ONCAlert | Upfront Therapy for mRCC

Next Steps in the Treatment of Acute GVHD

Targeted Oncology
Published Online:12:00 PM, Fri August 30, 2019

Aaron C. Logan, MD, PhD: Our experience with ruxolitinib has been, overall, favorable. We quickly made it our standard salvage agent even prior to its FDA approval. We were using it off-label quite extensively due to its rapid efficacy. The median time to response is just 7 days, so this is an agent that you can employ and quickly see a response for your patient. You know very quickly if they’re not likely to respond.

So we, for a couple of years now, have made this our standard approach for salvage therapy for steroid-refractory acute GVHD [graft-versus-host disease], and until there are any other agents available, I think it’s going to remain our standard.

Ongoing research with ruxolitinib right now includes REACH2, which is a confirmatory study for the REACH1 study that led to the FDA approval of the agent for refractory acute GVHD. This is a randomized study of ruxolitinib versus best available therapy. We’ll have some data in a couple of years from that study to confirm the efficacy of that agent.

REACH3 is a study of ruxolitinib in steroid-refractory or steroid-dependent chronic GVHD, and it’ll be very interesting to see what the efficacy of that agent is. Ultimately, we’ll need to compare ruxolitinib to ibrutinib, which is currently the only FDA-approved agent for steroid-refractory or steroid-dependent chronic GVHD.

As far as other agents, the JAK/STAT pathway is actually a particularly interesting pathway to inhibit. As I mentioned earlier, ruxolitinib, as a JAK1 and JAK2 inhibitor, is associated with significant myelosuppression that leads to cytopenias. So there are some alternative JAK1- or JAK2-specific inhibitors that are being investigated. There’s currently a JAK1-specific inhibitor called itacitinib that’s in phase I and now phase II investigation. It appears to be safe. We don’t know yet whether the efficacy rate is going to be the same as with ruxolitinib. There appears to possibly be a slightly lower incidence of myelosuppression with JAK1-specific inhibition, so it’ll be interesting to see whether a JAK1-specific inhibitor has the same efficacy without the same types of toxicities as ruxolitinib.

As far as other agents that are still moving forward under investigation, 1 agent that appears to be promising is alpha-1 antitrypsin, which has a response rate that’s actually fairly similar to ruxolitinib in the studies that have been done thus far—with the best overall response rate in the 70% range.

What’s unique about alpha-1 antitrypsin is it appears not to be associated with significant cytopenias. So if this is borne out in larger studies, this could be a significant advance, particularly for patients who have vulnerable grafts or engraftments and are at risk for clinically significant cytopenias.

Other investigations that are very interesting are looking at monoclonal antibodies to target either specific cytokines or specific chemokine pathways. One agent that appears to be of interest is vedolizumab, which is an anti-integrin antibody that has been approved for ulcerative colitis and has now been investigated for patients with steroid-refractory gut GVHD. This agent appears to be associated with a favorable response rate in that patient population. The agent would be specific for gut GVHD. It wouldn’t be generally employable for other types of steroid-refractory GVHD. However, there will be other antibodies looking at targeting other specific signaling or chemokine pathways that can inhibit the trafficking of T cells and their stimulation to try and treat steroid-refractory GVHD.

Transcript edited for clarity.

Aaron C. Logan, MD, PhD: Our experience with ruxolitinib has been, overall, favorable. We quickly made it our standard salvage agent even prior to its FDA approval. We were using it off-label quite extensively due to its rapid efficacy. The median time to response is just 7 days, so this is an agent that you can employ and quickly see a response for your patient. You know very quickly if they’re not likely to respond.

So we, for a couple of years now, have made this our standard approach for salvage therapy for steroid-refractory acute GVHD [graft-versus-host disease], and until there are any other agents available, I think it’s going to remain our standard.

Ongoing research with ruxolitinib right now includes REACH2, which is a confirmatory study for the REACH1 study that led to the FDA approval of the agent for refractory acute GVHD. This is a randomized study of ruxolitinib versus best available therapy. We’ll have some data in a couple of years from that study to confirm the efficacy of that agent.

REACH3 is a study of ruxolitinib in steroid-refractory or steroid-dependent chronic GVHD, and it’ll be very interesting to see what the efficacy of that agent is. Ultimately, we’ll need to compare ruxolitinib to ibrutinib, which is currently the only FDA-approved agent for steroid-refractory or steroid-dependent chronic GVHD.

As far as other agents, the JAK/STAT pathway is actually a particularly interesting pathway to inhibit. As I mentioned earlier, ruxolitinib, as a JAK1 and JAK2 inhibitor, is associated with significant myelosuppression that leads to cytopenias. So there are some alternative JAK1- or JAK2-specific inhibitors that are being investigated. There’s currently a JAK1-specific inhibitor called itacitinib that’s in phase I and now phase II investigation. It appears to be safe. We don’t know yet whether the efficacy rate is going to be the same as with ruxolitinib. There appears to possibly be a slightly lower incidence of myelosuppression with JAK1-specific inhibition, so it’ll be interesting to see whether a JAK1-specific inhibitor has the same efficacy without the same types of toxicities as ruxolitinib.

As far as other agents that are still moving forward under investigation, 1 agent that appears to be promising is alpha-1 antitrypsin, which has a response rate that’s actually fairly similar to ruxolitinib in the studies that have been done thus far—with the best overall response rate in the 70% range.

What’s unique about alpha-1 antitrypsin is it appears not to be associated with significant cytopenias. So if this is borne out in larger studies, this could be a significant advance, particularly for patients who have vulnerable grafts or engraftments and are at risk for clinically significant cytopenias.

Other investigations that are very interesting are looking at monoclonal antibodies to target either specific cytokines or specific chemokine pathways. One agent that appears to be of interest is vedolizumab, which is an anti-integrin antibody that has been approved for ulcerative colitis and has now been investigated for patients with steroid-refractory gut GVHD. This agent appears to be associated with a favorable response rate in that patient population. The agent would be specific for gut GVHD. It wouldn’t be generally employable for other types of steroid-refractory GVHD. However, there will be other antibodies looking at targeting other specific signaling or chemokine pathways that can inhibit the trafficking of T cells and their stimulation to try and treat steroid-refractory GVHD.

Transcript edited for clarity.
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