Unmet Needs Remain in GVHD, But Novel Approaches on Horizon

Danielle Ternyila
Published: Sunday, Mar 01, 2020

Corey S. Cutler, MD, MPH, of the Dana-Farber Cancer Institute

Corey S. Cutler, MD, MPH

Later-line therapies are one of several unmet needs for patients with acute or chronic graft-versus-host-disease (GVHD), but novel agents and other research efforts are emerging, explained Corey S. Cutler, MD, MPH.

In the frontline setting, the standard of care for both patients with acute and chronic GVHD remains corticosteroids. While this is a promising regimen, not all patients respond or may become refractory. In the second-line setting, patients with acute GVHD can be treated with the JAK1/2 inhibitor ruxolitinib (Jakafi).

Following failure on ruxolitinib, there is no real standard of care, requiring research efforts to improve outcomes for these patients.

Patients with chronic GVHD can be treated with ibrutinib (Imbruvica), which is FDA-approved for patients with steroid-refractory chronic GVHD. However, beyond the BTK inhibitor, there is no approved third-line option.

“We also have a number of second- and third-line therapies [for chronic GVHD] that are going to come on over the next few years,” said Cutler. “The goal here is we will make transplant much safer by improving GVHD outcomes overall.”

For example, the selective ROCK2 inhibitor KD025 was granted breakthrough therapy designation by the FDA in October 2018 for the treatment of adults with chronic GVHD after failure of ≥2 lines of systemic therapy. In interim findings of the ongoing phase II ROCKstar trial, KD025 elicited clinical responses in approximately two-thirds of patients with chronic GVHD, which included 3 complete responses.

Additional unmet needs that require a deeper focus include preventative strategies and determining upfront which patients will not respond to corticosteroids, Cutler explained.

In an interview with OncLive, Cutler, medical director of the Stem Cell Transplant Program, Dana-Farber Cancer Institute, discussed how physicians can optimize treatment management in patients with both acute and chronic GVHD.

OncLive: What are the current available treatment options for patients with acute GVHD?

Cutler: Acute GVHD is treated now initially with corticosteroids. Patients have about a 50% to 75% response rate to steroids, and those individuals who are refractory have a few options. Most recently, ruxolitinib was approved by the FDA for patients with steroid-refractory acute GVHD; it demonstrated response rates of approximately 55% in the REACH1 study. The randomized REACH2 trial has also been reported to be positive, although we have not yet seen those data.

When we move beyond ruxolitinib, there are a number of other therapies that are under current investigation. We hope to have a few of these approved in the next few years, but right now there is no real standard of care beyond corticosteroids.

What are the options for patients with chronic GVHD?

Corticosteroids, again, remain the mainstay of therapy in chronic GVHD. When patients become resistant to steroids, which is at least 50% to 60% of the patients within the first year after initiating therapy, there is 1 drug that is FDA-approved. Ibrutinib is approved for steroid-refractory chronic GVHD, based on the relatively impressive response rate in the 60% range that was reported in a small open-label phase II clinical trial.

Beyond ibrutinib, there is no approved third-line therapy. The most promising agent we will likely hear about in the next few years is KD025, which is a ROCK2 inhibitor. This trial recently presented data in the randomized phase II setting, demonstrating responses in approximately 65% of heavily pretreated patients. We are anxiously looking forward to the final analysis of that study, and hopefully there is a march towards the FDA following that.

How can management of this disease be optimized??

In terms of optimizing management for patients with acute GVHD, we do have to pay a lot of attention to the supportive care measures that go along with the treatment of patients with severe acute GVHD, such as bowel rest, total parenteral nutrition, or antibiotics for prevention of infection; these are all very important things. For skincare, we sometimes lean on our dermatology colleagues or even the burn unit for those who are severely affected. We can ask our hepatology colleagues for help in GVHD [cases in which the liver is affected].

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