Excellent Therapeutic Results Achieved in Salvage Therapy for Steroid-Refractory Grades III-IV Acute Gvhd with Basiliximab and Etanercept: A Multicenter Prospective Study

Introduction: Standard first-line therapy for the treatment of acute graft-versus-host disease (aGVHD) involves corticosteroids. However, fewer than half of patients have durable complete response. Steroid refractory aGVHD (SR-aGVHD) is associated with increased mortality, and long-term mortality rate remains around 70%. Second-line treatments included antithymoglobulin (ATG), mycophenolate mofetil (MMF), tacrolimus (FK), IL-2R antibodies, alemtuzumab, etanercept, infliximab, sirolimus and others. The overall complete remission (CR) rate from the 28 published retrospective studies that evaluating agents for second-line therapy of SR-aGVHD was 32%, the median survival was only about 6 months and no agent was clearly superior. To date, no consensus has been reached regarding the optimal secondary treatment of SR-aGVHD. Based on the pivotal roles of T cells and inflammatory cascade in aGVHD induction, since 2009 we performed a multicenter prospective study to assess the efficacy and safety of an approach to treat severe (grades III-IV) SR-aGVHD by the combination of basiliximab (anti-IL2-R) and etanercept (anti-TNFα).

Methods: We conducted an open-label, non-randomized, phase II study at three centers, Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou), Department of Hematology, Zhejiang Provincial People's Hospital (Hangzhou), and Department of Hematology, Guangzhou General Hospital of Guangzhou Military Command (Guangzhou), between January 2009 and October 2013. Patients fulfilled one of the following criteria were included: (1)when newly diagnosed with grades III-IV aGVHD or overlap syndrome and showed progression after 3 days, or no improvement after at least 7 days of treatment or partial response at 14 days with 2 mg/kg per day prednisolone; or (2) de novo grades I-II aGVHD but eventually evolved into grades III-IV during treatment with prednisolone. Basiliximab was given intravenously at 20mg/d on days 1, 4, 8, 15, 22, 29, 36 (if necessary). Etanercept was given subcutaneously at 25mg per dose twice a week for 4 weeks and then pursued at 25mg once a week for another 4 weeks. During combined therapy all patients received cyclosporine and maintained on therapeutic level. Prednisolone was tapered by 10% of the total dose twice weekly.

Results: (1) Forty-one patients with steroid-refractory grades III-IV aGVHD were included. Acute GVHD occurred at a median time of 13 days post-transplantation (range: 5-85). First-line treatment with 2 mg/kg/day steroids was initiated at GVHD diagnosis. Thirty patients (73.2%) were diagnosed as grade II aGVHD but evolved into severe aGVHD during treatment with prednisolone, and 11 patients (26.8%) were severe aGVHD at onset. Median time from diagnosis of aGVHD to study enrollment was 12 days (range 3-49). Fifteen patients (36.6%) presented with overall grade III aGVHD and 63.4% with grade IV. (2) Median number of infusions of basiliximab was 4 (range 2-7) and median number of etanercept was 8 (range 1-11). At day 28 after treatment by the combination therapy of basiliximab and etanercept was initiated, overall response (CR+PR) to second-line treatment was 92.7% with 78% of CR. The incidences of CR per organ was 100%, 80.5% and 85.4% for skin, gut and liver involvement, respectively. Nine of 24 evaluable patients developed chronic GVHD (cGVHD), in which 4 cases were with mild cGVHD and 5 with extensive cGVHD. (3)The cumulative incidence of a invasive pulmonary fungal infection at 12 months post-transplantation was 42.4%. Although twenty-eight patients (69.3%) experienced at least 1 cytomegalovirus (CMV) reactivation, all patients developed CMV-positive antigenemia without CMV disease. One patient developed viral encephalitis by human herpesvirus 6 (HHV6). No case of Epstein-Barr virus (EBV) reactivation was reported. Five-year overall survival (OS) rate after the combination therapy was 55.2% . A total of 17 patients died and causes of death ordered by the number of patients were invasive pulmonary fungal infection, (n=8, 47.1%), relapse (n=4, 23.5%), aGVHD (n=4, 23.5%), and arrhythmia (n=1, 5.9%).

Conclusions: Here we developed a novel salvage treatment approach for grades III-IV SR-aGVHD by using the combination of basiliximab and etanercept, which achieved a clinically meaningful response in approximately more than 90% of patients and 55.2% of 5-year OS.