Tocilizumab In The Treatment Of Steroid Refractory Graft Versus Host Disease: A Single Institutional Experience
Authors: Roddy Julianna V.F. , Haverkos Bradley M. , McBride Ali , Leininger Kathryn M , Andritsos Leslie A. , Devine Steven M. , Efebera Yvonne A 
Published: October 2019

Abstract

Introduction
Acute graft-versus-host-disease (aGVHD) is a frequent and often lethal complication of allogeneic hematopoeitic stem cell transplant (allo HSCT) despite current prophylactic regimen. It is fueled by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6), leading to damage of host tissues. Front-line treatment with glucocorticoids provide 30-40% complete response. Tocilizumab is a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody that binds to both soluble and membrane-expressed IL-6R, inhibiting IL-6–mediated proinflammatory activity. A case report and a recent small series (8 patients) with steroid refractory GVHD(SR GVHD) showed encouraging single agent activity of tocilizumab(Gergis et al, 2010; Drobyski et al, 2011). We report our experience on 9 patients who had SR aGVHD and received tocilizumab therapy.

Method
Tocilizumabwas administered intravenously at a dose of 8 mg/kg every 2 to 3 weeks. aGVHD grading and responses were based on consensus criteria (Przepiorka et al, 1995). Patients were monitored for toxicities and infections.

Results
The median age at transplant was 48 years (range 25-61). Four patients had double cord allo HSCT, 2 had matched related, 2 unrelated (with one 9/10 matched) and 1 haploidentical after a failed cord HSCT. Six patients had received myeloablative and 3 reduced intensity allo HSCT. All but one patient received tacrolimus and methotrexate for aGVHD prophylaxis, and all were in complete remission of their underlying disease at time of aGVHD. Table 1 includes responses and outcomes to tocilizumab therapy. All patients had GI involvement and 6 patients had two organs involved. Median aGVHD grade was 3 (range 3-4). The median time from first aGVHD onset to tocilizumab administration was 44 days (range 14-176). The median number of infusions was 2(1-6). There were no allergic or infusion-related events. Two patients (22%) had a complete response (CR), and two had mixed responses with CR in one organ, but no response in another. Only one of nine patients survived. Six patients (67%) died from aGVHD and its complications, one from CMV and one from septic shock. The median survival from start of tocilizumab was 26 days (range 13-759).

Conclusions
While the few tocilizumab treated patients with SR aGVHD reported in the literature have experienced a high response rate of 67%(CR and PR), our limited experience showed a less impressive 22% CR. Although tocilizumab has some activity in the treatment of SR aGVHD, it may not be significantly better than other available agents.

Disclosures:
Off Label Use: There is currently no standard of practice of steroid-refractory GVHD, every treatment option besides steroids are considered off-label. However, there is evidence to support its use. Tocilizumab Tocilizumab is a humanized anti–IL-6 receptor (anti–IL-6R) monoclonal antibody that binds both soluble and membrane-expressed IL-6R, inhibiting IL-6–mediated proinflammatory activity. In this study, we report our experience with the administration of tocilizumab, an anti-interleukin 6 receptor antibody, in the treatment of steroid refractory GVHD.