Mark A. Schroeder, MD, discusses emerging therapeutic strategies for patients with acute GVHD.
Mark A. Schroeder, MD
Approved and emerging therapies are altering the treatment landscape for patients with acute graft-versus-host disease (GVHD), according to Mark A. Schroeder, MD.
The FDA approved ruxolitinib (Jakafi) in May 2019 for the treatment of adult and pediatric patients ≥12 years of age with steroid-refractory acute GVHD. The approval was based on findings from the phase 2 REACH1 trial, which demonstrated that the combination of ruxolitinib with corticosteroids elicited a 57% overall response rate at day 28 in patients with steroid-refractory acute GVHD, with a complete response rate of 31%.
"There is a lot of investment in therapies for GVHD which is great for patients. If we can treat this major cause of mortality after transplant, we can improve outcomes for patients," said Schroeder. "We have a drug now that is FDA approved for the treatment of GVHD and still, 40% of patients are not responding to that therapy so there is a lot to improve upon. Improvements might come by moving these therapies up sooner in the treatment line or they might come from combining therapies."
In an interview with OncLive, Schroeder, an associate professor at the Washington University School of Medicine in St. Louis, discussed emerging therapeutic strategies for patients with acute GVHD.
OncLive: What is the prognosis like for acute GVHD?
Schroeder: Acute GVHD effects about half of all patients who undergo allogeneic stem cell transplant. The outlook for patients who develop acute GVHD is not good, especially if they develop steroid-refractory acute GVHD. In fact, 80% of patients who develop steroid-refractory acute GVHD will die of the disease within 6 months of development.
However, there are new therapies for acute GVHD; JAK inhibitors, α-1 antitrypsin, and a novel agonist antibody called IL-22. JAK inhibitor therapy works by blocking cytokines which are essential for stimulating GVHD response. JAK stat signaling is critical for immune cell development and by blocking this with a JAK inhibitor, such as ruxolitinib or itacitinib, you can block these essential signals which are critical for the proliferation of T cells or development of T-cell subsets that lead to suppression.
A critical cytokine called interferon-gamma signals through JAK 1/2 and by blocking JAK 1/2 you can abrogate GVHD, prevent T cells from trafficking to the organs that are involved with GVHD, such as the gut, and effect other sites of GVHD. Blocking interferon gamma or other cytokines decreases inflammatory milieu of GVHD and effects the presentation of antigens in the stimulation of T cell response. Recently, other groups have shown that by blocking interferon-gamma signaling, specifically in the gut, you can decrease damage to essential cells that regenerate the gut—intestinal stem cells.
The other aspect was α-1 antitrypsin, which works a little bit differently than JAK inhibition. It works more upstream in decreasing the inflammatory milieu in the gut; it is a serine protease inhibitor, so it blocks protease produced by cells like neutrophils, which leads to chronic inflammation. Inflammatory cytokines are then reduced [allowing you to] alter the number in the types of cells that are present within the gut or target organs of GVHD. The drug increases regulatory T cells, induces tolerogenic dendritic cells, and is in clinical development. In fact, a large phase 3 study is in development for α-1 antitrypsin where they are going to test α-1 antitrypsin for the initial therapy for GVHD.
The third therapy is an IL-22 agonist. This drug is a novel homodimer of IL-22 that is conjugated in the immunoglobulin and acts to stimulate the IL-22 receptor which is on epithelial cells that line the organs, such as the gut or lungs. By stimulating IL-22, which is on intestinal stem cells, you can promote intestinal regeneration. The concept behind the study is to give IL-22 to stimulate regeneration of the gut after it has been damaged by GVHD. It is in development for treatment-naïve, lower gastrointestinal GVHD with promising results.
JAK inhibition is in advanced clinical development as well. There was a phase 2 study that led to its FDA approval for steroid-refractory GVHD called the REACH1 study. There is also a number of other studies of the JAK1 selective inhibitor, itacitinib, which is in advanced clinical development for upfront treatment-naïve therapy for GVHD and prophylaxis setting.
What considerations are made for the appropriate treatment of each patient?
There are a number of therapies. The only FDA approved therapy for GVHD is ruxolitinib but across the board, for other therapies that could be used initially for steroid-refractory GVHD, it is really dependent on the institution, investigator, how the patient is presenting and if they can tolerate oral medicines or intravenous medications; JAK inhibitors are orally dosed. There are other avenues for decreasing T-cell proliferation where the damage induced by GVHD can be given intravenously.
There is not an agreed-upon standard for GVHD. But, ruxolitinib is commonly what we are choosing for patients, with response rates of 55% at day 28 reported in the phase 2 study.
What has been your experience with ruxolitinib?
We are the first to show in a mouse model of GVHD ruxolitinib blocked interferon-gamma signaling and altered T-cell trafficking. We helped to initially design the phase 1 study for the JAK1 selective drug itacitinib. That has been completed and has been submitted for publication. The response rates in that phase 1 study were around 70% for patients with steroid-refractory and -naïve GVHD.
The phase 3 randomized study for upfront treatment with the JAK1 selective inhibitor itacitinib did not meet its primary endpoint of day 28 overall response, but the response rates in both the itacitinib and placebo group were high. Based on the REACH1 study for the use of ruxolitinib for steroid-refractory GVHD, that has been a standard approach that we will institute for someone who develops that disease. The standard remains for upfront treatment that steroids should remain the standard for initial therapy for GVHD.
FDA Approves Jakafi (ruxolitinib) for the Treatment of Patients with Acute Graft-Versus-Host Disease. Incyte. Published May 24, 2019. https://bit.ly/2WiRktX?rel=0. Accessed April 22, 2020.