New Chronic GVHD Treatments Show Promise, but Long-Term Outcomes Are Not Well Understood

First-line treatment of moderate to severe chronic graft-versus-host disease is often steroids, which are associated with substantial morbidity. However, the FDA has recently approved novel therapies that are more targeted.

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Novel agents to treat chronic graft-versus-host disease (GVHD) have reduced the overall steroid burden and improved chronic GVHD control, while imparting fewer long-term side effects, according to a retrospective, single center study from Tel Aviv Sourasky Medical Center.

The results were published in the journal Cancers. For patients with chronic GVHD who have steroid-refractory disease, the one-year overall survival rate is approximately 80%, the authors noted. The FDA has approved four drugs for chronic GVHD: ibrutinib in 2017, ruxolitinib in 2021, belumosudil in 2021 and most recently, axatilimab in August 2024.

“These medications were approved based on studies showing improvement in symptom control with an acceptable toxicity profile, yet, to date, no survival benefit has been shown,” they explained. While steroids suppress the immune response and reduce inflammation “in a non-specific fashion,” these new drugs target specific pathways associated with chronic GVHD.

Steroids in the first-line treatment is the standard practice to treat moderate to severe chronic GVHD at many centers; however, there is substantial morbidity associated with this practice.

“While, in general, the safety profile of these novel FDA-approved medications appears to be better compared to prolonged steroid therapy, currently there is a lack of data regarding the impact of these novel agents on non-GVHD secondary outcomes,” the researchers wrote.

They retrospectively analyzed all patients over the age of 18 years with chronic GVHD after their first bone marrow transplant to understand advances in the treatment pattern and the impact on long-term follow-up end points in patients with steroid-refractory chronic GVHD.

A total of 91 patients who received a transplant between 2012 and 2020 were included and divided into three treatment periods: 2012-2014 (Group 1, 15 patients), 2015-2017 (Group 2, 39 patients) and 2018-2020 (Group 3, 37 patients). Acute myeloid leukemia was the most common reason for a transplant. Group 1 more commonly received myeloablative preparative regimen (87%) with the use declining thereafter (62% in Group 2 and 41% in Group 3).

Groups 2 and 3 also had a higher percentage of older patients and unrelated donor (URD) grafts. The mean age of patients in Group 1 was 43 years compared with 45 years in Group 2 and 57 years in Group 3. Groups 2 and 3 also had a significantly lower mean cumulative steroid dose compared with Group 1 and they also had a lower proportion of cumulative steroid dose to total chronic GVHD treatment days.

A majority (62%) of patients in Group 1 had osteopenia and osteoporosis diagnoses compared with only 33% in Group 2 and 16% in Group 3. Patients in groups 2 and 3 also had better glycemic control and a lower incidence of cardiovascular events and mean number of hospitalizations per patient.

Patients in groups 2 and 3 also had higher rates of employment reintegration (56% in Group 2 and 43% in Group 3 vs 20% in Group 1), and reintegration also happened faster for groups 2 and 3. At 24 months, none of the patients in Group 1 were free of immunosuppressive therapy (IST), compared with 31% in Group 2 and 36% of patients in Group 3. At 36 months, 20% of patients in Group 1, 34% in Group 2, and 47% in Group 3 were IST-free.

The three groups had similar three-year relapse incidence, non-relapse mortality and overall survival rates. There were also no differences between the groups regarding rates of depression.

The nature of the study (single center and retrospective) is one limitation that the authors noted because of the associated biases and difficulties attributing changes in treatment patterns and secondary outcomes to a single factor. In addition, the sample size was relatively small, highlighting the need for larger prospective trials with a longer follow-up period to draw long-term conclusions.

“We hypothesize that the use of novel IST agents with a safer side-effect profile and greater [long-term] follow-up and intervention can lead to better quality of life for these patients, which may ultimately result in improved overall survival,” the authors concluded.