Thalidomide was used in the sixties as a sedative and antiemetic agent. Severe teratogenic effects, however, led to its removal from the market. It has been rein-troduced over the last decade for the treatment of ENL (erythema nodosum leprosum) and received FDA approval for this indication in 1998. It is currently used in combination with dexamethasone, in place of conventional chemotherapy, for the initial management of multiple myeloma. The drug has been found to have multiple mechanisms of action that would make it an ideal therapeutic agent in various cancers, especially melanoma, multiple myeloma, and MDS. These include accelerating degradation of TNFa RNA message; potent inhibition of angiogenesis via its action on VEGF and bFGF, and inhibition of the transcriptional regulator NF-kB.40-42 In addition, thalidomide alters cellular adhesion and stimulates the Th1 immune response, possibly enhancing an antitumor response.43 Thus, thalidomide shows anti-TNFa, antiangiogenic, and immune-modulatory properties.
A phase II trial was conducted at Rush University Medical Center in which 83 MDS patients of all subtypes were given thalidomide 100 mg once a day escalating to a target dose of 400 mg a day.44 The overall response rate was 19%. Fifty-one patients were evaluable at 12 weeks, of whom 16 (almost 30%) had an erythroid response using the IWG criteria, 2/3 of which were major responses, most of those becoming transfusion independent or achieving a >50% reduction in transfusion requirements. Improvement in thrombocytopenia or neutropenia was less significant. The most common reason patients were unable to complete the trial was due to toxicities, namely neuropathy, constipation, fatigue, and fluid retention at a dose beyond 200 mg a day. For 10 of the 16 responders, the median time to response was 16-20 weeks, and the majority of responders had lower risk disease: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS), or a low or int-1 IPSS.
The North Central Cancer Treatment Group study, N998B, was a phase II multicenter trial with more aggressive dose escalation to 1000 mg/day of thalidomide, and was closed early due to excessive grade III
toxicities in more than 85% of patients at a median interval of less than 2.5 months.45 In those patients who tolerated treatment, median time to response was once again not reached until 16 weeks. A national, randomized phase III, placebo-controlled trial to assess overall clinical benefit of low-dose thalidomide in MDS patients with low-risk disease is nearing completion.
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