TCT Meeting 2019 | Primary results of the BMT CTN 1501 trial: sirolimus versus prednisone as an initial steroid-free treatment for acute graft-versus-host disease

On 23 February 2019 at the 2019 TCT Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR in Houston, Texas, USA, Joseph A. Pidala presented the primary results of the BMT CTN 1501 trial. This multi-center, open-label, randomized, prospective phase II study assessed the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus versus prednisone as a steroid-free initial therapy for standard risk, acute graft-versus-host-disease (aGvHD).

Patients and methods

All findings reported as prednisone versus sirolimus

• Previously untreated pediatric and adult standard-risk patients with aGvHD were recruited:
  • Biopsy confirmation was not required
  • No prior systemic immunosuppressive therapy
  • Topical treatments were permitted
  • Clinical risk according to the refined Minnesota (MN) criteria was determined
  • Biomarker samples were taken for Ann Arbor (AA) staging
• Patients were randomized (1:1) to:
  • Sirolimus: study protocol-determined dose
  • Prednisone: 2 mg/kg/day starting dose, decreasing throughout the study
• Primary objective: CR/PR rate at day-28 in patients with AA1/2 biomarker status
• Secondary objectives:
  • CR/PR + ≤0.25 mg/kg/day prednisone at day 28 post-randomization
  • Steroid exposure
  • Complications due to infection
  • Toxicity events
  • Disease- and GvHD-free survival
• Biomarker assessment was conducted post-randomization, in patients with AA1/2 (N = 122):
  • Sirolimus (n = 58)
  • Prednisone (n = 64)
  • Additional: AA3/missing (n = 5)
• Both arms had similar aGvHD organ staging, any grade:
  • Skin: 70% vs 66%
  • Upper gastrointestinal (GI): 44% vs 45%
  • Lower GI: 11% vs 0%
  • Liver: 2% vs 0%
• MN-risk category at enrolment:
  • Stage 1-3 skin: 50% vs 53.4%
  • Stage 1-2 GI: 29.7% vs 34.5%
  • Stage 1-3 skin and stage 1 GI: 18.8% vs 12.1%
  • Stage 1-3 skin and stage 1-4 liver: 1.16% vs 0%

Key findings

All findings reported as prednisone versus sirolimus

• CR/PR at day 28, P = 0.68:
  • CR: 62% vs 56%
  • PR: 11% vs 9%
• CR/PR at day 56, P = 0.07:
  • CR: 76% vs 57%
  • PR: 3% vs 8%
• Steroid-sparing effect in the sirolimus arm: day 28 CR/PR + ≤0.25 mg/kg/day (P < 0.001)
  • Yes: 31.7% vs 66.7%
  • No: 68.3% vs 33.3%
• Safety:
  • Steroid-refractory aGvHD: 20.3% vs 3.4%
  • Serious grade ≥3 adverse events: 7.81% vs 12.07%
  • Infections: 48.4% vs 34.5%
• Six-month estimates:
  • Non-relapse mortality: 9.4% (95% CI, 3.8–18.1%) vs 12.7% (95% CI, 5.5–23.0%)
  • Event-free survival: 45.2% (95% CI, 32.8–56.8%) vs 45.5% (95% CI, 32.0–58.1%)

Conclusion

• Sirolimus provided comparable day-28 CR/PR rates to the standard of care (prednisone)
• An improvement in day-28 CR/PR with prednisone ≤0.25mg/kg/day was observed in the sirolimus arm
• Steroid therapy may not be required in approximately 2/3 of patients treated MN-SR, AA1/2
  • Rescue with prednisone following sirolimus also did not lead to a high rate of steroid-refractory GvHD
• Long-term outcomes were comparable between study arms
• No additional toxicity in AEs, infections or steroid-refractory GvHD was observed
• The group plan to continue their analysis of the comprehensive data collected, including long-term outcome analysis, patient-reported outcomes, and treatment toxicity analyses