Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)

Myelodysplastic syndromes (MDS) encompass a spectrum of clinically diverse hematopoietic stem cell malignancies for which there are few treatment options. These disorders display remarkable heterogeneity in their hematologic and pathologic features, with a wide-ranging natural history. Complex interactions between the affected clone and the bone marrow microenvironment drive the pathogenesis and progression of MDS, resulting in ineffective hematopoiesis, blast accumulation, and a variable predisposition for progression to acute leukemia. For early stage, lower-risk patients with MDS, the mainstay of therapy is supportive care, especially red blood cell transfusions, to alleviate the symptoms of anemia. However, these interventions do not target the underlying pathobiology of disease and have questionable impact on the natural disease course. Dysregulated inflammatory, apoptotic, and angiogenic cytokines play major roles in the pathobiology of MDS and represent attractive therapeutic targets. Lenalidomide is an orally bioavailable analogue of thalidomide with more potent immunomodulatory, antiangiogenic, and antitumor activities than the parent compound and with a better safety profile. In nonclinical studies, the effects of lenalidomide include potentiation of clonogenic response to erythropoietin, activation of integrin-mediated adhesion, cell cycle arrest, sensitization to apoptotic signals, and abrogation of cellular response to receptor-initiated trophic signals. These effects have the potential to impact survival and apoptosis of erythropoietic progenitor cells and their progeny. Data from clinical trials of lenalidomide in MDS have shown erythropoietic- and cytogenetic-remitting activities that frequently result in transfusion independence, particularly in patients with 5q- deletion and lower-risk MDS. Decreases in microvessel density in bone marrow specimens from responding patients provide supportive evidence of an antiangiogenic effect in MDS. Adverse effects, most commonly myelosuppression, are generally manageable with dose reduction and growth factor support. Multicenter phase II and III studies are under way to further assess the erythroid and cytogenetic response rates in distinct subtypes of MDS, including 5q- deletion, and to optimize its clinical application.