Failure-free survival after initial systemic treatment of chronic graft-versus-host disease

Abstract

This study was designed to characterize failure-free survival (FFS) as a novel end point for clinical trials of chronic graft-versus-host disease (GVHD). The study cohort included 400 consecutive patients who received initial systemic treatment of chronic GVHD at our center. FFS was defined by the absence of second-line treatment, nonrelapse mortality, and recurrent malignancy during initial treatment. The FFS rate was 68% at 6 months and 54% at 12 months after initial treatment. Multivariate analysis identified 4 risk factors associated with treatment failure: time interval <12 months from transplantation to initial treatment, patient age ≥60 years, severe involvement of the gastrointestinal tract, liver, or lungs, and Karnofsky score <80% at initial treatment. Initial steroid doses and the type of initial treatment were not associated with risk of treatment failure. Lower steroid doses after 12 months of initial treatment were associated with long-term success in withdrawing all systemic treatment. FFS offers a potentially useful basis for interpreting results of initial treatment of chronic GVHD. Incorporation of steroid doses at 12 months would increase clinical benefit associated with the end point. Studies using FFS as the primary end point should measure changes in GVHD-related symptoms, activity, damage, and disability as secondary end points.

Figure 1

FFS after systemic treatment of chronic GVHD. (A) initial treatment, (B) second-line treatment. The dark gray area represents treatment failure due to recurrent malignancy. The light gray area represents treatment failure due to nonrelapse mortality (NRM), and the black area represents treatment failure due to treatment change. The white area represents FFS. The dashed line represents cumulative incidence of successful withdrawal of all systemic IST during initial treatment.

Figure 2

Treatment failure rates according to risk groups. (A) current study, (B) prior multicenter prospective trial. Standard risk, 0 to 2 risk factors; high risk, 3 to 4 risk factors. Risk factors included time interval <12 months from transplantation to initial treatment, patient age ≥60 years, severe involvement (score 3) of the gastrointestinal tract, liver, or lungs, and Karnofsky score <80% at initial treatment. Results for the high-risk group were not plotted in B, because only 2 patients were included in this group. These 2 patients had early treatment failure at 15 and 19 days after initial treatment, respectively.

Figure 3

Long-term success in withdrawing all immunosuppressive treatment. Results were analyzed according to the presence or absence of (A,E) prior treatment change and prednisone (PDN) doses at (B-D) 6 and (F-H) 12 months after initial treatment. Withdrawal of all immunosuppressive treatment after resolution of GVHD among patients without recurrent malignancy was counted during any line of treatment in A and E and during initial treatment among patients initially treated with steroids in B-D and F-H. Patients with recurrent malignancy before the landmark were excluded in all analyses, and patients with treatment change before the landmark were excluded in the analyses shown in B-D and F-H.