Emerging Treatment Strategies for Chronic GVHD

EP: 1.Background on Graft-vs-Host Disease: Risk Factors and Prevention

EP: 2.Acute vs Chronic GVHD: Identification and Stratification

EP: 3.Frontline Treatment Options for Chronic GVHD

EP: 4.Defining Steroid-Refractory and Steroid-Dependent GVHD

EP: 5.Identifying and Managing Steroid-Refractory Chronic GVHD

EP: 6.Ibrutinib’s Approval and Use in Chronic Graft-Versus-Host Disease

EP: 7.Belumosudil’s Approval and Use in Chronic Graft-Vs-Host Disease

EP: 8.Mechanism of Action of Ruxolitinib

EP: 9.REACH3 Trial: Approval of Ruxolitinib in Chronic GVHD

EP: 10.Chronic GVHD: Real-World Use of Ruxolitinib

EP: 11.Selecting Second-Line Therapy for Chronic GVHD

EP: 12.Chronic GVHD: Novel Treatment Approaches With Approved Agents

EP: 13.Novel Targeted Agents in GVHD: The FLIGHT and AGAVE-201 Trials

EP: 14.HSCT Approaches to Retain GVL While Preventing GVHD

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EP: 15.Emerging Treatment Strategies for Chronic GVHD

Transcript:

Yi-Bin Chen, MD: As we conduct more trials for the treatment of chronic graft-versus-host disease [GVHD], by the time it's diagnosed there's a certain amount of fixed organ damage, and that's what I tell my patients. When I see them, I say, I don't have the expectation that we're going to get back to fully normal at this point, but there's a percentage of your symptoms that are reversible, and we're going to work on that, but there's a percentage that's fixed organ damage that we're not able to reverse. When I see a patient, I cannot predict what percentage is what, and I'm wrong when I try, but there are patients who are able to get almost complete responses and others who get almost no responses. Part of that is probably the underlying biology and heterogeneity disease, and part of that is probably because we don't have the optimal agents or treatments. If you look at the trials that we hail over the last few years that got approval, of ibrutinib, belumosudil, and ruxolitinib, if you look at the overall responses, the majority of those are partial responses; there's very few complete responses seen in this disease. I think that illustrates the whole story.

How do we fix that? One way is to think, well, we just need better treatments, another way is to say, by the time that patients present and we diagnose it, it's probably too late. So, do we educate our patients better? Do we monitor them differently? Can we develop biomarkers that we can read along the way in transplant to better risk-stratify patients, and then do preemptive interventions before chronic graft versus hosts develops? That's a huge area that people are trying to figure out. It takes a lot of collaboration, and a lot of blood samples to figure out if there's something in those first few months after transplant that can tell us, who's going to develop chronic GVHD. Once you can accurately identify those patients, can you have an intervention that can modify those outcomes? And then, should we not worry about this and try and prevent it all together? The research in graft-versus-host disease prevention has had a long story over the last few decades, and we're just starting to do large trials that are focused on the prevention of chronic, because it used to be focused on preventing acute due to how dramatic it was and the early mortality we had. As we've improved upon survival of acute, we can now shift and think about prevention of chronic. We used to think that anything that prevented acute would prevent chronic and that's because acute graft versus host disease is the biggest clinical risk factor to develop chronic, but the newer agents that are targeting specific pathways for acute may not in do that. We must figure out if that is true.

In addition to the novel agents that we're studying for the prevention of chronic, there are newer methods of graft manipulation. We've had a long series of doing T-cells depletion based on either positive selection or negative selection. T-cell depletion is not done at many institutions, partly because the laboratory resources needed and the expertise, but the newer methods of being able to cell sort at a fast and efficient rate, and being able to identify more specific populations, may lead to what we want, which is the preservation of graft-versus-leukemia or graft-versus-malignancy, and the prevention of both acute and chronic graft-versus-host disease. That all remains to be seen. There's a lot of avenues going on in terms of studying those novel forms of manipulation, as well as novel agents. We just had an approval in graft-versus-host disease prevention and unrelated donors, and we look forward to the other agents that are being studied as well. We talked the achievement of ruxolitinib instead of refractory chronic, which has a lot of data that says it would work better earlier on. Thinking about using ruxolitinib as initial therapy or even preemptive or prophylactic therapy, is certainly on our mind as we move forward.

Corey Cutler, MD, MPH, FRCPC: There are many other interesting clinical compounds out there that are being tested, and I think we're going to see the approval of one or more additional agents in the coming years, we'll go from 0 to 4 or 5 potential therapeutic agents in 5 years. That's a tremendous progress for our field. Eventually, we are going to figure out firm biomarkers that will point to pathways to target in individual patients, this will be personalized medicine in chronic GvHD. That is coming. We're doing those studies right now by collecting large data sets and large numbers of samples from patients to eventually go back and analyze for informative biomarkers and pathway analysis. That's the future in chronic GVHD, a personalized approach, finding the right drug initially for the patient to prevent the long-term sequelae of chronic GVHD, prevent chronic steroid toxicity, and to get more patients into complete and durable remissions with their chronic GVHD.

Transcript edited for clarity.