Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial

Abstract

We conducted a phase III study to test the hypothesis that initial therapy with "lower dose" prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with grade IIa manifestations (upper gastrointestinal symptoms, stool volumes <1.0 L/day, rash involving <50% of the body surface, no hepatic dysfunction; n=102) were randomized to start treatment with prednisone at 1 mg/kg/day or 0.5 mg/kg/day. Those with grade IIb or higher manifestations (rash involving ≥50% of the body surface, stool volumes ≥1.0 L/day or hepatic involvement; n=62) were randomized to start treatment with prednisone at 2 mg/kg/day or 1 mg/kg/day. The primary study end point (a ≥33% relative reduction of the mean cumulative prednisone dose by day 42 after initial treatment with lower dose prednisone) was not reached. With a median follow up of 36 months (range 7-53), initial treatment with lower dose prednisone appeared to be effective for patients presenting with grade IIa manifestations since it did not increase the likelihood of requiring secondary immunosuppressive therapy. Further exploratory analyses suggested that for patients presenting with skin-predominant grade IIb or higher manifestations, initial treatment with lower dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy (41% vs. 7%; P=0.001). In summary, initial treatment of newly diagnosed acute graft-versus-host disease with lower dose prednisone is effective. Within the statistical limitations of the study, results showed no suggestion that initial use of lower dose prednisone adversely affected survival.

Figure 1.

Stratification and randomization. During the enrollment period for the study from April 2009 to May 2013, 737 patients were newly diagnosed with ≥ grade IIa acute GvHD. One hundred and sixty-four patients (22%) were enrolled and stratified according to severity of manifestations at symptom onset. Patients in cohort A with grade IIa-manifestations (upper gastrointestinal symptoms of anorexia, nausea, vomiting attributed to acute GvHD, with stool volumes < 1 L/day, rash involving < 50% of the body surface, and no hepatic dysfunction) were randomized to start GvHD-therapy with a prednisone-equivalent dose of either 1 or 0.5 mg/kg/day. Those in cohort B with ≥grade IIb-manifestations (rash involving ≥ 50% of the body surface, stool volumes ≥ 1 L/day or hepatic involvement with total serum bilirubin > 2 mg/dL) were randomized to start treatment with a prednisone-equivalent dose of either 2 or 1 mg/kg/day. Randomization was further stratified on recurrence risks of underlying malignancies (standard vs. high) and pre-transplant comorbidity (hematopoietic cell transplant comorbidity index, 0–1 vs. ≥ 2). Two patients were randomized within the incorrect stratum and were allocated to doses for which they were not eligible, leaving 162 patients (grade IIa manifestations, n=102; ≥grade IIb-manifestations, n=60) who initiated prednisone treatment according to study. Twelve patients could not be included in the analysis of the primary end point (departure from Center before treatment day 42, n=7; study withdrawal, n=2; death before treatment day 42, n=3).

Figure 2.

Primary end point: prednisone use according to initial dose and GvHD-grade at onset of symptoms. (A) Patients who presented with Grade IIa-manifestations (cohort A; n=91); initial prednisone dose, 0.5 mg/kg/day (solid line) or 1 mg/kg/day (dashed line). (B) Patients who presented with ≥grade IIb-manifestations (cohort B; n=59); initial prednisone dose, 1 mg/kg/day (solid line) or 2 mg/kg/day (dashed line). The graphs show mean prednisone doses per day until day 42 after starting treatment. Only patients who completed 42 days of prednisone treatment were included in the cumulative dose analysis (n=150).

Figure 3.

Pre-specified secondary “no harm” end points according to initial treatment with lower-dose or higher-dose prednisone. (A) Kaplan-Meier estimates of overall survival after initiation of prednisone therapy among all patients, (B) among those in cohort A, and (C) among those in cohort B. (D) Cumulative incidence of non-prednisone secondary systemic immunosuppressive therapy after initiation of prednisone therapy among all patients, (E) among those in cohort A, and (F) among those in cohort B. Secondary systemic immunosuppressive therapy in cohort B included mycophenolate mofetil (n=6), ATG (n=3), sirolimus (n=2), alemtuzumab (n=1), or etanercept (n=1). Solid line: patients who started treatment with lower-dose prednisone (0.5 mg/kg/day or 1 mg/kg/day for those in cohorts A and B, respectively). Dashed line: patients who started treatment with higher-dose prednisone (1 mg/kg/day or 2 mg/kg/day for those in cohorts A and B, respectively).

Figure 4.

Additional secondary “no harm” end points according to initial treatment with lower-dose or higher-dose prednisone. (A) Cumulative incidence of non-relapse mortality among all patients, (B) among those in cohort A, and (C) among those in cohort B after initiation of prednisone therapy. (D) Cumulative incidence of relapse and (E) chronic GvHD requiring systemic immunosuppressive therapy among all patients after initiation of prednisone therapy. Solid line: patients who started treatment with lower-dose prednisone (0.5 mg/kg/day or 1 mg/kg/day for those in cohorts A and B, respectively). Dashed line: patients who started treatment with higher-dose prednisone (1 mg/kg/day or 2 mg/kg/day for those in cohorts A and B, respectively).