A Progress Report on Chronic GVHD. The Grades Are Not So Great

With the important exception of trials that have established post-transplant cyclophosphamide (PTCy) as a way to prevent chronic graft-vs-host disease (GVHD), most areas targeted for clinical trial research are lagging behind goals set in 2020, according to a group of experts convened to assess the progress.

“Overall, modest progress has been made on most initiatives,” says the abstract of the group’s findings published last month in the journal Transplantation and Cellular Therapy. The conclusion of the report notes that more effective prevention of chronic GVHD has made it more difficult to study because of the lower incidence and fewer patients. “Intelligent use of the available patient population and application of cutting-edge investigative techniques to highly informative biologic samples is even more important,” the conclusion.

In 2020, the National Institutes of Health convened a consensus development project on criteria for clinical trials for chronic GVHD with an eye toward identifying gaps in understanding, prevention and treatment. In October 2024, as part of the 7th International Chronic Graft-versus-Host Symposium in Vancouver, leaders of the working groups associated with the 2020 consensus conference made presentations about the accomplishments in their areas. They were asked to score the progress as red (no significant progress), yellow (some progress) or green (substantial progress). They gave the red, yellow or green grades for 20 areas. All received yellow or red grades with the exception of clinical trials to prevent moderate to severe chronic GVHD, which yielded the evidence supporting PTCy.

Here is a brief rundown of some of the working groups’ reports.

Etiology and prevention

Two large prospective randomized trials have shown that 7% of those who received PTCy along with tacrolimus and mycophenolate mofetil developed moderate to severe chronic GVHD compared with 17% who received the standard tacrolimus-methotrexate prophylaxis, this working group reported. The group mentioned two other emerging therapies for preventing chronic GVHD: the ORCA-T platform and the addition of ruxolitinib to calcineurin inhibitor and methotrexate. The ORCA-T platform utilizes infusions of hematopoietic stem cells with purified regulatory T cells, which are then followed by conventional T cells with or without tacrolimus. The working group mentions research linking the prevention of chronic GVHD to higher relapse rates, but there is evidence pointing in the opposite direction. “While most studies of these newer approaches have not shown higher rates of relapse, longer follow-up of prospective randomized studies with large patient numbers will be critical to fully evaluate the relapse risk in the context of newer chronic GVHD prevention strategies,” the group noted.

Clinical implementation and early diagnosis

Recognition of early signs, symptoms and other diagnostic determinants of GVHD that are reliably associated with highly morbid forms of the condition would allow for earlier effective treatment, preventing morbidity and premature mortality, this working group said. The group mentioned education imperatives, a GVHD app that is embedded in the American Society of Transplant and Cellular Therapy (ASTCT) handheld application, and a hybrid model being tested at several sites in Europe that combines standard physician assessments and electronic health-facilitated integrated care. Routine use of pulmonary function tests is part of ASTCT guidelines at the time that chronic GVHD is diagnosed, but adherence is poor, said the working group. The group also mentioned the importance of routine eye exams and machine learning to identify skin conditions associated with GVHD. The group recommended identifying “metrics of success” for the implementation of community-based efforts in the early identification and accurate diagnosis of chronic GVHD and studies that would compare the staging of chronic GVHD before and after the implementation of educational interventions.

Preemptive therapy

Preemptive therapy is defined as an intervention delivered after the stem cell transplant that targets those with a high chance of developing chronic GVHD. This working group noted the distinction between preemptive therapy and universal prophylaxis and between therapies when chronic GVHD has occurred. Preemptive therapy may hinge on identifying biomarkers, and the working group said progress has been made in that regard, but none of the biomarkers have the predictive value needed to guide clinical trials. The group mentions as alternatives subclinical indicators of final common pathways in blood — or focusing on tissues rather than blood. Moreover, the group said that until more progress is evident, preemptive trials will need to be limited to “very safe and well-tolerated agents.”

Treatment

Treatment choices have increased for patients with chronic GVHD, but the understanding of the interactions between clinical manifestations of chronic GVHD and the biological impact of therapies is limited, this working group said. The group called for “detailed correlative scientific studies” to be incorporated into prospective clinical trials to evaluate the biological effects of systemic therapeutics. Identifying biological correlates could redefine treatment paradigms, the group said, leading to personalized approaches “in which a patient’s biomarker signature could be used to select therapies. The group said the prevention of chronic GVHD with PTCy and other interventions will put a premium on efficiency.

“This will also mean that single- or (small) multicenter biology-based trials will be more challenging and costly to perform successfully in the future,” the working group said. “The development of alternative trial designs such as platform trials, master protocols, use of common control groups for comparison with novel agents or digital twins for control populations is highly recommended.”