cells and can help decrease the expression of fibrotic mechanisms. In clinical studies, the ROCK2 inhibitor belumosudil produced relatively good response rates in organs such as the lung, with, strikingly, complete remissions in some cases. Those with limited lung dysfunction when entering the study had higher rates of response to belumosudil than those with more advanced disease, so early intervention can alter the trajectory of the disease. So, the ROCK2 pathway is central to the pathogenic effector T-cell axis.

Another axis involves pathogenic B cells, the production of autoantibodies, and the activation of the monocyte/macrophage pathway. CSF1R-dependent monocytes are instrumental in profibrotic macrophage development and function, and the effect is to promote sustained inflammation, tissue injury, and fibrosis. Recently, a clinical study evaluating the CSF1R inhibitor axatilimab suggested that there was some potential benefit of targeting this axis in patients with cGVHD, although further clinical studies are still needed. Overall, these studies highlight how we are starting to find clinical interventions that directly impact dysregulated pathways to produce meaningful benefit.

cGVHD is a complication of allogeneic transplant that weighs heavily because it is caused by our treatment, albeit a treatment that may be lifesaving. The classic manifestations may involve the eyes, mouth, skin, gut, central organs, and mucosa. 

We have learned that regular follow-up post allogeneic transplant over the long term is essential to identify potential complications sooner rather than later. Years ago, many of us would see patients return to the transplant center 1 or 2 years post transplant with significant disabilities due to manifestations of cGVHD. Historically, this included skin that was essentially leather bound; patients could not flex their elbows, move their legs, or bend over; at times, skin fibrosis over the chest area could be so severe that it would limit their ability to take a deep breath. 

Since that time, we have improved in several areas. We have learned to identify at-risk patients earlier by routinely and objectively measuring cGVHD-associated symptoms and manifestations. We have also recently learned how to better treat these patients with more effective therapies. If we are following a patient carefully, we can look for the earliest signs of cGVHD, and, when we see them, we can treat these patients differently. We will not try to taper the patient off of immunosuppressant therapy. Rather, we will try to minimize the further deterioration of their function by either increasing their immunosuppression or adding another immunosuppressant.

Before the recent advent of newer agents, there were really limited options for treating patients with cGVHD. Now, with the advent of belumosudil, which has antifibrotic activity, and ruxolitinib, which has been shown in randomized trials to improve outcomes, I think that we have even more incentive to follow patients carefully and intervene appropriately the moment we see early signs of cGVHD.

As Dr Giralt alluded to, patients with cGVHD are generally not under the direct care of transplant medicine providers anymore. Many of our patients live far away, which makes routine follow-up more difficult. This is not ideal considering that the manifestations of cGVHD need to be picked up early. 

We are especially concerned with lung cGVHD, which can be one of the most devastating complications of transplantation and may be irreversible. Unfortunately, we may not hear about these patients until they come for their 6-month or 1-year follow-up visits. Referring clinicians should know that, oftentimes, the chest x-ray will be normal, so it is important to conduct routine pulmonary function studies and identify any changes at the earliest opportunity. One option to consider could be the home monitoring of pulmonary functioning using FEV1 monitoring, which might give us a clue that there is a deterioration that requires intervention. We also now have some therapies that are different than what we had before and can potentially give us the opportunity to intervene earlier and in a more effective way. 

The other issue that we struggle with is that the complicated disease mechanisms that are involved in patients who develop cGVHD are sometimes difficult to tease apart, and we still do not have very good animal models. That has been a big challenge to understanding the basic pathophysiology of cGVHD and how different regulatory and effector mechanisms interact. We have made progress, but we still have a lot to learn about the pathophysiology of cGVHD. We do have some tools and therapies that we can now consider, and that is an exciting development.