Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease.

GVHD of the gastrointestinal (GI) tract is the main cause of non-relapse mortality following allogeneic HCT. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA 2/3 scores correlate with resistance to treatment and higher non-relapse mortality (NRM). We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA 2/3 GVHD. Seventy-five evaluable patients were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events (AEs) in more than 10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared to 150 well matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and corticosteroids alone controls (60% vs. 58%; P=0.67 and 48% vs. 48%; P=1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival (OS) at 12 months in patients treated with natalizumab plus corticosteroids compared to controls treated with corticosteroids alone (38% vs 39%, P=0.80 and 46% vs 54%, P=0.48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high risk GVHD.