Acute GvHD: Clinical Presentation, Risk Factors and Treatment Options

Transcript:

Corey Cutler, MD, MPH FRCPC: Let’s talk about the presentation of acute graft-vs-host disease [GVHD] and some standard therapeutics. Doris, tell us about the clinical presenting signs of acute graft-vs-host disease.

Doris M. Ponce, MD: Acute GVHD can go from mild to severe symptoms, but it usually affects the skin with a rash that could be mild to an extremely severe, full-body rash; GI [gastrointestinal] symptoms, which could be upper or lower nausea, vomiting, diarrhea; and lower-GI diarrhea. The higher in volume means that it’s more advanced and more severe. Also, there could even be GI obstruction leading from the GI tract and LFTs [liver function tests]—liver affections that can be manifested, like liver dysfunction or hypogammaglobulinemia.

Corey Cutler, MD, MPH, FRCPC: Hannah, we do clinical trials and try to talk to one another about graft-vs-host disease, so it’s important that we speak the same language with the staging and grading of GVHD. Can you tell us about how we can do that and the systems we use?

Hannah K. Choe, MD: We’ve standardized the MAGIC [Mount Sinai Acute GVHD International Consortium] grading system, which assigns a stage to each organ system. Staging is to the percentage of body surface area for the skin: less than 25%, 25% to 50%, greater than 50%, and 50% or more, or generalized erythroderma. Within the GI tract, [we measure] the volume of diarrhea—specifically cutoffs of less than 500 mL per day, or up to 1 L, or up to 1500 mL, or even more than 1500 mL per day. The upper GI is cut or dry, whether you have persistent nausea, vomiting, or anorexia. The liver is based on your bilirubin level. The staging for each these is 2, 2 to 6, above 6, and above 15. You have a composite score of each stage, and that gets assigned a grade. The overall grade gets rated as grade 0 through 4. That grading then determines the likelihood of nonrelapse mortality for the patient, in fact. It’s a composite score based on stages to a grade.

Corey Cutler, MD, MPH, FRCPC: We’ve heard about the symptoms, and we’ve heard about the grading. What about risk assessment, both clinical and biochemical? Tell us about that.

Yi-Bin Chen, MD: With risk assessment, we’ve been motivated to risk assess or risk stratify patients. Many of us feel that the inability to risk stratify patients has led to failure of clinical trials over the last couple of decades. This is a big reason why we hadn’t made much progress. If we’re able to risk stratify patients, it’s better for counseling patients. More important, for clinical trials, it allows you to enroll biologically more similar patients and make some progress.

There are 2 basic systems in play that we use to risk stratify patients with new acute GVHD. One is clinical, which is very straightforward. It’s based on the grading system that Hannah mentioned, and that’s called the Minnesota clinical risk score. The University of Minnesota looked at a large number of patients that they had treated for acute GVHD and how they presented, and they’re able to classify about 14% of their patients as high risk and 86% as standard risk. It’s a pretty simple calculation because you have the patient in front of you, and you’re able to make that classification right away.

The other system for risk stratification is based on noninvasive biomarkers. The most work has been done by MAGIC. Their biomarkers system, which is commercially available, is called the MAP, or MAGIC algorithm probability. It’s based on the measurement of 2 biomarkers, ST2 and REG3⍺, which are injury signals from the GI mucosa. Through a proprietary algorithm, the MAP calculates a risk score at the diagnosis of acute GVHD that can predict for a high or low risk of nonrelapse mortality. Having those 2 systems has allowed us to design interventional clinical trials to say, “Only enroll high risk,” or “Only enroll low risk.” Hopefully, with that, we’re able to make some progress.

Corey Cutler, MD, MPH, FRCPC: When we talk about the treatment and deciding on treatment based on risk, we all think the standard therapy for grades 2 to 4 graft-vs-host disease is intravenous corticosteroids at a dosage of approximately 2 mg/kg per day—with some exceptions—and perhaps dosing down in skin-only disease. There have been some advances in this setting. We all know that steroids are terribly toxic. We all have this love-hate relationship with our steroids. They work rapidly, and they’re generally effective. But they cause tons of toxicity, and patients don’t like using them in the long term. There are at least 2 studies that I’m aware of that look at replacing steroids with novel or different agents, predominantly in lower-risk disease. Doris, tell us about the study that looked at sirolimus in that setting.

Doris M. Ponce, MD: This was a BMT CTN [Blood and Marrow Trials Clinical Trials Network] study, which was developed as collaborative national approach to multicenter studies. In the study, patients were randomized to sirolimus or corticosteroids. Patients had a standard-risk graft-vs-host disease. Topical steroids were allowed. There was a lower amount of patients with lower graft-vs-host disease in this analysis. A majority were affected by skin and/or the upper GI tract. In that analysis, the primary end point was exposure to steroids, and the sirolimus arm had less exposure to systemic corticosteroids compared with the randomized corticosteroid.

The other thing that was very interesting was that overall, the treatment responses weren’t significantly different, which is an important assessment. However, this clinical trial also shows that the sirolimus arm did have some adverse events, like TMA [thrombotic microangiopathy]. Some patients didn’t tolerate treatment as well, and some eventually required steroids. This concept is very novel. It’s customized for standard risk. As a community, we have a lot of interest in looking in this clinical trial design because it opens the door to other options that are steroid-free.

Corey Cutler, MD, MPH, FRCPC: There was 1 additional abstract that we saw presented at ASH [American Society of Hematology Annual Meeting] looking at itacitinib as monotherapy for newly diagnosed acute graft-vs-host disease. Tell us about that 1.

Hannah K. Choe, MD: That looked at patients who had Minnesota standard and an MAP score that was low risk, so AA1, or Ann Arbor Score 1, in patients receiving itacitinib monotherapy for 28 days. If they were having at least a partial response, continuing for another 28 days. That was an alternative to corticosteroids. What we saw from the results of that abstract is that the outcomes were very similar. Patients did very well when not receiving steroids. It wasn’t that they didn’t improve upon the steroids, but the fact that you can avoid steroids is a fantastic option for patients who would otherwise be forced to get high-dose steroids if there’s no other treatment. That’s a very promising study.

Corey Cutler, MD, MPH, FRCPC: Those 2 approaches deal with patients with very low-risk disease.

Transcript edited for clarity.