CYCLOSPORINE - A REVIEW OF ITS PHARMACOLOGICAL PROPERTIES AND ROLE INTHE MANAGEMENT OF GRAFT-VERSUS-HOST DISEASE

Patients with haematological disease, such as leukaemia or aplastic an aemia may receive bone marrow transplantation (BMT) to improve long te rm survival: In patients receiving allogeneic BMT, T cells from donor marrow may mount an immunological attack on host tissues (e.g. skin, l iver gastrointestinal tract) and this is manifested as graft versus ho b disease (GVHD). Indeed, GVHD is associated with significant morbidit y and mortality and is the most important complication following allog eneic BMT. Cyclosporin, an immunosuppressive agent with relatively sel ective and reversible effects on T helper cells, has been evaluated al one and in combination with methotrexate in a number of clinical trial s for the prevention of GVHD in patients receiving allogeneic BMT matc hed at the major histocompatibility complex from sibling donors. In ge neral cyclosporin monotherapy achieved similar clinical outcomes to th ose seen with methotrexate monotherapy in comparative studies; however cyclosporin has become a cornerstone of GVHD prophylaxis and these dr ugs are usually administered concomitantly for prevention of GVHD in c ontemporary clinical practice. Comparative studies demonstrated a sign ificantly lower incidence of grade II to IV acute GVHD with a combined prophylactic regimen of cyclosporin plus methotrexate than with eithe r drug used alone. The probability of long term survival tended to be or was significantly higher with the combined regimen than with monoth erapy. Patients with established grade II to acute GVHD generally do n ot respond well to therapy Cyclosporin has not been extensively evalua ted informal trials in this clinical setting; however; available data suggest that it is as effective as corticosteroids, which are generall y considered to be first-line therapy. Some patients may require combi ned treatment such as a corticosteroid plus cyclosporin and/or antithy mocyte globulin. In conclusion, cyclosporin appears to be as effective as corticosteroids in treating established GVHD. For prophylaxis of G VHD inpatients receiving BMT for haematological disease, cyclosporin i s a cornerstone of therapy and is usually used in combination with met hotrexate, since their combined use is more effective than either drug used alone. While other strategies for prevention of GVHD have also s hown promise, including in vitro T cell depletion of donor marrow no a gent or regimen is ideal, since adverse events, increased leukaemic re lapse rates, graft rejection and infection remain important concerns. However of currently available therapeutic options for prevention of G VHD, the optimal immunosuppressive regimen appears to be a combination of cyclosporin plus methotrexate.