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Denileukin Difitox (Ontak) For The Treatment Of Advanced Steroid-Refractory GVHD: Single Institution Experience

Year: 2009

Type: article

Abstract: Steroid Resistant (SR)-GVHD is associated with high mortality when in encountered in allogeneic stem cell transplantation . Denileukin Diftitox (DD), a recombinant fusion protein composed of the cytocidal A chain of Diphtheria toxin and binding portion of IL-2, has potent activity against activated CD25+ T cells important in the etiology of GVHD. It has been reported that DD may have therapeutic activity for the treatment of SR-GHVD (Ho et al, BLOOD 2004). This approach was adopted within our institution for SR-GVHD, defined as lack of response or disease progression after at least 7 days of treatment with methylprednisolone at 2 mg/kg. Between 3/2003 and 6/2008, 20 patients with advanced SR-GVHD following allogeneic transplantation were treated with DD at OHSU, 7 after MRD and 13 after URD (six matched, one A antigen mismatch, and six allele mismatch) .GVHD prophylaxis consisted of cyclopsporine, methotrexate, and steroid (19) or cyclosporine plus MMF (1). Nineteen patients developed acute SR-GVHD overall grade III (7) and IV (12) while one patient developed chronic extensive SR-GVHD. Twelve patients received DD as first salvage therapy while 8 patients were treated with other agents prior to DD (6 had one and 2 had two prior salvage therapies including MMF and Etanercept). Planned treatment was DD at a dose of 600 mcg (9mcg/kg) on days 1, 3, 5, 15, 17, and 19. Median days to DD therapy after stem cell transplant was 38.Ten patients showed response (4 CR and 6 PR defined as at least a one overall grade improvement), six were non responders, and four patients died before completion of treatment. One patient remains alive. Causes of death included GVHD (8), opportunistic infection (5), respiratory failure (2), transplant-associated microangiopathy (2), ICH (1), and relapse (1). Median survival for the entire group was 30.5 days from the onset of DD (4–1839+) with median survival of 116 days for patients who received all 6 doses of DD. Despite measurable responses in 50% of patients, no survival benefit was observed. Profound immune suppression was significant among responders, contributing to opportunistic infection and death. Thus, DD may be most beneficial if used earlier in the course or in lower grade aGVHD. Responses can be achieved in advanced SR-GVHD with DD but novel approaches still remain the research target for these patients given poor overall survival .

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2008.12.396