Failure-Free Survival After Initial Systemic Treatment Of Chronic GVHD

Failure-free survival (FFS) has been proposed as a useful and meaningful endpoint for clinical trials testing second-line systemic treatment of chronic graft-versus-host disease (GVHD) [Blood 2013;121:2340], but this endpoint has not been evaluated in the context of initial systemic treatment. The current study was designed to (1) determine the FFS rate after initial systemic treatment for patients with moderate or severe chronic GVHD according to NIH criteria, (2) elucidate risk factors associated with treatment failure, and (3) examine whether the dose of prednisone at 6 months after treatment predicts subsequent withdrawal of all immunosuppression after resolution of chronic GVHD. Results of initial treatment were compared to those after second-line treatment.

The study cohort included 400 consecutive relapse-free patients who received initial systemic treatment at our center between 2006 and 2010. FFS was defined as the absence of second-line systemic treatment, nonrelapse mortality and recurrent malignancy during initial treatment. Cox regression models were used to identify risk factors for treatment failure. Covariates at transplant included patient age, disease risk, conditioning intensity, graft source, donor relation, HLA matching and gender matching. Covariates at initial treatment of chronic GVHD included time from transplantation, involved site, number of involved sites, Karnofsky score, NIH global score, classic vs. overlap subcategory, thrombocytopenia, hyperbilirubinemia, progressive onset, steroid dose before initial treatment, and type and number of agents used for initial treatment.

The median age of patients was 51 years (range, 0-79), and the median time from transplantation to initial systemic treatment was 6.8 months (range, 2.6-58). The FFS rate after initial systemic treatment was 68% (95% CI, 63-72%) at 6 months (Figure 1). Treatment change was the predominant category of treatment failure. Multivariate Cox models identified 3 risk factors associated with treatment failure (Table): interval time <12 months from transplantation to initial systemic treatment, patient age ≥60 years and Karnofsky score <80% at initial treatment. No specific initial treatment was associated with lower risk of treatment failure compared to others. Two risk groups were defined according to the number of identified risk factors (Figure 2). FFS rates at 6 months for patients with 0 or 1 risk factor and for those with 2 or 3 risk factors were 73% and 62%, respectively. The cumulative incidence of successful withdrawal of all immunosuppression was 13% (95% CI, 9-16%) at 24 months and 23% (95% CI, 19-28%) at 48 months (Figure 1). Lower doses of prednisone at 6 months were associated with a trend toward a higher rate of subsequent withdrawal of all immunosuppression among patients initially treated with prednisone-containing regimens. The rates of FFS at 6 months and successful withdrawal of all immunosuppression at 48 months were approximately 15% and 10% higher, respectively, after initial systemic treatment as compared to second-line systemic treatment.

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FFS is a useful basis for interpreting results of initial treatment for chronic GVHD. Risk groups defined by this study should be taken into account when clinical trials of initial systemic treatment for chronic GVHD are designed and when results are interpreted.

No relevant conflicts of interest to declare.