Unmet Needs Remain in GVHD, But Novel Approaches on Horizon

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].

For patients with chronic GVHD, there are many more supportive care measures available. We do talk about local care of individually affected organs, such as topical care of the eye, the mouth, or skin, and the gastrointestinal tract. These are all extraordinarily important, and some of these local measures for chronic GVHD treatment are just as important, if not more important, than the systemic therapies we use to treat these patients.

What types of preventative strategies are in place for GVHD?

Part of the big issue in GVHD is prevention. That is a topic we have not spent a lot of time on, but there are more and more novel preventative GVHD research regimens that are out there. There are strategies that are looking at ways to manipulate the stem cell graft, take out specific T-cell fractions, or modulate the graft to prevent GVHD.

There is also a number of posttransplant medical interventions we can take. The posttransplant cyclophosphamide regimen is becoming very important. In addition, we have the use of other immunosuppressive agents, such as abatacept (Orencia), which is a costimulatory blockade agent that can help prevent GVHD.

What additional challenges in GVHD still remain?

The main challenges are early identification of patients who are not going to do well with corticosteroids, understanding which patients require augmented therapy upfront, and which patients can actually receive de-escalated therapy. We now know we can treat individuals with lower-risk acute GVHD with sirolimus (Rapamune) alone, based on a recent presentation from the Blood and Marrow Transplant Clinical Trials Network.

We have developed biomarkers for acute GVHD. They are less developed for chronic GVHD, but the acute GVHD biomarkers might be helpful in predicting which patients are going to require escalated therapy, which patients will ultimately respond to corticosteroids, and which patients are going to require augmented therapy early on.

The key takeaway is that for a field that had absolutely no drugs approved 3 years ago, we now have 2 drugs approved with a third that is likely to be approved in the next 12 to 18 months. We have made significant advances.

We have yet to see the readout of some large randomized phase III trials, which certainly could change the face of GVHD. We have trials looking at initial therapy for patients with chronic GVHD, which will read out very soon testing ibrutinib, and that is going to be very important. We also have a number of second- and third-line therapies that are going to come on over the next few years. The goal here is we will make transplant much safer by improving GVHD outcomes overall.

Cutler CS, Lee S, Arai S, et al. Interim analysis of KD025-213: a phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025 in subjects with chronic graft versus host disease (cGVHD) after at least 2 prior lines of systemic therapy (The ROCKstar study; NCT03640481). Presented at: 2020 Transplant and Cellular Therapies Meeting; February 19-23, 2020; Orlando, FL. Abstract LBA2. bit.ly/2SQF8Os.

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