Treatment Strategies for Managing Patients with Graft-Versus-Host-Disease

James L. Ferrara, MD

James L. Ferrara, MD

The mainstay of frontline treatment for patients with graft-versus-host-disease (GVHD) has been corticosteroids, but the landscape continues to evolve following the FDA approval of ruxolitinib (Jakafi), a JAK2 inhibitor, as treatment of acute GVHD. More agents are under evaluation for the treatment of this patient population, including other JAK1/2 inhibitors, immunomodulatory agents, and monoclonal antibodies.

Ruxolitinib received its approval from the FDA in May 2019 based on findings from the REACH1 trial. The agent is approved for patients with steroid-refractory acute GVHD, but more clinical trials are evaluating this agent in other settings, as well as in chronic GVHD in the phase III REACH3 trial.

In the REACH1 trial, ruxolitinib combined with corticosteroids induced a 57% overall response rate (ORR) at day 28 and a complete response rate of 31% in patients with steroid-refractory acute GVHD. Thephase III REACH2 trial also demonstrated a significant improvement in ORRin this patient population.

While this advance appears effective for the treatment of GVHD,more research is needed to determine treatments that could replace the use of steroids, says James L. Ferrara, MD. JAK1/2 inhibitors, as well as some other treatment strategies, are appearing promising in the treatment landscape.

In an interview withTargeted Oncology, Ferrara, professor of Medicine, Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai, discussed the prognosis of patients with GVHD and the current treatment strategies. He also highlighted his experience with ruxolitinib and the remaining challenges in this space.

TARGETED ONCOLOGY: What is the prognosis of patients who develop GVHD?

Ferrara:About 40% of patients who receive an allogeneic transplant get acute GVHD. The usual treatment is systemic steroids, but if patients do not respond to systemic steroids, the mortality rate increases significantly to about 40% to 60% mortality. We are looking for new drugs to treat GVHD, particularly to use drugs earlier on for the patients who are at high risk. Those patients tend to be those with lower gastrointestinal (GI) disease, but we would also like to have ways of treating patients who have low risk, perhaps those who have only skin disease and are unlikely to have lower GI disease. [We would like] to be able to use either a lower dose of steroids or no steroids at all for those patients at low-risk.

TARGETED ONCOLOGY: What are the treatment strategies?

Ferrara:The primary treatment strategy is systemic steroids. Additional treatment strategies are to try and target the GI tract. One way to do that is to use monoclonal antibodies that would prevent the trafficking of T cells to the GI tract, such as vedolizumab (Entyvio) or natalizumab (Tysabri). Another strategy is to use an immunomodulatory agent, such as alpha 1 antitrypsin which has a number of immunomodulatory effects, and that is being used in GVHD trials now. An exciting area is the use of JAK1/2 inhibitors. The JAK-STATpathway transduces signals after cytokines have found their receptors. We now have a JAK2 inhibitor that has been approved for the use in patients with steroid-resistant acute GVHD. Other JAK inhibitors are now being studied as primary treatment for acute GVHD.

TARGETED ONCOLOGY: What has been your experience with ruxolitinib?

Ferrara:Ruxolitinib has a good response rate. We are using it for patients who have GI disease and whom we are concerned about. It has a good efficacy profile, but the difficulty with ruxolitinib is it also can be myelosuppressive. There are patients whose white counts decrease after ruxolitinib treatment. Sometimes we cannot get the full therapeutic dose in, so it is a bit of a balancing act. However, for patients who have serious GI disease, ruxolitinib is an attractive option, at least if they can tolerate the drug.

TARGETED ONCOLOGY: What are the remaining challenges in this space?

Ferrara:The biggest challenge in treating GVHD is to suppress the immune system that is specifically causing the disease. We have drugs that are increasingly specific. Steroids are not specific at all. Steroids decimate the immune system. We want to get to nonsteroidal approaches for this disease. 

TARGETED ONCOLOGY: Where do you see this field headed?

Ferrara:I predict that in the future as we find some of these other approaches that are effective, particularly in steroid-resistant disease, we will bring them forward in clinical trials to treat patients as their primary treatment using this with either a very low dose of steroids or no steroids at all. That is almost certainly going to help accelerate the immune constitution of these patients that is so critical for their long-term health and survival.

Reference:

Jagasia M, Perales M-A, Schroeder MA, et al. Results from REACH1, a single-arm phase 2 study of ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-vs-host disease. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 601.