ONCAlert | Upfront Therapy for mRCC

Future Therapies and Unmet Needs for GVHD

Targeted Oncology
Published Online:1:40 PM, Tue January 21, 2020

Yi-Bin A. Chen, MD: As we move into the next decade of graft-vs-host disease management, it’s become apparent that global systemic immunosuppression is likely not the best way to proceed. All of us have started to look at other pathways to prevent and treat chronic graft-vs-host disease, in hopes of mitigating the risk of that complication while, at the same time, preserving the immune system of our recipients.

A few other therapies have been studied recently and are worth mentioning. Proteasome inhibitors such as bortezomib showed promising results in single-center studies for graft-vs-host disease prevention. When taken to a large study conducted by the BMT CTN [Blood and Marrow Transplant Clinical Trials Network], there was no difference between the comparison of tacrolimus and methotrexate.

We at Massachusetts General Hospital have done a lot of work with the monoclonal antibody vedolizumab. This agent is approved for the treatment of inflammatory bowel disease and modulates lymphocyte trafficking, specifically to the intestine. There have been several anecdotal reports showing success in using this agent for the treatment of steroid-refractory intestinal graft-vs-host disease, which is possibly the most difficult subset of our patients to treat. Last year we published our results from a phase I study showing safety of combining vedolizumab with tacrolimus-methotrexate for graft-vs-host disease prevention. This has been taken to an ongoing, international phase III study to investigate its role in graft-vs-host disease prevention.

Another agent that merits mentioning is alpha-1-antitrypsin. Alpha-1-antitrypsin is a naturally occurring protease inhibitor that generally causes modulation of the inflammatory response when given systemically. There are 2 reports that have shown its success in the treatment of steroid-refractory acute graft-vs-host disease. It is now being studied in larger studies—1 for graft-vs-host disease prevention and 2 national studies that will be studying it for the up-front treatment of graft-vs-host disease as well.

The last agent I should mention is KD025. This is an agent developed by Kadmon [Holdings, Inc] that is a ROCK kinase inhibitor, and it has recently shown very compelling results for the treatment of steroid-refractory chronic graft-vs-host disease. We anticipate that this agent may be approved in the near future for our patients.

In terms of unmet needs, graft-vs-host disease remains quite difficult to treat. For acute graft-vs-host disease, a subset that is the most refractory and frustrating are those with acute intestinal graft-vs-host disease. This subset of patients is what all newer therapies should focus on treating. For chronic graft-vs-host disease, the 2 subsets of patients that are quite frustrating are those with sclerodermatous graft-vs-host disease and those with pulmonary involvement, more commonly called bronchiolitis obliterans syndrome.

Newer therapies for chronic graft-vs-host disease may have to become organ specific as we move forward to try to treat these difficult subsets of patients. I think the challenges remain regarding how to effectively conduct trials in a disease that’s very heterogeneous. Trials for graft-vs-host disease have suffered because of the enrollment of patients who are probably biologically distinct; thus, any effect from a specific agent might have been lost in the noise of that heterogeneity.

Also, all our patients who develop graft-vs-host disease after transplant have many competing risks, and oftentimes, these competing risks blur the picture when trying to assess the safety or activity of any newer agents. Better ways are to risk stratify patients for trials, or develop newer end points that are more accurate and represent what we’re really trying to progress to, are surely needed.

Transcript edited for clarity.

Yi-Bin A. Chen, MD: As we move into the next decade of graft-vs-host disease management, it’s become apparent that global systemic immunosuppression is likely not the best way to proceed. All of us have started to look at other pathways to prevent and treat chronic graft-vs-host disease, in hopes of mitigating the risk of that complication while, at the same time, preserving the immune system of our recipients.

A few other therapies have been studied recently and are worth mentioning. Proteasome inhibitors such as bortezomib showed promising results in single-center studies for graft-vs-host disease prevention. When taken to a large study conducted by the BMT CTN [Blood and Marrow Transplant Clinical Trials Network], there was no difference between the comparison of tacrolimus and methotrexate.

We at Massachusetts General Hospital have done a lot of work with the monoclonal antibody vedolizumab. This agent is approved for the treatment of inflammatory bowel disease and modulates lymphocyte trafficking, specifically to the intestine. There have been several anecdotal reports showing success in using this agent for the treatment of steroid-refractory intestinal graft-vs-host disease, which is possibly the most difficult subset of our patients to treat. Last year we published our results from a phase I study showing safety of combining vedolizumab with tacrolimus-methotrexate for graft-vs-host disease prevention. This has been taken to an ongoing, international phase III study to investigate its role in graft-vs-host disease prevention.

Another agent that merits mentioning is alpha-1-antitrypsin. Alpha-1-antitrypsin is a naturally occurring protease inhibitor that generally causes modulation of the inflammatory response when given systemically. There are 2 reports that have shown its success in the treatment of steroid-refractory acute graft-vs-host disease. It is now being studied in larger studies—1 for graft-vs-host disease prevention and 2 national studies that will be studying it for the up-front treatment of graft-vs-host disease as well.

The last agent I should mention is KD025. This is an agent developed by Kadmon [Holdings, Inc] that is a ROCK kinase inhibitor, and it has recently shown very compelling results for the treatment of steroid-refractory chronic graft-vs-host disease. We anticipate that this agent may be approved in the near future for our patients.

In terms of unmet needs, graft-vs-host disease remains quite difficult to treat. For acute graft-vs-host disease, a subset that is the most refractory and frustrating are those with acute intestinal graft-vs-host disease. This subset of patients is what all newer therapies should focus on treating. For chronic graft-vs-host disease, the 2 subsets of patients that are quite frustrating are those with sclerodermatous graft-vs-host disease and those with pulmonary involvement, more commonly called bronchiolitis obliterans syndrome.

Newer therapies for chronic graft-vs-host disease may have to become organ specific as we move forward to try to treat these difficult subsets of patients. I think the challenges remain regarding how to effectively conduct trials in a disease that’s very heterogeneous. Trials for graft-vs-host disease have suffered because of the enrollment of patients who are probably biologically distinct; thus, any effect from a specific agent might have been lost in the noise of that heterogeneity.

Also, all our patients who develop graft-vs-host disease after transplant have many competing risks, and oftentimes, these competing risks blur the picture when trying to assess the safety or activity of any newer agents. Better ways are to risk stratify patients for trials, or develop newer end points that are more accurate and represent what we’re really trying to progress to, are surely needed.

Transcript edited for clarity.
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