Tocilizumab In The Treatment Of Steroid Refractory Graft Versus Host Disease: A Single Institutional Experience

Abstract

IntroductionAcute 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. MethodTocilizumabwas 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. ResultsThe 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).Table 1Response and Outcome to TocilizumabPatientDay of aGVHD OnsetOverall Grade of GVHD PriorOrgan Involvement (stage)GVHD Treatments PriorDay to Tocilizumab Administration from Transplant# of DosesOverall Response to TocilizumabCurrent StatusDays Surviving since Tocilizumab InitiationPrimary Cause of Death1+ 263GI (2) Liver ( 2)Steroids Basiliximab+ 706CRDead308Infection- CMV2+304GI (3) Liver (4)Steroids Budesonide+ 1762NRDead25aGVHD3+183GI (4) Liver (1)MMF Budesonide Steroids+ 391GI : NR Liver: CRDead20aGVHD4+603GI (2)Steroids Tacrolimus MMF+ 746CRAlive and disease free759NA5+ 253Skin (2) GI (4)Steroids Sirolimus Budesonide+861NRDead13Alveolar hemorrhage aGVHD6+ 903GI (1) Liver(2)Budesonide Steroids Tacrolimus+2662GI: CR Liver: NRDead26Klebsiella pneumonia, septic shock7+283GI (4)Sirolimus Budesonide Steroids+972NRDead33aGVHD8+433Liver (3) GI(3)MMF Budesonide Steroids+852NRDead16aGVHD9+294GI (4) Liver (4)Steroids MMF budesonide+432NRDead107aGVHD ConclusionsWhile 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.