Tocilizumab Is Highly Active for Severe Steroid-Refractory Acute Graft-Versus-Host Disease of the Gastrointestinal Tract

Abstract

Introduction: Severe steroid-refractory (SR) gastrointestinal acute graft-versus-host disease (GI-GVHD) is associated with significant mortality in allogeneic hematopoietic cell transplantation (HCT) recipients. Although numerous agents have been studied for this indication, long-term outcomes remain dismal. Tocilizumab, an interleukin-6 receptor monoclonal antibody, is active in SR GI-GVHD with varying efficacy and impact on survival. Tocilizumab was recently adopted at our center as initial therapy for SR GI-GVHD.Methods: We retrospectively evaluated the efficacy of tocilizumab for the treatment of SR biopsy-proven GI-GVHD in 5 consecutive adult allogeneic HCT recipients between October 2015 and July 2016. All patients had stage IV GI GVHD (Glucksberg criteria) without other organ involvement at time of tocilizumab initiation. Three patients underwent myeloablative conditioning and two reduced-intensity conditioning for a hematologic malignancy (AML n=3; ALL n=1; myelofibrosis n=1). SR GI-GVHD was defined as progressive symptoms after 3 days or no improvement after 7 days of methylprednisolone 2 mg/kg/day. Tocilizumab 8 mg/kg was administered approximately every 2 weeks until achievement of complete response (CR), defined as resolution of all manifestations of GI GVHD, progression or initiation of other therapy. Serum levels of pro-inflammatory cytokines (IFN-γ, IL-2, IL-2R, IL-6, IL-7, IL-15, TNF-α) were measured prior to and after the start of tocilizumab using multiplex arrays.Results: All 5 patients (100%; 95% CI, 0.52 - 1.00) achieved a CR after a median time of 9 days (range, 8 - 13) from tocilizumab initiation. The median time to response onset (improvement in GVHD stage by at least 1) was 1 day (range, 1 - 2). Tocilizumab was administered at a median of 17 days (range 8 - 25) from GVHD diagnosis and 15 days (range, 7 - 18) from initiation of high-dose steroids. The median number of tocilizumab doses administered was 2 (range, 1 - 4). Two patients achieved CR after a single dose and 3 patients required multiple doses of tocilizumab to achieve CR (2 doses n=1; 3 doses n=1; 4 doses n=1). At a median follow up of 5.6 months (range, 2.1 - 8.5) from initiation of tocilizumab, 3 of 5 patients are alive and free of their underlying hematologic malignancy. One patient died from complications related to biopsy-proven liver GVHD that developed after tocilizumab initiation and 1 patient died from polymicrobial sepsis. Serum levels of IL-6 prior to the start of tocilizumab ranged from 4 - 21 pg/mL (normal 0 - 12). As all patients responded, no associations between serum levels of pro-inflammatory cytokines, including IL-6, and tocilizumab response could be identified.Conclusion: Tocilizumab appears to be a highly active agent for the treatment of SR GI-GVHD. Detailed evaluation through prospective clinical trials is warranted. DisclosuresFrey:Servier: Consultancy; Amgen: Consultancy; Novartis: Research Funding. Mangan:Incyte: Other: Advisory Board; Novartis: Research Funding. Gill:Novartis: Patents & Royalties, Research Funding. Cohen:Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Other: Spouse Employment.