Lenalidomide (Revlimid) A more potent analog of thalidomide, CC-5013 or lenalidomide, is currently under investigation. CC-5013 is an oral immunomodu-latory derivative (ImiD) of thalidomide that lacks the neurotoxicity of its parent compound, but shows 100fold higher anti-TNF activity and 50-2000-fold higher potency for stimulating T-cell proliferation. In addition, CC5013 has antiangiogenic and antiapoptotic properties. It inhibits VEGF signaling in endothelial cells and myeloblasts, increasing adhesion of hematopoietic progenitors to bone marrow stroma, which results in sustained growth arrest and preferential extinction of myelodysplastic clones.46 It also downregulates adhesion molecules and apoptosis inhibitory proteins, thereby increasing receptor-induced apoptosis.
The safety and efficacy of lenalidomide was studied in 45 patients with MDS with RBC transfusion-dependent disease or symptomatic anemia.47 Patients received treatment with one of three CC5013 doses: 10 or 25 mg daily or 10 mg/day for 21 days every 4 weeks. Patients were assessed at 8 and 16 weeks according to IWG criteria. Thirty-three patients were evaluable for response after completing 8 weeks or more of therapy. Most patients (88%) were in the low/int-1 risk group. Twenty-one (64%) patients achieved an erythroid response, 19 of which were major responses; major cytogenetic responses (>50%) were achieved in 11 of 17 informative patients, with restoration of normal cytogenetics in 10. Erythroid responses were higher in those with RA or low/int-1 IPSS score or del(5q31-33). In this subset of patients with del(5q), there was also resolution of megakaryocytic dysplasia, but not a significant reduction in bone marrow blast percentage. MVD as well as bone marrow and plasma VEGF levels were decreased in responders. Multicenter phase II trials have completed in patients with 5q— syndrome and non 5q— low/int-1 MDS.
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