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

Abstract

This study attempted to characterize causes of treatment failure, identify associated prognostic factors, and develop shorter-term end points for trials testing investigational products or regimens for second-line systemic treatment of chronic graft-versus-host disease (GVHD). The study cohort (312 patients) received second-line systemic treatment of chronic GVHD. The primary end point was failure-free survival (FFS) defined by the absence of third-line treatment, nonrelapse mortality, and recurrent malignancy during second-line treatment. Treatment change was the major cause of treatment failure. FFS was 56% at 6 months after second-line treatment. Lower steroid doses at 6 months correlated with subsequent withdrawal of immunosuppressive treatment. Multivariate analysis showed that high-risk disease at transplantation, lower gastrointestinal involvement at second-line treatment, and severe NIH global score at second-line treatment were associated with increased risks of treatment failure. These three factors were used to define risk groups, and success rates at 6 months were calculated for each risk group either without or with various steroid dose limits at 6 months as an additional criterion of success. These success rates could be used as the basis for a clinically relevant and efficient shorter-term end point in clinical studies that evaluate agents for second-line systemic treatment of chronic GVHD.

Figure 1

Failure-free survival after second-line treatment of chronic GVHD. 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 onset of third-line systemic treatment. The white area represents FFS. The dashed line represents cumulative incidence of successful withdrawal of all systemic immunosuppressive treatment (IST) during second-line treatment.

Figure 2

Cumulative incidence of treatment failure according to risk groups. The low-risk group included patients with no risk factor, the intermediate-risk group included those with 1 risk factor, and the high-risk group included those with 2 or 3 risk factors. Risk factors included high-risk disease at transplantation, lower gastrointestinal involvement at second-line treatment, and severe NIH global score at second-line treatment.

Figure 3

Successful withdrawal of systemic IST according to steroid doses at 6 months after second-line treatment. (A) ≤0.3 mg/kg per day vs >0.3 mg/kg per day, (B) ≤0.2 mg/kg per day vs >0.2 mg/kg per day, and (C) ≤0.1 mg/kg per day vs >0.1 mg/kg per day. PDN, prednisone-equivalent steroid doses.