Treatment of aGVHD with OKT3: clinical outcome and side-effects associated with release of TNF alpha.

Monoclonal antibodies are increasingly used for treatment of acute graft-versus-host disease (aGVHD) in bone marrow transplantation. We treated seven patients with steroid resistant aGVHD with the monoclonal anti-T cell antibody OKT3. Though five patients showed improvement of aGVHD, only two became long-term survivors. OKT3 treatment was accompanied by deterioration of microangiopathy and prolonged increase of tumor-necrosis-factor alpha serum levels indicating activation of monocytes/macrophages in vivo, as this was not observed in a control group of patients receiving anti-T cell globulin. These findings may be related to immunostimulatory activity reported for OKT3 in vitro. Strategies interfering with cytokine release should improve clinical results of OKT3 treatment.

Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation.

Acute graft-versus-host disease, interstitial pneumonitis, endothelial leakage syndrome, and veno-occlusive disease are major complications of bone marrow transplantation. Though several new regimens for prophylaxis and treatment of these syndromes have been introduced, the overall incidence has been only slightly reduced over the last few years. We retrospectively analyzed tumor necrosis factor alpha (TNF alpha) serum levels between day -8 and day 100 after bone marrow transplantation in 56 patients transplanted in our unit for a variety of hematological diseases. In 34 patients with uneventful courses, mean TNF alpha levels rose to a maximum of 76 +/- 29 pg/mL. In contrast, 22 patients with major transplant related complications showed mean increases of TNF alpha of 492 +/- 235 pg/mL (P less than .0001). Increases of TNF alpha occurred before interstitial pneumonitis and severe acute graft-versus-host disease with a latency of 25 to 54 days. Early complications such as endothelial leakage syndrome and veno-occlusive disease were closely associated with increases of TNF alpha serum levels. Our study suggests two pathways of TNF alpha release: activation of host macrophages and stimulation of donor cells in the course of acute graft-versus-host disease. Cytokine monitoring should be helpful for prediction and earlier treatment of major transplant related complications.

Microangiopathy in patients on cyclosporine prophylaxis who developed acute graft-versus-host disease after HLA-identical bone marrow transplantation.

Severe microangiopathy has been reported as a rare complication of cyclosporine A (CsA) prophylaxis in allogeneic bone marrow transplantation (BMT). We found morphological and biochemical changes indicative of generalized endothelial damage in 49 of 66 allogeneic marrow graft recipients receiving cyclosporine, but none in 11 patients treated with methotrexate for prophylaxis of graft-v-host disease (GVHD). Changes occurred after engraftment of bone marrow and consisted of intravascular hemolysis with red cell fragmentation and de novo thrombocytopenia. They were preceded by a decrease in activated partial thromboplastin time and fibrinogen indicating activation of coagulation. Endothelial damage as the central lesion of microangiopathy was confirmed by a simultaneous increase of factor VIII related antigen. Severe microangiopathy was observed in ten patients and was fatal in seven. Risk factor analysis revealed a highly significant association of microangiopathy with severity of acute GVHD (aGVHD) (P less than .001) and use of CsA prophylaxis (P less than .001). Our data suggest endothelial damage as a result of cellular activation and subsequent release of cytokines in the course of a aGVHD, which is not inhibited by CsA prophylaxis.