Prednisone/sirolimus vs prednisone/sirolimus/calcineurin-inhibitor for the treatment of chronic graft-versus-host disease

On 28 June 2018, Paul A. Carpenter, from the Fred Hutchinson Cancer Research Center, Seattle, WA, USA, and colleagues, published the results of a randomized, adaptive phase II/III multicenter trial (NCT01106833) in Haematologica. The study evaluated whether prednisone/sirolimus (PDN/SRL) or prednisone/sirolimus/photopheresis is more effective than prednisone/sirolimus/calcineurin-inhibitor (PDN/SRL/CNI), for the treatment of patients with chronic graft-versus-host disease (cGvHD) who were either treatment naïve or early inadequate responders. Primary endpoints of the study included assessing the proportion of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III.

One hundred patients were enrolled and evaluated for the phase II primary endpoint. Based on the Z-statistic evaluating complete and partial response rates (51% vs 50%, Z = 0.11; stopping boundary = Z6 ≤ 0.9), there was not enough supporting data for the phase III evaluation. However, 151 enrolled subjects were followed for phase III endpoints. In total, 13 (10%) patients did not have a complete NIH cGvHD diagnosis at enrolment and were ineligible.

Patient characteristics:

• Median age in the 2-drug arm: 50.2 years
• Median age in the 3-drug arm: 54.7 years
• The prednisone/sirolimus/photopheresis-arm closed prematurely due to slow accrual
• The prednisone/sirolimus (2-drug arm) and prednisone/sirolimus/calcineurin-inhibitor (3-drug arm) arms ended in phase II for statistical futility with 138 evaluable subjects

Key findings in the 2-drug vs 3-drug arms:

• Efficacy
  • 6-month overall response: 48.6% vs 0%, P = 0.87
  • 2-year complete response: 14.7% (95% CI, 7.3–25.4) vs 5% (95% CI, 7.4–27.4), P = 0.90
  • 2- year failure-free survival: 48.6% vs 2%, P = 0.78
  • 2-year overall survival: 81.5% vs 74%, P = 0.28
  • 2-year progression-free survival: 78.6% vs 3%, P = 0.14
• Safety
  • The proportion of patients with grade 3–5 toxicities: 63.9% vs 1%
  • Thrombotic microangiopathy: 1.4% vs 5%
  • Increase in serum creatinine from baseline to 2 months: 0 mg/dL (SD = 0.2) vs 1 mg/dL (SD = 0.3), P = 0.002
  • 2- and 6- month serum creatinine levels: 1.5% vs 7%, P = 0.025; 7.8% vs 24.0%, P = 0.016
  • Severe to life-threatening/fatal infection episodes: 40.9% vs 5%, P = 0.682

In conclusion, the comparison of two versus three drugs showed similar outcomes with the calcineurin-inhibitor-free cGvHD therapy. In this randomized trial, there was no significant difference in response rates between the two treatment cohorts. Furthermore, this data indicates that initial therapy for cGvHD with PDN/SRL is a tolerable alternative and more efficient than PDN/SRL/CNI. The authors added that “for early cGvHD therapy, novel approaches that improve rates of CR/PR and FFS are required. Due to the inherent complexity of cGvHD trials, we advise real-time diagnostic checklists to ensure patient eligibility, and real-time data auditing to protect data integrity.”