First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation

Abstract

Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of aGVHD, practices differ among centers with respect to the initial glucocorticoid dose, the use of additional immunosuppressive agents, and the approach to withdrawal of treatment after initial improvement. Despite many studies, practices vary considerably with respect to the selection of agents for treatment of glucocorticoid-resistant or refractory GVHD. Investigators and clinicians have recognized the lack of progress and lamented the absence of an accepted standard of care for secondary treatment of aGVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of aGVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Because the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous results and the design of future studies.

Figure 1

Relationship between number of patients enrolled and the Kaplan-Meier estimate of survival at 6 months for each study of initial systemic therapy. The dotted line shows the weighted average 6-month survival estimate for all studies with standard-dose glucocorticoid treatment. Curved lines approximate the upper and lower boundaries of the 95% confidence interval for the weighted average at any given number of patients enrolled in a study. Squares indicate results of the experimental arms in phase 3 studies, and diamonds indicate results of prospective phase 2 studies and pilot studies. Points between the upper and lower boundaries identify studies with results that are statistically consistent with the weighted average. The point below the lower boundary identifies a study with outlier 6-month survival results that are statistically inconsistent with the weighted average. The asterisk indicates a phase III study that showed a statistically significant difference in survival between the 2 arms. The other phase III study with outlier low survival did not show a statistically significant difference between the two arms.

Figure 2

Relationship between number of patients enrolled and the overall CR rate for each study of initial systemic therapy. The dotted line shows the overall CR rate for all studies with standard-dose glucocorticoid treatment. Curved lines approximate the 95% confidence limits for the overall CR rate at any given number of patients enrolled. Squares indicate results of the experimental arm in phase 3 studies, and diamonds indicate results of prospective phase 2 studies and pilot studies. The asterisk indicates a phase II study that showed a statistically significant improvement in survival compared to historical controls at the same institution.

Figure 3

Relationship between number of patients enrolled and the overall CR/PR rate for each study of initial systemic therapy. The dotted line shows the overall PR/CR rate for all studies with standard-dose glucocorticoid treatment. Curved lines approximate the 95% confidence limits for the overall PR/CR rate at any given number of patients enrolled. Squares indicate results of the experimental arm in phase 3 studies, and diamonds indicate results of prospective phase 2 studies and pilot studies. The asterisk indicates a phase III study that showed a statistically significant difference in survival between the 2 arms.

Figure 4

Relationship between number of patients enrolled and the Kaplan-Meier estimate of survival at 6 months for each study of second-line therapy. The dotted line shows the weighted average 6-month survival estimate for all studies. Curved lines approximate the 95% confidence limits for the weighted average at any given number of patients enrolled. Squares indicate prospective studies, and diamonds indicate retrospective studies.

Figure 5

Relationship between number of patients enrolled and the overall CR rate for each study of second-line therapy. The dotted line shows the overall CR rate for all studies. Curved lines approximate the 95% confidence limits for the overall CR rate at any given number of patients enrolled. Squares indicate prospective studies, and diamonds indicate retrospective studies.

Figure 6

Relationship between number of patients enrolled and the CR/PR rate for each study of second-line therapy. The dotted line shows the overall PR/CR rate for all studies. Curved lines approximate the 95% confidence limits for the overall PR/CR rate at any given number of patients enrolled. Squares indicate prospective studies, and diamonds indicate retrospective studies.