Immunomodulatory Drugs (IMiDs™): A New Treatment Option for Myelodysplastic Syndromes

Vishakha      Kale; Alan   F.   List

Abstract

The IMiDs™ represent a new proprietary class of thalidomide analogues that possess greater potency and less toxicity than the parent compound. As a group, these agents share the pharmacologic property of modulating cellular response to ligand activation, the precise biologic effect of which is cell lineage and stimulant-dependent. Lenalidomide (CC-5013; Revlimid™), a second generation IMiD, has shown significant erythropoietic activity in patients with lower risk MDS that have failed or are not candidates for recombinant erythropoietin treatment. Unlike cytokine therapy, lenalidomide suppresses select MDS clones and enhances erythropoietin receptor signaling to restore erythropoiesis. Activity is greatest in patients with interstitial deletions involving chromosome 5q31.1. A multicenter phase II study reported a 76% overall transfusion response rate in transfusion-dependent patients with deletion 5q, with 67% achieving transfusion independence after a median interval of 4.6 weeks of treatment. Cytogenetic responses were observed in 73% of patients with complete cytogenetic remission in 45% patients. Both transfusion response and cytogenetic response frequency were independent of karyotype complexity, raising excitement that this new treatment strategy might favorably alter the natural history of disease in higher risk patients with deletion 5q. Lenalidomide was approved by the U.S. Food and Drug Administration on December 27, 2005, for the treatment of IPSS Low and intermediate-1 risk MDS patients with del(5q) abnormality. A phase III Intergroup trial (ECOG 2905) will test the capacity to potentiate erythropoietin response by comparing response to lenalidomide monotherapy to the combination of darbepoetin and lenalidomide in non-deletion 5q MDS patients.

Keywords: CC-5013, del(5q), IMiDs, immunomodulatory drugs, lenalidomide, MDS, myelodysplastic syndrome

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