Clinical Insights on the Future of GVHD Treatment

EP: 1.Patient Profile: A 48-Year-Old Man with Chronic GVHD

EP: 2.Transplant Conditioning Regimens and GVHD Prophylaxis

EP: 3.Overview of GVHD Types and Symptoms

EP: 4.Therapy Options for Patients with Chronic GVHD

EP: 5.Treatments for Steroid-Refractory Chronic GVHD

EP: 6.Second-Line Approaches to Treating GVHD

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EP: 7.Clinical Insights on the Future of GVHD Treatment

Case: A 48-Year-Old Man with Chronic GVHD

• 48-year-old man undergoes myeloablative conditioning followed by matched unrelated donor hematopoietic cell transplant for acute myeloid leukemia w/ tacrolimus + methotrexate as graft versus host disease prophylaxis
  • The donor is a cytomegalovirus seropositive 50-year-old woman with 3 children
• Day +22, acute GvHD of skin emerged, successfully treated with slow steroid taper
• Bone marrow testing performed at 6 months and 12 months post-transplant show AML in complete remission
• 1.5 years post-transplant, new-onset skin changes with hyperpigmentation, lichen-planus and superficial sclerodermatous-like features on lower trunk and lower extremities (not confirmed); 15% BSA involved
• Prednisone initiated, initial dose 0.5 mg/kg/d (max 10 mg/kg per week), then 4-week taper
• After 7 days of prednisone, initial improvement in BSA involvement (now 10% to 15%), with no improvement in range of motion, remained stable thereafter on 0.5 mg/kg every other day

Transcript:

Yi-Bin Chen, MD: This is an exciting time in treatment for graft-vs-host disease. We’ve made a lot of progress recently, and seeing the approval of new agents, there is unprecedented investment in trying to prevent and treat graft-vs-host disease. This has really been exciting. Ultimately, it will translate to improvement for our patients, which is what it’s all about. Starting with graft-vs-host disease prevention, the emergence of post-transplant cyclophosphamide has been a revolution in the field. It was first shown in mismatched donors via haploidentical or mismatched unrelated donors. It has spread and is growing rapidly in popularity in conventionally matched donors. The recent BMT CTN 1703 trial suggests that post-transplant cyclophosphamide-based platform should be the standard in reduced-intensity well-matched donor transplants. Its popularity is growing in the myeloablative setting, where we don’t have a prospective trial showing it should be the standard, but many centers have adopted it and there are more trials to come.

The approval of abatacept [Orencia] in unrelated transplant is also a cool story. It remains to be seen where that’s going to fit into prophylaxis. Going forward, there are more avenues in prophylaxis that we’re exploring. Some interesting findings were presented from results of the phase 3 study using the monoclonal antibody vedolizumab, targeting gut lymphocyte trafficking at the recent Center for International Blood & Marrow Transplant Research Tandem Meetings. This showed that it had a benefit when added to standard calcineurin inhibitor–based prophylaxis. There’s an ongoing phase 3 trial using the Orca-T platform, which is a proprietary cell-sorting technology—graft engineering to prevent graft-vs-host disease. There’s a lot of movement in the field. Many of us are thrilled with the progress post-transplant cyclophosphamide has brought to our field. But we’d also admit that we shouldn’t be happy with where we are. Post-transplant cyclophosphamide can probably use a little fine-tuning in terms of the dose of cyclophosphamide and pairing it with additional agents to optimize outcomes.

Moving forward, there are trials trying to specifically prevent chronic graft-vs-host disease. This has included the agents taken after transplant or in a high-risk population to prevent chronic graft-vs-host disease. This includes anti–B-cell agents. There are ongoing discussions about using these novel agents for chronic graft-vs-host disease, whether it’s belumosudil or ruxolitinib, to incorporate prophylactic strategies as well. The next few years are going to be super-exciting in prevention, and we’re going to see a lot of progress.

In terms of treatment, if you look at acute graft-vs-host disease, the vast majority of the attention appropriately has been paid to lower–GI [gastrointestinal] manifestations. We’ve realized that treating acute graft-vs-host disease as 1 disease is probably not the right way to do it. Moving forward with the risk-stratified trials has been a priority in the field. That’s happening and great to see. For high-risk patients, whether they’re defined by clinical manifestations or biomarkers, the trials are ongoing. This generally involves steroids plus agent X or something like that.

For low-risk patients, stratified by whichever system, there’s a thought into starting at a lower dose of steroids, tapering faster, using another agent, or not using steroids at all. There have been a couple of trials done for low-risk patients. The BMT CTN [Blood & Marrow Transplant Clinical Trials Network] did a trial with sirolimus [Rapamune]. MAGIC [Mount Sinai Acute GVHD International Consortium] used itacitinib, the JAK1 inhibitor, showing the feasibility of such trials. This type of stratification is the key to figuring out how we move forward.

Treatment has started to move away from cumulative immunosuppression. In acute graft-vs-host disease, given all the attention to the lower GI tract, we realized how important preservation of intestinal stem cells is to allow organ healing. This whole field, or these agents geared toward organ resiliency or stem cell sparing, is super-refreshing. The ongoing trials using IL-22, GLP-2, or RIP1 kinase to spare the stem cell niche is an exciting way moving forward. We need to see the outcomes of these trials.

Lastly, for acute graft-vs-host disease, in thinking about the microbiome and how that affects or can modify the outcome, and using interventions such as fecal microbiota transplantation, those trials are ongoing as well. For chronic graft-vs-host disease, the themes are the same. We’re moving away from cumulative immunosuppression and focusing on specific pathways that are less immunosuppressive and have less off-target toxicity, and we’ve already seen approvals in the 3 agents doing that, and we’re thinking about how we can do that more. Axatilimab has just completed accrual in its pivotal study, which is targeting activating the macrophages that are thought to be active in the fibrosis cascade, along the themes of belumosudil. We look forward to the analysis of those results. Many of us participate in that trial and are excited for that agent.

The theme of biomarkers is much more mature in acute graft-vs-host disease, given that they’re commercially available. These are biomarkers of mucosal damage—REG3-⍺ and ST2—that have much evidence showing the ability to stratify patients, so we’ve allowed those risk-stratify trials based on biomarkers. We need those for chronic graft-vs-host disease. They’re a lot more difficult because some of us don’t have the sample stored and patients are so much more heterogeneous. Continued investigation into systems to risk stratify patients for chronic graft-vs-host disease will allow us to conduct the correct trials. All of us would love chronic graft-vs-host disease trials that don’t use steroids. We’d love to see these agents that are approved used earlier in therapy without steroids and see the response rates. We also want to use them in combination and help the ability to not need steroids. It’s a super-exciting time with the trials I’ve mentioned. Although the directions are certainly not all inclusive, they are some of the ones that I’ll be paying attention to in the next few years.

Transcript edited for clarity.