Vedolizumab may help prevent lower GI acute GVHD after unrelated stem cell transplant
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Vedolizumab showed greater efficacy than placebo when added to standard prophylaxis for prevention of lower gastrointestinal acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, according to a study.
The initial findings of the GRAPHITE trial, presented at 2023 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, also showed vedolizumab (Entyvio, Takeda) had a safety profile similar to that of placebo.
Background
Grade 2 to grade 4 acute GVHD is common after allogeneic HSCT despite routine prophylaxis, Yi-Bin Chen, MD, director of the hematopoietic cell transplant and cellular therapy program at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, said during a presentation.
Vedolizumab, a gut-selective anti-lymphocyte trafficking antibody approved to treat inflammatory bowel disease, has been studied for treatment of refractory acute GVHD with mixed results, Chen said. It appeared safe and well-tolerated in a phase 1b study for prevention of acute GVHD among adults who received allogeneic HSCT.
The GRAPHITE study examined the safety and efficacy of vedolizumab vs. placebo for intestinal acute GVHD prevention.
Methodology
The study, conducted at 94 centers globally, included 333 patients undergoing first allogeneic HSCT from unrelated donors for treatment of hematologic malignancies. Researchers randomly assigned patients to 300 mg vedolizumab (n = 168) or placebo (n = 165) via IV on the day before and days 13, 41, 69, 97, 125 and 153 after transplant. All patients received standard-of-care GVHD prophylaxis with a calcineurin inhibitor and methotrexate or mycophenolate mofetil.
Lower GI acute GVHD-free survival analyzed though day 180 after transplant served as the primary endpoint. Researchers followed patients for 1 year.
The full analysis set includes 333 patients (median age, 55 years) who underwent transplant and received at least one dose of vedolizumab or placebo. The treatment groups had similar baseline characteristics, including percentage of patients who received peripheral blood grafts (86.6% placebo vs. 83.9% vedolizumab) and had an 8/8 HLA-matched donor (90.9% vs. 90.5%). A higher percentage of patients in the vedolizumab group (26.5% vs. 16%) were beyond first complete remission.
Results
The study met its primary endpoint, with the vedolizumab group exhibiting a higher rate of lower GI acute GVHD-free survival at day 180 after transplant vs. the placebo group (85.5% vs. 70.9%; HR = 0.45; 95% CI, 0.27-0.73). Intestinal acute GVHD occurred in 18.8% of patients who received placebo vs. 7.1% of patients who received vedolizumab and drove the difference in deaths between the groups (9.7% vs. 7.1%), Chen said.
When researchers removed five patients who had clinical stage zero lower GI acute GVHD events from the analysis, they found similar results.
Vedolizumab also showed statistically significant improvement in key secondary endpoints, including intestinal acute GVHD and relapse-free survival (HR = 0.56; 95% CI, 0.37-0.86), grade C-D acute GVHD-free (any organ involvement) survival (HR = 0.59; 95% CI, 0.39-0.91), non-relapse mortality (HR = 0.48; 95% CI, 0.22-1.04) and OS (HR = 0.63; 95% CI, 0.34-1.17). The vedolizumab benefit extended to exploratory endpoints at 1 year after transplant, including intestinal acute GVHD-free survival (HR = 0.53; 95% CI, 0.35-0.81) and stage 2 to stage 4-free survival (HR = 0.64; 95% CI, 0.4-1.03).
The vedolizumab group had a slightly higher rate of serious infections than the placebo group (74% vs. 67.3%), but otherwise the groups had similar rates of adverse events, including grade 3 or higher (92.3% vs. 89.1%), drug-related (28.4% vs. 24.8%) and serious drug-related (6.5% vs. 8.5%) adverse events.
Implications, next steps
“This is the first positive phase 3 study for the specific prevention of lower GI GVHD,” Chen said. “We certainly need to look at maximum stage of GI GVHD to truly understand the impact of what we prevented here, and also perhaps the impact on chronic GVHD, as well.”
It remains unclear how to incorporate vedolizumab and other new agents into the rapidly changing landscape of GVHD prevention, Chen added.
“I certainly feel that this should be studied in combination with post-transplant cyclophosphamide, but with the decreasing number of events, I think efficacy studies will be very difficult and almost impossible to do to figure out the true value of our novel agents,” he said.
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Chen Y-B, et al. Abstract LBA2. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, Feb. 15-19, 2023; Orlando.
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