Combined tumor necrosis factor-α (TNF–α) and interleukin-2 (IL-2) blockade in acute steroid refractory graft-versus-host disease (SR-GVHD) following allogeneic hematopoietic stem cell transplantation (HCT)

Abstract

7023 Background: SR-GVHD is a frequent and often fatal complication of HCT. A variety of inflammatory cytokines have been implicated in the pathogenesis of GVHD; single agent therapy against targets such as the IL-2 receptor α chain (daclizumab) or TNF-α (infliximab) has modest activity in SR-GVHD. We hypothesized that concomitant blockade of both TNF-α and IL-2 pathways would be more effective in controlling SR-GVHD than inhibition of either cytokine alone. Methods: The incidence of and outcome following SR-GVHD in 141 pts undergoing nonmyeloablative HCT from an HLA-matched family donor at our institution between February 2001 and November 2008 were analyzed. All SR-GVHD pts were treated with a combination of daclizumab (1 mg/kg, days1, 4, 8, 15, 22) and infliximab (10 mg/kg, days1, 8, 15, 22); in addition, aspergillus prophylaxis, empiric broad-spectrum antibiotics, and a rapid reduction in the dose of corticosteroids was initiated in order to minimize the risk of opportunistic infections associated with immunosuppression. Results: Twenty-three pts (23/141, 16%) developed SR-GVHD (median age 35 y, range 17–65 y); involved organs included the GI tract (n = 23), liver (n = 3), and skin (n = 8). We observed a remarkably high response rate following therapy, with 20/23 (87%) pts experiencing complete resolution of GVHD. Responses were usually delayed (median onset 2 weeks) but durable. The most notable complication associated with therapy was the development of opportunistic infections (invasive fungal infections in 3 pts); in 2/3 of these cases, prophylactic antifungal therapy had been discontinued prematurely due to drug toxicity. The median survival for the SR-GVHD cohort was 255 days (range 67–2,148 days), with 10/23 pts surviving at the time of this analysis. Causes of death included underlying cancer (5 pts), CMV disease (2 pts), and infectious complications (5 pts). Conclusions: These data suggest combined TNF-α /IL-2 blockade is a highly effective therapeutic option for pts with SR-GVHD and highlight the need for aggressive antimicrobial prophylaxis in the management of this condition. No significant financial relationships to disclose.