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Arthritis Drug Cuts GVHD Risk in Stem Cell Transplants

A widely used arthritis drug reduced the rate of acute graft-versus-host disease (GVHD) in both HLA-matched and -mismatched allogeneic stem-cell transplants, a randomized study showed.

The incidence of grade 3/4 acute GVHD after matched transplants decreased from 14.8% with standard prophylaxis to 6.8% with the addition of abatacept (Orencia). In a small group of patients who had 7/8-HLA-mismatched transplants, grade 3/4 acute GVHD at day 100 declined significantly from 30.2% with standard prophylaxis to 2.3% with add-on abatacept (P<0.001).

Treatment with abatacept was not associated with increased rates of disease relapse or infection, investigators reported in the Journal of Clinical Oncology.

“We found really striking results, particularly with those who were mismatched stem-cell transplants, in preventing acute GVHD,” said Benjamin Watkins, MD, of Aflac Cancer and Blood Disorders Center and Emory University in Atlanta. “This was a pretty rigorously run trial … and I think with these initial results, it’s becoming more standard at many institutions to use abatacept in settings like this, and we’ve started to see some momentum to actually using it off study.”

“I think the key here is that the study shows safety and efficacy, especially for patients who don’t have a matched unrelated donor, which disproportionately impacts minorities,” added co-author Muna Qayed, MD, also of the Aflac Center and Emory University. “What we can see here is that abatacept can be an option that can be safely added to the transplant to open up the donor pool for these patients.”

Allogeneic stem-cell transplant is effective for aggressive hematologic malignancies and often is the only option for cure. When HLA-matched related donors are unavailable, unrelated donors can be used, but have an increased risk of nonrelapse mortality driven by acute and chronic GVHD and infection, Watkins and co-authors noted. Use of donor cells from an HLA-mismatched unrelated donor increases the risks, including rates of severe acute GVHD as high as 37% and nonrelapse mortality as high as 45%.

No approved agents exist for the prevention of acute GVHD. Preclinical studies suggested that abatacept, a T-cell costimulation inhibitor, can prevent GVHD, providing the rationale for a first-in-human trial that demonstrated the feasibility and safety of abatacept in the transplant setting.

The authors reported findings from a subsequent phase II trial evaluating abatacept as add-on therapy to GVHD prophylaxis with a calcineurin inhibitor and methotrexate. Investigators in the multicenter trial enrolled children and adults with hematologic malignancies into two cohorts. One group included patients with 8/8-HLA-matched unrelated donors, and the other was limited to 7/8-HLA-mismatched unrelated donors.

Patients with matched donors were randomized to a calcineurin inhibitor and methotrexate plus abatacept or placebo. Participants in the mismatched cohort received standard prophylaxis plus abatacept and were compared against patients from the Center for Blood and Marrow Transplant Research (CIBMTR) database, all of whom received calcineurin inhibitor/methotrexate prophylaxis against GVHD.

The primary endpoint for both cohorts was the incidence of grade 3/4 acute GVHD at day 100. A key secondary endpoint was severe acute GVHD-free survival (SGFS) at day 180. The trial had the statistical power to detect a reduction in acute GVHD from 20% to 10% in the matched cohort and from 30% to 10% in the mismatched cohort. The null hypothesis would be rejected if the outcome was associated with P<0.2, and the secondary endpoint would be analyzed only if the primary endpoint met criteria for statistical significance.

Data analysis for the matched cohort included 142 transplant recipients who had a median follow-up of 716 days. The addition of abatacept reduced the hazard for acute GVHD at 100 days by 55% (80% CI 0.22-0.9, P=0.13). The SGFS rate at day 180 was 93.2% with abatacept and 82% with control prophylaxis, a difference that represented a 63% reduction in the hazard ratio (80% CI 0.19-0.73, P=0.05). The addition of abatacept did not increase the rate of relapse, which was 21.5% at 2 years versus 23.6% for the placebo group.

The mismatched cohort had 43 evaluable recipients who had a median follow-up of 708 days. As compared with the CIBMTR control group, the addition of abatacept reduced the hazard for acute GVHD at day 100 to a value of 0.0. A similar impact was observed in the analysis of SGFS, which improved from 58.7% in the control group to 97.7% in the patients who received standard prophylaxis plus abatacept (HR 0.0, P<0.001). The 2-year point estimates for relapse were 9.3% with the addition of abatacept and 21.5% in the CIBMTR control group.

Nonrelapse mortality, relapse-free survival, and overall survival at 2 years all improved numerically with abatacept in the 8/8 group and significantly in the 7/8 cohort.

“We saw a very favorable safety profile with abatacept,” said Watkins. “In the initial part of the study, we looked very closely at viral infections … and there was no significant difference in viral infections between the placebo patients and patients who received abatacept.”

  • Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow


The study was sponsored by Boston Children’s Hospital in collaboration with the FDA Office of Orphan Products Development.

Watkins reported a relationship with Bristol Myers Squibb, as well as patent/royalty/intellectual property interests. Qayed reported relationships with Novartis and Mesoblast.