Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease

Abstract

We evaluated short-term response endpoints for acute graft-versus-host disease treatment trials. We postulated that response endpoints should correlate with reduced symptom burden and decreased subsequent treatment failure, defined as non-relapse mortality, recurrent malignancy, or additional systemic treatment. The cohort included 303 consecutive patients who received initial systemic steroid treatment for acute graft-versus-host disease. Response was evaluated at day 28 after initial treatment, which in all cases preceded the onset of chronic graft-versus-host disease. At day 28, 36% of patients had a complete response, 26% had a very good partial response, 10% had another degree of partial response (other partial response) and 28% had no response. As expected, the symptom burden was lower in patients with very good partial response compared to those with other partial response. The frequencies of subsequent treatment failure were similar in patients with complete and very good partial responses, but lower than in patients with other partial response or no response at day 28. The frequency of second-line treatment was lower in patients with very good partial response than in those with other partial response. Risk factors associated with a lower probability of complete or very good partial response at day 28 were unrelated or human leukocyte antigen-mismatched related donor grafts and liver or gastrointestinal involvement at onset of initial treatment. Taken together, these results suggest that endpoints in acute graft-versus-host disease treatment trials should distinguish between very good partial response and other partial response. Our results support the use of complete or very good partial response at day 28 as an appropriate short-term primary endpoint.

Figure 1.

Categories of treatment failure after initial treatment of acute GVHD. The blue area represents failure due to recurrent malignancy. The red area represents failure due to non-relapse mortality (NRM), and the black area represents failure due to second-line systemic treatment for acute GVHD. The yellow area represents the cumulative incidence of chronic GVHD, which was treated as a competing risk.

Figure 2.

Day 28 response and longer-term outcomes according to response categories. (A) Response rates at days 28. Traditional partial response (PR) is subdivided into very good partial response (VGPR) and other PR. CR indicates complete response, and NR indicates no response. (B) Cumulative incidence of chronic GVHD as a competing risk according to day 28 response. (C) Non-relapse mortality (NRM) according to day 28 response. (D) Cumulative incidence of treatment failure according to day 28 response.

Figure 3.

Six-month outcomes according to day 28 response categories in all 303 patients. Outcomes at 6 months after initial systemic treatment were classified as treatment change, NRM, recurrent malignancy, chronic GVHD and failure-free survival without chronic GVHD. Proportions of individual outcomes at 6 months are shown according to response categories at day 28 after initial treatment. NRM: non-relapse mortality; CR: complete response; VGPR: very good partial response; PR: partial response; NR: no response.

Figure 4.

Effects of incorporating a minimum percent reduction of the initial steroid dose in the CR/VGPR definition of response at day 28. (A) Sensitivity (black line) and specificity (red line) in predicting the absence of failure at 6 months according to threshold reductions of the steroid dose. (B) Six-month outcomes after CR/VGPR with or without =30% reduction of the prednisone (PDN) dose.