Second step forward: Thalidomide and GVHD:
Abstract #4482 (publish only)
THALIDOMIDE IN GVHD - IS ANTI-GVHD EFFECT SEPARABLE FROM THE ANTIANGIOGENESIS
S. Kulkarni*, R. Powles, J. Mehta, C. Horton*, J. Treleaven*, S. Meller*, A. Atra*, C.R. Pinkerton*, S. Singhal
Royal Marsden Hospital, Surrey, UK
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The outcome of patients with steroid-refractory acute or chronic GVHD is poor. We have evaluated thalidomide extensively in both situations. Recently it has been shown that thalidomide has anti angiogenesis action and can be used as anti leukaemia agent. This analysis was undertaken to find the effect of thalidomide in inducing response in GHVD (especially chronic) and see if the anti GVHD (and anti-GVL) effect can be compensated by anti-angiogenesis effect by changing the relapse incidence. 41 patients (29M, 12F, 4-52 y, median 28) with hematologic malignancies who develop limited (n = 17) or extensive (n = 24) chronic GVHD after BMT from matched siblings (n = 35) or unrelated donors (n = 6) received the drug (50800 mg/d, median 600) after responding inadequately to previous therapy with cyclosporine (n = 28), corticosteroids (n = 37), azathioprine (n = 25), tacrolimus (n = 1), murine anti-IL-2 receptor antibody (n = 1), or methotrexate (n = 1). The duration of therapy was 1 day to 2 years (median 60 days). Response was inevaluable in 8 because of short treatment duration (<2 weeks 0 as a result of GVHD-related death (n = 5) or adverse effects requiring drug discontinuation (n = 3). 20 patients did not respond, 9 patients had complete/excellent partial resolution of GVHD, and 4 had some improvement. The overall response rate was 39.4% (13 of 33). Four patients with bronchiolitis obliterans organizing pneumonia (BOOP) showed no change in pulmonary status on thalidomide. One patient developed peripheral neuropathy after 2 years of treatment. The drug was stopped due to drowsiness in 4, and the dose had to be reduced in 1. Six had constipation and one thrombocytopenia. Currently 17 patients are alive, including 9 responding to thalidomide. 24 including 4 thalidomide responders, died of complications of GVHD (n = 17), relapse (n = 3), interstitial pneumonitis (n = 2), or second cancers (n = 2). Two patients with chronic GVHD relapsed (1 each of AML and CML). The relapse rate was 4.9%. Both the relapses occured in non-responders to thalidomide and both died due to relapsed leukaemia. Since 22/41 had advanced disease at the time of presentation this relapse rate may be considered as low. Weather this is the effect of extensive GVHD or the anti-angiogenesis effect of thalidomide is contributory certainly needs investigation. We conclude that thalidomide is activity in chronic GVHD. Its anti-angiogenesis properties and effect on leukaemia relapse needs to be evaluated.
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