ALBERT

Description: Abstract 2232 Poster Board II-209 Introduction Chronic graft-versus-host disease (cGVHD) is the major long term complication of allogeneic stem cell transplantation and shares similarities with auto-immune diseases, like systemic sclerosis (SSc).Although the contribution of donor T cells in the development of both acute and chronic GVHD is beyond doubt; the role of B cells is less defined. However, two observations suggest that B cells do contribute to chronic GVHD. First, autoantibodies can be detected in 15-90% of chronic GVHD patients. Furthermore, several small-scale retrospective clinical studies demonstrated that in vivo depletion of B cells with the CD20-specific Ab rituximab results in amelioration of chronic GVHD symptoms in heavily pretreated steroid-refractory patients. Objective In order to prospectively investigate B cell depletion as therapy for cGVHD, we have studied the efficacy of the CD20-specific antibody rituximab in patients with steroid-refractory extensive cGVHD. Methods In an ongoing prospective phase I/II study 15 patients with steroid-refractory extensive cGVHD were treated with rituximab (375 mg/m2 per week for 4 consecutive weeks). Clinical responses were monitored monthly for 1 year according to the NIH criteria (EudraCT 2008-004125-42). Results A total of 60 rituximab infusions were administered to 15 patients with steroid-refractory cGvHD. Toxicity was limited to one infectious event and one allergic reaction. Clinical responses were so far analyzed in 12 patients. Median follow-up was 6.5 months (range 1-13). Eight patients showed a partial response (67%) of which 5 patients (42%) had an ongoing response up to 1 year of follow-up and 3 patients (25%) relapsed. Two relapsed patients were retreated with rituximab 8 months after cessation of the initial rituximab treatment and showed again a partial response. In patients with deep sclerosis (n=10), sclerotic features disappeared completely or partially in 8 patients (80%). In patients with involvement of eyes (n=10), mucosa (n=4) and gastro-intestinal tract (n=4) response was observed in 50%, 25% and 25% of patients, respectively. Consequently, prednisone dosage could be reduced in 7 patients (58%). In 4 patients (33%) prednisone treatment was stopped completely. Conclusion Rituximab treatment is a feasible and effective treatment in patients with steroid refractory cGVHD. In addition, also patients with relapse of cGVHD after cessation of rituximab treatment can be successfully treated. Thereby, sclerotic lesions of the skin improved in the majority of patients whereas eye, mucosal and gastro-intestinal tract involvement was less reversible. We speculate that the lack of improvement of eye and mucosal involvement is a consequence of an early and irreversible destruction of lacrimal and salivary glands and this argues for an upfront application of rituximab in patients with cGVHD. Disclosures: Off Label Use: Rituximab, a monoclonal anti-CD20 antibody, is used to deplete B-cells in the treatment of chronic GVHD.

Description: Background: Acute leukemia and high risk myelodysplastic syndrome patients experience prolonged neutropenia after treatment with intensive chemotherapy, leading to a high risk of acquiring potentially fatal invasive fungal infections (IFI). Pharmacoeconomic analysis is considered a valuable tool to justify the significant costs involved in managing these fungal infections. The present study evaluates the cost-effectiveness of posaconazole versus standard azoles for the prevention of IFIs in neutropenic patients in the Netherlands. Methods: A decision-tree model was developed that starts with the choice of antifungal prophylaxis: posaconazole or standard azole treatment (fluconazole or itraconazole). The decision tree was estimated using data from a recently published prospective, randomized, double blind, multi-center trial that compared both treatments in neutropenic patients receiving remission-induction chemotherapy for AML/MDS (Cornely et al., 2007). Following initiation of prophylaxis, clinical events are modeled with chance nodes reflecting probabilities of IFIs, IFI related death, and death from other causes. It is assumed that patients surviving the prophylactic period will have a life expectancy that reflects that of the underlying condition. This allows translation of the trial outcomes to a lifetime horizon. Data on life expectancy, quality of life, medical resource consumption and costs were obtained from the literature. Model outcomes include incremental cost per IFI avoided, incremental cost per life years saved and incremental cost per QALYs gained. Results: The total cost (treatment of breakthrough IFI + prophylaxis) for posaconazole amounted to €4,566 (95% uncertainty interval €3,574 –€5,769), which is €63 (−€1,552 - €1,903) less than costs with standard azoles. Posaconazole prophylaxis resulted in 0.1 (0.03 – 0.15) QALYs gained in comparison to prophylaxis with standard azoles. Results from a probabilistic sensitivity analysis indicate that there is a 87% probability that the cost per QALY gained with posaconazole is below €20,000, a commonly accepted threshold for cost-effectiveness. Additional scenario analyses with different assumptions confirmed these findings. Conclusion: Given the underlying data and assumptions, our economic evaluation demonstrated that posaconazole prophylaxis is cost and QALY saving compared to fluconazole / itraconazole in neutropenic AML/MDS patients after intensive chemotherapy.