Lenalidomide Therapy of Myelodysplastic Syndromes

Partial or complete deletion of the long arm of chromosome 5 [del(5q)], with or without additional karyotypic abnormalities, is present in 10-15% of myelodysplastic syndromes (MDS). Anemia in these MDS responds less often to erythroblastic stimulating agents. However, immunomodulatory, anti-cytokine, and anti-angiogenic agent Lenalidomide (CC5013, Revlimid®) leads to red blood cells transfusion independence of low risk MDS with del(5q). The low risk del(5q) MDS is now recognized as a distinct pathologic subtype of MDS with markedly better clinical responses with lenalidomide treatment compared to non del(5q) MDS patients. Several mechanisms of action are believed to contribute to the therapeutic effect of lenalidomide. They include the effect on the immune system, with cytokine production, Tand natural killer cells co-stimulation, stimulation of erythropoiesis, substantional improvement in the hematopoiesis-supporting potential of bone marrow stroma and significant decrease in the adhesion of bone marrow CD34+ cells, and anti-inflammatory effects and angiogenesis inhibition. The exact mechanism of action of lenalidomide on del(5q) clones is not known, but there appears to be several candidate (tumor suppressor) genes whose expression may be modulated by lenalidomide treatment. The addition of lenalidomide inhibited the in vitro proliferation of erythroblasts harboring del(5q) while the proliferation of cells from normal controls and cells without 5q deletion was not affected. Patients with mutated TP53 were shown to have poorer erythroid and cytogenetic responses to lenalidomide and a higher potential for acute myeloid leukemia (AML) evolution. The mechanism of lenalidomide action is different in non-del(5q) MDS, where lenalidomide restores and promotes effective erythropoiesis without direct cytotoxic effect. Recent trials have focused on combining lenalidomide with other agents active in MDS.